1 Pa g e 1 of 212 WHY ZEBRAS DON'T GET ULCERS Third Edition ROBERT M. SAPOLSKY Copyright © 1994,1998 by W. H. Freeman, and 2004 by Robert M. Sapolsky ISBN:9780805073690 For Lisa, my best friend, who has made my life complete CONTENTS Preface xi 1 Why Don't Zebras Get Ulcers? 1 2 Glands, Gooseflesh, and Hormones 19 3 Stroke, Heart Attacks, and Voodoo Death 37 4 Stress, Metabolism, and Liquidating Your Assets 57 5 Ulcers, the Runs, and Hot Fudge Sundaes 71 6 Dwarfism and the Importance of Mothers 92 7 Sex and Reproduction 120 8 Immunity, Stress, and Disease 144 9 Stress and Pain 186 10 Stress and Memory 202 11 Stress and a Good Night's Sleep 226 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

2 Pa g e 2 of 212 12 Aging and Death 239 13 Why Is Psychological Stress Stressful? 252 14 Stress and Depression 271 15 Personality, Temperament, and Their Stress-Related Consequences 309 16 Junkies, Adrenaline Junkies, and Pleasure 335 17 The View from the Bottom 353 18 Managing Stress 384 Notes 419 Illustration Credits 517 Index 521 PREFACE If so, glance over at the guy down the aisle when he's not Perhaps you're reading this while browsing in a bookstore. looking, the one pretending to be engrossed in the Stephen Hawking book. Take a good look at him. He's probably not Instead, he probably appears missing fingers from leprosy, or covered with smallpox scar s, or shivering with malaria. at most of us have—cholesterol levels that are high for an perfectly healthy, which is to say he has the same diseases th than in a hunter-gatherer of his age, a tendency to dampen his tension with ape, hearing that has become far less acute Valium. We in our Western society now tend to get different diseases than we used to. But what's more important, we tend to get different kinds of diseases now, with very different causes and consequences. A millennium ago, a young hunter-gatherer inadvertently would eat a reedbuck riddled w ith anthrax and the consequen ces are clear—she's dead a few days later. Now, a young lawyer unthinkingly decides that red meat, fried foods, and a couple of beers per dinner tury later, maybe he's crippled with constitute a desirable diet, and the conseq uences are anything but clear—a half-cen cardiovascular disease, or maybe he's taking bike trips with his grandkids. Which outcome occurs depends on some obvious nuts-and-bolts factors, like what his liver does with cholesterol, what levels of certain enzymes are in his fat cells, whether he has any congenital weaknesses in the wall s of his blood vessels. But the outcome will also depend actors as his personality, the amount of emot ional stress he experiences over the years, heavily on such surprising f cry on when those stressors occur. whether he has someone's shoulder to think about the diseases that now afflict us. It involves There has been a revolution in medicine concerning how we recognizing the interactions between the body and the mind, the ways in which emotions and personality can have a tremendous impact on the functioning and health of virtually every cell in the body. It is about the role of stress in making some of ys in which some of us cope with stressors, and the critical notion that you us more vulnerable to disease, the wa cannot really understand a disease in vacu from that disease. o, but rather only in the context of the person suffering This is the subject of my book. I begin by trying to clarify the meaning of the nebulous concept of stress and to teach, onse to stress. I then focus with a minimum of pain, how various hormones and parts of the brain are mobilized in resp on the links between stress and increased ing, chapter by ch apter, through the risk for certain types of disease, go effects of stress on the circulatory syst em, on energy storage, on growth, reproduction, the immune system, and so on. Next I describe how the aging process may be influenced by the amount of stress experienced over a lifetime. I then most common and arguably most crippling of psychiatric disorders, major examine the link between stress and the depression. As part of updating the material for this third edition, I have added two new chapters: one on the interactions between stress and sleep, and one on what stress has to do with ad diction. In addition, of the chapters that ition, I rewrote about a third to half of the material. appeared in the previous ed Some of the news in this book is grim—sustained or repeated stress can disrupt our bodies in seemingly endless ways. both physiologically and disease. Instead, we cope, Yet most of us are not incapacitated by stress-related acularly successful at it. For the reader who has held on until the end, the psychologically, and some of us are spect final chapter reviews what is known about stress management and how some of its princi ples can be applied to our ch to be optimistic about. everyday lives. There is mu 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

3 Pa g e 3 of 212 I believe that everyone can benefit from some of these ideas and can be excited by th e science on which they are offer. It throws some of ulating puzzles that life has to based. Science provides us with some of the most elegant, stim of moral debate. Occasionally, it improv es our lives. I love science, and it the most provocative ideas into our arenas ce means that you cannot also or feel that choosing scien pains me to think that so many are terrified of the subject ed by nature. Science is not meant to cure us of mystery, but to reinvent and choose compassion, or the arts, or be aw reinvigorate it. Thus I think that any science book for nonscientists should attempt to convey that excitement, to make the subject interesting and accessible even to those near the who would normally not be caught dead of mine in this book. Often, it has meant simplifying complex ideas, and as a subject. That has been a particular goal counterbalance to this, I include copi ok, often with annotations concerning ous references at the end of the bo e main text. These references are an excellent entree for controversies and subtleties about material presented in th those readers who want something more detailed on the subject. Many sections of this book contain material about which I am far from expert, and over the course of the writing, a and verification of facts. I thank them all for their for advice, clarification, large number of savants have been called generosity with their time and expertise: Nancy Adler, John Angier, Robert Axelrod, Alan Baldrich, Marcia Barinaga, tisto, Tom Belva, Anat Biegon, Vic Bo ff (whose brand of vitamins graces Alan Basbaum, Andrew Baum, Justo Bau the cupboards of my parents' home), Carlos Camargo, Ma tt Cartmill, M. Linette Casey, Richard Chapman, Cynthia Clinkingbeard, Felix Conte, George Daniels, Regio DeSilva, Irven DeVore, Klaus Dinkel, James Doherty, John chael Fanselow, David Feldman, Caleb Tuck Finch, Paul Fitzgerald, Gerry Dolph, Leroi DuBeck, Richard Estes, Mi Friedland, Meyer Friedman, Rose Frisch, Roger Gosden, Bob Grossfield, Kenneth Haw-ley, Ray Hintz, Allan , Stephen Laberge, Emmit Lam, Jim Latcher, Richard ce Knauft, Mary Jeanne Kreek Hobson, Robert Kessler, Bru ebeskind, Ted Macolvena, Jo Lazarus, Helen Leroy, Jon Levine, Seymour Levine, John Li di Maxmin, Michael Miller, Ronald Myers, Carol Otis, Daniel Pearl, Ciran Phibbs, Peter Milner, Gary Moberg, Anne Moyer, Terry Muilenburg, , Sam Ridgeway, Carolyn Ristau Jenny Pierce, Ted Pincus, Virginia Price, Gerald Reaven , Jeffrey Ritterman, Paul Rosch, Ron Rosenfeld, Aryeh Routtenberg, Paul Saenger, Sa ul Schanburg, Kurt Schmidt-Nielson, Carol Shively, J. David Singer, Bart Sparagon, David Speigel, Ed Spielman, Dennis Styne, Steve Suomi, Jerry Tally, Carl Thoresen, Peter Tyak, David Wake, Michelle Warren, Jay Weiss, Owen Wolkowitz, Carol Worthman, and Richard Wurtman. to the handful of people—friends, collabora tors, colleagues, and ex-teachers—who took I am particularly grateful time out of their immensely busy schedules to read chapters. I shudder to think of the errors and distortions that would have remained had they not tactfully told me I didn't kn ow what I was writing about. I thank them all sincerely: ester; Stephen Bezruchka of the University of Washington; Marvin Brown of Robert Ader of the University of Roch California, Berkeley; Craig Heller of o; Laurence Frank at the University of the University of California, San Dieg Stanford University; Jay Kapl an of Bowman Gray Medical School; Ichiro Kawachi of Harvard University; George s Nemeroff of Emory University; Knob of the Scripps Clinic; Charle Seymour Reichlin of Tufts/New England Medical Center; Robert Rose of the MacArthur Foundation; Tim Meier of y Weiss of Emory University; and Redford Williams of Duke Stanford University; Wylie Vale of the Salk Institute; Ja University A number of people were instrumental in getting this book off the ground and into its final shape. Much of the e were presented under the dical education lectures. Thes material in these pages was developed in continuing me auspices of the Institute for Cortext Research and Development, and its director, Will Gordon, who gave me much n of the Portable Stanford series first planted the idea freedom and support in exploring this material. Bruce Goldma for this book in my head, and Kirk Jensen recruited me for W H. Freeman and Company; both helped in the initial d Lisa Pereira, have been of shaping of the book. Finally, my secretaries, Patsy Gardner an tremendous help in all the logistical aspects of pulling this book together. I thank you all, and look forward to working with you in the future. I received tremendous help w the book, and for that I thank Audrey e first edition of ith organizing and editing th and, above all, my editor, Jonathan Cobb, who was a Herbst, Tina Hastings, Amy Johnson, Meredyth Rawlins, chel, Amy Trask, Georgia wonderful teacher and friend in this pr ocess. Help in the second edition came from John Mi Sheridan Sellers. ifer MacMillan, and Neal, Kathy Bendo, Paul Rohloff, Jenn Lee Hadler, Victoria Tomaselli, Bill O' Natural History magazine, helping to merge the cu ltures of art and science in Liz Meryman, who selects the art for that beautiful publication, graciously consented to read the manuscript and gave splendid advice on appropriate was responsible for making my idea for the cover such a artwork. In addition, I thank Alice Fernandes-Brown, who pleasing reality. In this new edition help came from Rita Quintas, Denise Cronin, Janice O'Quinn, Jessica Firger, and Richard Rhorer at Henry Holt. This book has been, for the most part, a pleasure to write and I think it reflects one of the things in my life for which I at is both my vocation and avocation. I thank the mentors am most grateful—that I take so much joy in the science th late Howard Klar, Howard me to enjoy science: the who taught me to do science and, even more so, taught Eichenbaum, Mel Konner, Lewis Krey, Bruce McEwen, Paul Plotsky, and Wylie Vale. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

4 Pa g e 4 of 212 A band of research assistants have b , Roger Chan, Mick een indispensable to the writing of th is book. Steve Bait na Spudich, and Paul Stasi have wandered Markham, Kelley Parker, Michelle Pearl, Sere the basements of archival ne articles into coherency. In the e world with questions, distilled arca libraries, called strangers all over th line of duty, they have sought out drawings of opera castrati, the daily menu at Japanese-American internment camps, the causes of voodoo death, and the history of firing squads. Al l of their research was done with spectacular competence, speed, and humor. I am fairly certain th without their help and am absolutely is book could not have been completed certain its writing would have been much less enjoyable. And finally, I thank my agent, Katinka Matson, and my editor, Robin Dennis, who have been just terrific to work with. I look forward to many more years of collaborations ahead. Parts of the book describe work carried out in my own laboratory, and these studies have been made possible by funding from the National Institutes of Health, the National Institute of Mental Health, the National Science the Alzheimer's Association, and the Adler Foundation. Foundation, the Sloan Foundation, the Klingen-stein Fund, The African fieldwork described herein has been made possible by the long-standing generosity of the Harry Frank Guggenheim Foundation. Finally, I heartily thank the MacArthur Foundation for supporting all aspects of my work. Finally, as will be obvious, this book cites the work of a tremendous number of scientists. Contemporary lab science is typically carried out by large teams of people. Throughout the book, I refer to the work of "Jane Doe" or "John Smith" for the sake of brevity—it is al most always the case that such work was carried out by Doe or Smith along with a band of junior colleagues. There is a tradition among stress physiologists who dedicate their books to their spouses or significant others, an unwritten rule that you are supposed to incorporate somethin g cutesy about stress in the dedication. So, to Madge, for my wife who, over the course of the last who attenuates my stressors; for Arturo , the source of my eustress; umpteen years, has put up with my st ress-induced hypertension, ulcerative co litis, loss of libido, and displaced aggression. I will forgo that style in the actual dedication of this book to my wife, as I have something simpler to say. 1 WHY DON'T ZEBRAS GET ULCERS? It's two o'clock in the morning and you're lying in bed. You have something immensely important and challenging to that next day—a critical m eeting, a presentation, an exam. You have to get a decent night's rest, but you're take deep, slow breaths, try to imagine restful mountain still wide awake. You try different strategies for relaxing— asleep in the next minute, y our career is finished. Thus scenery—but instead you keep thinking that unless you fall you lie there, more tense by the second. If you do this on a regular basis, somewhere around two-thirty, when you're really getting clammy, an entirely new, disruptive chain of thought will no doubt intrude. Suddenly, amid all your other worries, you begin to contemplate headache. The that frequent that nonspecific pain you've been having in your side, th at sense of exhaustion lately, realization hits you—I'm sick, fatally sick! Oh, why didn't I recognize the symptoms, why did I have to deny it, why didn't I go to the doctor? When it's two-thirty on those mornings, I always have a brai n tumor. These are very useful for that sort of terror, ble nonspecific symptom to a brain tu because you can attribute every conceiva mor and justify your panic. Perhaps you do, too; or maybe you lie there thinking that you have cancer, or an ulcer, or that you've just had a stroke. Even though I don't know you, I feel confident in predicting that you don't lie there thinking, "I just know it; I have leprosy." True? You are exceedingly unlikely to obsess about getting a serious case of dysentery if it starts pouring. ced that our bodies are teeming with intestinal parasites or liver flukes. And few of us lie there feeling convin 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

5 Pa g e 5 of 212 Influenza pandemic, 1918. Of course not. Our nights are not filled ria, or bubonic plague. Cholera doesn't with worries about scarlet fever, mala water fever, and elephantia sis are third world exotica. run rampant through our communities; river blindness, black Few female readers will die in childbir th, and even fewer of those reading this page are likely to be malnourished. Thanks to revolutionary advances in medicine and public health, our patterns of disease have changed, and we are no longer kept awake at night worrying about infectious diseases (except, of course, AIDS or tuberculosis) or the diseases of poor nutrition or hygiene. As a measure of this, death in the United States in consider the leading causes of 1900: pneumonia, tuberculosis, and influenza (and, if you were young, female, and inclined toward risk taking, childbirth). When is the last time you heard of scads of people dying of the flu? Yet the flu, in 1918 alone, killed many times more people than throughout the course of that most barbaric of conflicts, World War I. Our current patterns of disease would be unrecognizable to our great-grandparents or, for that matter, to most kely to die in different ways t different diseases and are li mammals. Put succinctly, we ge ently living in the less privileged areas of this from most of our ancestors (or from most humans curr planet). Our nights are filled with worries about a different class of diseases; we are now living well enough and long enough to slowly fall apart. ease, cancer, cerebrovascular The diseases that plague us now are ones of slow accu mulation of damage—heart dis disorders. While none of these diseas es is particularly pleasant, they certainly mark a big improvement over week of sepsis or dengue feve recent shift in the patterns r. Along with this relatively succumbing at age twenty after a disease process. We have come to recognize the vastly of disease have come changes in the way we perceive the complex intertwining of our biology and our emotions, the endless ways in which our personalities, feelings, and thoughts both reflect and influence the events in our bodies. One of the most interesting manifestations of this recognition is understanding that extreme emotional disturba nces can adversely affect us . Put in the parlance with has been the recognition that and a critical shift in medicine stress can make us sick, which we have grown familiar, slow accumulation can be either cause d or made far worse by stress. many of the damaging diseases of ive clinicians intuitively recognized the role of individual In some respects this is nothing new. Centuries ago, sensit lity to disease. Two individuals could get the same disease, yet the courses of their illness differences in vulnerabi could be quite different and in vague, subjective ways might reflect the personal character istics of the individuals. Or a clinician might have sensed that certain types of people we re more likely to contract certain types of disease. But e vague clinical perceptions has made stress ry, the addition of rigorous science to thes since the twentieth centu physiology—the study of how the body responds to stressful events—a real discipline. As a result, there is now an extraordinary amount of physiological, biochemical, and mo lecular information availabl e as to how all sorts of ents. These intangibles can include emotional turmoil, intangibles in our lives can affect very real bodily ev position in society, and how our society tr eats people of that position. And they can psychological characteristics, our s up our blood vessels or is safely cleared from the influence medical issues such as whether cholesterol gum circulation, whether our fat cells stop listening to insulin and plunge us into diabetes, whether neurons in our brain will survive five minutes without oxygen during a cardiac arrest. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

6 Pa g e 6 of 212 This book is a primer about stress, stress -related disease, and the mechanisms of coping with stress. How is it that our us sick? Why are some of us especially ressful emergencies, while other ones make bodies can adapt to some st vulnerable to stress-related diseases, and what r personalities? How can purely does that have to do with ou psychological turmoil make us sick? Wh at mighl stress have to do with our the speed at which we age, or how well our vulnerability to depression, memories work? What do our patterns of y's ladder? Finally, how can we increase ith where we stand on the rungs of societ stress-related diseases have to do w the stressful world that surrounds us? the effectiveness with which we cope with SOME INITIAL CONCEPTS Perhaps the best way to begin is by making a mental list of the sorts of things we find stressful. No doubt you would eadlines, family relationships, money worries. But what immediately come up with some obvious examples—traffic, d eciocentric human. Think like a zebra for a second." Suddenly, new items might if I said, "You're thinking like a sp ators, starvation. The need for that prompting illustrates appear at the top of your list—serious physical injury, pred something critical— you and I ar e more likely to get an ulcer than a zeb ra is. For animals lik e zebras, the most upsetting things in life are acute physical crises. You are that zebra, a lion has ju st leapt out and ripped your stomach open, you've managed to get away, and now you have to spend the next hour evading the lion as it continues to stalk you. Or, perhaps just as stre ssfully, you are that lion, half-starved, and you had better be able to sprint across the to eat or you won't survive. These ar l events, and they e extremely stressfu savanna at top speed and grab something demand immediate physiological adaptations if you are going to live. Your body's responses are brilliantly adapted for handling this sort of emergency. n your crops, and for the next challenges. The locusts have eate An organism can also be plagued by chronic physical six months, you have to wander a dozen miles a day to get enough food. Drought, famine, parasites, that sort of unpleasantness—not the sort of experience we have often, bu t central events in the live s of non-westernized humans and most other mammals. The body's stress-responses are reasonably good at handling these sustained disasters. disruptions. Regardless of how Critical to this book is a third category of ways to get upset— psychological and social poorly we are getting along with a family member or ho w incensed we are about losing a parking spot, we rarely rare event when we have to st settle that sort of thing with a fistfight. Likewise, it is a alk and personally wrestle down our dinner. Essentially, we humans live well enough and long enough, and are smart enough, to generate all sorts of stressful events Robert Longo, Untitled Work on Paper, 1981. (Two yuppies contesting the last double latte at a restaurant?) cial Security is going to last purely in our heads. How many hippos worry about whether So as long as they will, or a first date? Viewed from the perspective of the evolution of the animal kingdom, what they are going to say on ed to humans and other social primates. We can t invention, mostly limit sustained psychological stress is a recen rovoking our bodies into an accompanying uproar) linked to mere thoughts.* experience wildly strong emotions (p pieces of wood now Two people can sit facing each other, do ing nothing more physically strenuous th an moving little s, during their tournaments, can place and then, yet this can be an emotiona lly taxing event: chess grand master metabolic demands on their bodies that begin to approach eak of a competitive event.+ those of athletes during the p s just signed the order to fire a hated than sign a piece of paper: if she ha Or a person can do nothing more exciting rival after months of plotting and maneuvering, her physiolog ical responses might be shockingly similar to those of a 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

7 Pa g e 7 of 212 * The neurologist Antonio Damasio recounts a wonderful study done on the conductor Herbert von Karajan, showing that the maestr o's heart would a piece of music as when he was conducting it. race just as wildly when he was listening to n of the Kasparov-Karpov chess tournament of 1990: "Kasp arov kept pressing + Perhaps journalists are aware of this fa ct; consider this descriptio lee." with more of the same and the game became a me e end, Karpov had to oppose threats of violence for a murderous attack. Toward th of a competitor. And if someone spends months on end savanna baboon who has just lunged and slashed the face me emotional problem, this might very well lead to illness. twisting his innards in anxiety, anger, and tension over so running for your life, or that lion sprinting for your meal, This is the critical point of this book: if you are that zebra ly adapted for dealing with such short-term physical your body's physiological response mechanisms are superb emergencies. For the vast majority of b ort-term crisis, after which it's either easts on this planet, stress is about a sh over with or you're over with. When we sit around and worry about stressful things, we turn on the same physiological ed chronically. A large body of responses—but they are potentially a disaster when provok evidence suggests that the fact that we so often activat e a physiological system that has predominantly, out of stress-related disease emerges, evolved for responding to acute physical emergencies, but we turn it on for months on end, worrying about mortgages, relationships, and promotions. This difference between the ways that we get stressed and the ways a zebra does lets us begin to wrestle with some concept that you were tortured with in ninth-grade biology and hopefully have definitions. To start, I must call forth a Ah, that dimly remembered not had to think about since— homeostasis. concept, the idea that the body has an ideal level of oxygen that it needs, an ideal degree of acidity, an ideal temperat ure, and so on. All these different variables the state in which all sorts of physiol are maintained in homeostatic balance, ogical measures are being kept at the optimal level. The brain, it has been noted, has evolved to seek homeostasis. This allows us to generate some simple initial workin g definitions that would suffice for a zebra or a lion. A stressor stress-response is what your is anything in the outside world that knocks you out of homeostatic balance, and the body does to reestablish homeostasis. But when we consider ourselves and our human propensity to worry ourselves sick, we have to expand on the notion of anticipation of stressors merely being things that knock you out of homeostatic balance. A stressor can also be the that happening. Sometimes we are smart enough to see things coming and, based only on anticipation, can turn on a stress-response as robust as if the event had actually occurr ed. Some aspects of anticipato ry stress are not unique to humans—whether you are a huma n surrounded by a bunch of thugs in a dese rted subway station or a zebra face to ing physically damaging acing, even though noth r heart is probably r face with a lion, you has occurred (yet). But unlike less cognitively sophisticated species, we can turn on the stress-response by thinking tic balance far in the future about potential stressors that may throw us out of homeosta . For example, think of the m of locusts descend on his African farmer watching a swar crops. He has eaten an adequate breakfast and is not arving, but that farmer will still be undergoing a stress-response. Zebras and suffering the homeostatic imbalance of st lions may see trouble coming in the next minute and mob ilize a stress-response in anti cipation, but they can't get stressed about events far in the future. And sometimes we humans can be stressed by things that simply make no sense to zebras or lions. It is not a general Internal Revenue Service, ab out public speaking or fears mammalian trait to become anxious about mortgages or the of what you will say in a job interview, about the inevitability of death. Our human experience is replete with blood loss, or temperature extremes. the physical world of hunger, injury, psychological stressors, a far cry from When we activate the stress-response out of fear of something that turns out to be real, we congratulate ourselves that this cognitive skill allows us to mobilize our defenses early . And these anticipatory defens es can be quite protective, in that a lot of what the stress-response is about is prep arative. But when we get into a physiological uproar and at all, or over something we cannot do anything about, we call it things like activate the stress-response for no reason s," "paranoia," or "anxiety," "neurosi "needless hostility." Thus, the stress-response can be mobilized not only in response to physical or psychological insults, but also in sing—a physiological system ponse that is the most surpri expectation of them. It is this generality of the stress-res activated not only by all sorts of physical disasters but by just thinking about them as well. This generality was first appreciated about sixty-five years ago by one of the godfathers of stress physiology, Hans Selye. To be only a bit ts as a discipline because this man was both a very insightful scientist and lame at facetious, stress physiology exis handling lab rats. In the 1930s, Selye was just beginning his work in endocrinology, the study of hormonal communication in the body. Naturally, as a young, unheard-of assistant professor, he was fishing around for something with which to start his act from the ovary, and colleagues were ll had just isolated some sort of extr research career. A biochemist down the ha wondering what this ovarian extract did to the body. So Selye obtained some of the stuff from the biochemist and set about studying its effects. He attempted to inject his rats daily, but 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

8 Pa g e 8 of 212 apparently not with a great display of dexterity. Selye would try to inject the rats, miss them, drop them, spend half the morning chasing the rats around the room or vice versa, flailing with a broom to get them out from behind the this, Selye examined the rats and discovered something sink, and so on. At the end of a number of months of cers, greatly enlarged ad renal glands (the source of two important stress extraordinary: the rats had peptic ul hormones), and shrunken immune tissues. He was delighted; he had discovered the effects of the mysterious ovarian extract. of the ovarian extract. And, daily with saline alone, instead Being a good scientist, he ran a control group: rats injected thus, every day they too were injected, dropped, chas ed, and chased back. At the end, lo and behold, the control rats tissues of the immune system. ed adrenal glands, and atrophy of had the same peptic ulcers, enlarg Now, your average budding scientist at this point might throw up his or her hands and furtively apply to business school. But Selye, instead, reasoned through what he had observed. The physiological changes couldn't be due to the and the experimental groups. What did ovarian extract after all, since the same changes occurred in both the control ions. Perhaps, he han-trauma-free inject ? Selye reasoned that it was his less-t the two groups of rats have in common thought, these changes in the rats' bodies were some sort of nonspecific responses of the body to generic unpleasantness. To test this idea, he put some rats on the roof of the research building in the winter, others down in the boiler room. Still others were exposed to forced exercise, or to surgical procedures. In all cases, he found increased incidences of peptic ulcers, adrenal enla rgement, and atrophy of immune tissues. We know now exactly what Selye was observing. He had just discovered the tip of the iceberg of stress-related disease. Legend (mostly promulgated by Selye himself) has it that Selye was the person who, searching for a way to describe the nonspecificity of the un pleasantness to which the rats were responding, borrowed a term from physics and proclaimed that the rats were undergoing "stress." In fact, by the 1920s the term had already been introduced to medicine in roughly the sense that we understand it today by a physiologist named Walter Cannon. What Selye did was to formalize the concept with two ideas: ■ The body has a surprisingly similar set of responses (which he called the general adaptation syndrome, but which we now call the stress-response) to a broad array of stressors. ■ If stressors go on for too long, they can make you sick HOMEOSTASIS PLUS: THE MORE STRESS- APPROPRIATE CONCEPT OF ALLOSTASIS ling and Joseph Eyer of in recent years in work The homeostasis concept has been modified originated by Peter Ster the University of Pennsylvania and exte nded by Bruce McEwen of Rockefeller University* They have produced a lliantly modernizes new framework that I steadfastly tried to ignore at first and have now succumbed to, because it bri rks even better in making sense of stress (although not all folks in my the homeostasis concept in a way that wo wine in a new bottle" imagery). business have embraced it, using "old The original conception of homeostasis was grounded in tw o ideas. First, there is a single optimal level, number, true—after all, the ideal amount for any given measure in the body. But that can't be blood pressure when you're ing. What's ideal under basal conditions is different than sleeping is likely to be different than when you're ski jump field uses this Zen-ish sound bite about how allostasis is during stress, something central to allostatic thinking. (The re I understand what that means, but it always elicits about "constancy through change." I'm not completely su meaningful and reinforcing nods when I toss it out in a lecture.) The second idea in homeostasis is that you reach that ideal se t point through some local regulatory mechanism, llion different ways, each with its own given set point can be regulated in a zi whereas allostasis recognizes that any water shortage in California. Homeos tatic solution: mandate smaller toilet consequences. Thus, suppose there's a tanks.+ Allostatic solutions: smaller toilet tanks, convin ce people to conserve water, buy rice from Southeast Asia instead of doing water-intensive farming in a semi-arid st ate. Or suppose there's a wa ter shortage in your body. out, tighten things up there, produce less urine for water Homeostatic solution: kidneys are the ones that figure this lls the kidneys to do their thing, sends signals to withdraw conservation. Allostatic solutions: brain figures this out, te n, mouth, nose), makes you feel thirsty Homeostasis is water from parts of your body where it easily evaporates (ski is about the brain coordinating body-wide changes, often about tinkering with this valve or that gizmo. Allostasis including changes in behavior. * McEwen and his work are going to pop up fr equently in this book field (as well as a wonderful man and, a long time ago, , as he is the giant of this my thesis advisor). thinking about the inner workings of toilet + Physiologists actually spend a lot of time bowls 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

9 Pa g e 9 of 212 A final feature of allostatic thinking dovetails beautifully with thinking about stressed humans. The body doesn't pull off all this regulatory complexity only to correct some set also make allostatic changes point that has gone awry It can of a set point that is likely to go awry. And thus we hark back to the critical point of a few pages anticipation in anticipation of challenges, tivate the stress-response in back—we don't get stressed being chased by predators. We ac at would make no sense to a zebra. and typically those challenges are the pu rely psychological and social tumult th asis has to say about stress-related disease. We'll be returning repeatedly to what allost WHAT YOUR BODY DOES TO ADAPT TO AN ACUTE STRESSOR Within this expanded framework, a stressor can be defined as anything that throws your body out of allostatic balance lostasis. The secretion of certain hormones, the inhibition of and the stress-response is your body's attempt to restore al others, the activation of particular parts of the nervous system, and so on. And regardless of the stressor— injured, starving, too hot, too cold, or psychologically stressed—you turn on the same stress-response. physiology, it makes no sense at first glance. In physiology, It is this generality that is puzzling. If you are trained in specific responses and adaptations. Warming a body challenges to the body trigger specific one is typically taught that causes sweating and dilation of blood vessels in the skin. Chilling a body causes just the opposite—constriction of very specific and different ph ysiological challenge from those vessels and shivering. Being too hot seems to be a that the body's responses to these being too cold, and it would seem logical two very different states should be ead, what kind of crazy bodily syst whether you are too hot or too extremely different. Inst em is this that is turned on cold, whether you are the zebra, the lion, Why should your or a terrified adolescent going to a high school dance? body have such a generalized and stereo typical stress-response, regardless of the predicament you find yourself in? When you think about it, it actually makes sense, given the ad aptations brought about by the stress-response. If you're some bacterium stressed by food shortage, you go into a suspended, dormant state. But if you're a starving lion, you're one intent on eating you, you stick you're some plant stressed by some going to have to run after someone. If poisonous chemicals in your leaves But if you're a zebra being chased built around the f act that your core of the stress-response is by that lion, you have to run for it. For us vertebrates, the muscles are going to work like crazy. And thus the muscles need energy, right now, in the most readily utilizable e in your fat cells for some building project next spring. One of the hallmarks form, rather than stored away somewher hibition of further storage. from storage sites and the in of the stress-response is the rapid mobilization of energy Glucose and the simplest forms of proteins and fats come pouring out of your fat cells, liver, and muscles, all to stoke whichever muscles are struggling to save your neck. If your body has mobilized all that glucose, it also needs to deliver it to the critical muscles as rapidly as possible. ng rate increase, all to transport Heart rate, blood pressure, and breathi nutrients and oxygen at greater rates. Equally logical is another feature of the stress-response. During an emergency, it makes sense that your body halts long-term, expensive building projects. If there is a tornado b earing down on the house, this isn't the day to repaint the garage. Hold off on the long-term projects until you know there is a long term. Thus, during stress, digestion is inhibited—there isn't enough time to derive the energetic benefits of the slow process of digestion, so why waste energy on it? You have better things to do than digest breakfast when you are trying to avoid being someone's lunch. The same thing goes for growth and reproduction, both expe nsive, optimistic things to be doing with your body (especially if you are female). If the lion's on your tail, two steps behind you, worry about ovulating or growing antlers or making sperm some other time. During stress, growth and tissue repair is curtailed, sexual drive decreases in ulate or to carry pregnancies to term, while males begin to have trouble with both sexes; females are less likely to ov erections and secrete less testosterone. The immune system, which defends against infections and Along with these changes, immunity is also inhibited. illness, is ideal for spotting the tumor cell that will kill you in a year, or making enough antibodies to protect you in a few weeks, but is it really needed this instant? The logi c here appears to be the same —look for tumors some other chapter 8, there are some major problems with this idea time; expend the energy more wisely now. (As we will see in that the immune system is suppressed during stress in order to save energy. But that idea will suffice for the moment.) Another feature of the stress-response becomes apparent during times of extrem e physical pain. With sufficiently sustained stress, our unted It's the middle of a battle; perception of pain can become bl ldier is shot, grievously injured, and the man doesn't even soldiers are storming a stronghold with wild abandon. A so notice it. He'll see blood on his clothes and worry that one of his buddies near him has been wounded, or he'll wonder why his innards feel numb. As the batt le fades, someone will point with am azement at his injury—didn't it hurt like u are that zebra and your hell? It didn't. Such stress-induced an algesia is highly adaptive and well documented. If yo 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

10 Pa g e 10 of 212 innards are dragging in the dust, you sti ll have to escape. Now would not be a part icularly clever time to go into shock from extreme pain. ory skills. Suddenly certain Finally, during stress, shifts occur in cognitive and sens aspects of memory improve, which is always helpful if you're trying to figure out how to get out of an emergency (Has this happened before? Is ifying movie on there a good hiding place?). Moreover, yo out watching a terr ur senses become sharper. Think ab at the tensest part. The slightest noise—a television, on the edge of your seat nearly jump out creaking door—and you of your skin. Better memory, sharper detection of sensations—all quite adaptive and helpful. or lion. Energy is mobili ly adapted for that zebra Collectively, the stress-response is ideal zed and delivered to the ects are deferred until the disaster has passed. Pain is tissues that need them; long-term building and repair proj blunted, cognition sharpened. Walter Cannon, the physiologist who, at the beginning of the century, paved the way for trated on the adaptive aspect godfather of the field, concen much of Selye's work and is generally considered the other of the stress-response in dealing with emergencies such as these. He form ulated the well-known "fight-or-flight" syndrome to describe the stress-response, and he viewed it in a very positive light. His books, with titles such as The were suffused with a pleasing optimism about th Wisdom of the Body, e ability of the body to weather all sorts of stressors. Yet stressful events can sometimes make us sick. Why? Selye, with his ulcerated rats, wrestled w ith this puzzle and came up with an answer that was sufficiently wrong that it is generally thought to have cost him a Nobel Prize for all his other work. He developed a three-part view of how the stress-response worked. In the initial (alarm) stage a stressor is noted; metaphorical alarms go off in your head, telling you that you are hemorrhaging, too cold, low on blood sugar, or whatever. The second stage (adaptation, or resistance) comes with the successful mo bilization of the stress-response system and the reattainment of allostatic balance. It is with prolonged stress that one enters the third stage, which Selye termed "exhaustion," where stress related diseases emerge. Selye believed that one be comes sick at that point because stores of the runs out of ammunition, suddenly we se are depleted. Like an army that hormones secreted during the stress-respon have no defenses left agai nst the threatening stressor. crucial hormones are actually depleted during even the most It is very rare, however, as we will see, that any of the sustained of stressors. The army does not run out of bullets. Instead, the body spends so much on the defense budget a hidden agenda here). It is not so that it neglects education and health care and social services (okay, so I may have much that the stress-response the stress-response can become more runs out, but rather, with sufficient activation, that logical. This is a critical concept, because especially when the stress is purely psycho damaging than the stressor itself, it underlies the emergence of much stress-related disease. you examine the things that occur in me harmful makes a certain sense when That the stress-response itself can beco reaction to stress. They are generally sh and dollar-foolish, but they are the ortsighted, inefficient, and penny-wise sorts of costly things your body has to do to respond effectively in an emergency. And if you experience every day as an emergency, you will pay the price. you will never store any surplus energy. You will e cost of energy storage, If you constantly mobilize energy at th fatigue more rapidly, and your risk of developing a form of diabetes will even in crease. The consequences of chronically activating your cardiovascular system are similarly damaging: if your blood pressure rises to 180/100 when you are sprinting away from a lion , you are being adaptive, but if it is 180/ 100 every time you see the mess in your teenager's bedroom, you could be heading for a cardiovascular disaster. If you constantly turn off long-term ned in later chapters, you reasons that will be explai building projects, nothing is ever repaired. For paradoxical become more at risk for peptic ulcers. In kids, growth can be inhibited to the point of a rare but recognized pediatric endocrine disorder—stress dwarfism— and in adults, repair and remodeling of bone and other tissues can be disrupted. If you are constantly under stress, a variety of reproductive disorders may ensue. In females, menstrual tirely; in males, sperm co unt and testosterone levels may decline. In both cycles can become irregu-lar or cease en sexes, interest in sexual behavior decreases. But that is only the start of your problems in response to chronic or repealed stressors. If you suppress immune function too long and too much,you are now more likely to fall victim to a number of infectious diseases, and be less capable of combating them once you have them. brain that function more cleverly Finally, the same systems of the by one class of hormones secreted during stress can also be damaged 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

11 Pa g e 11 of 212 during stress. As will be discussed, this may have something to do with how rapidly our brains lose cells during aging, and how much memory loss occurs with old age. ttain allostasis, but it the face of repeated stressors, we may be ab All of this is pretty grim. In le to precariously rea doesn't come cheap, and the efforts to re wear us down. Here's a way to think establish that balance will eventually ated disease. Put two little kids on a seesaw, and they can about it: the "two elephants on a seesaw" model of stress-rel pretty readily balance themselv es on it. This is allostatic balance when nothing stressful is going on, with the children representing the low levels of the various stress hormones that will be presented in coming chapters. In contrast, the torrents of those same stress hormones released by a stressor can be thought of as two massive elephants on the nce a seesaw with two constantly try to bala can balance themselves as well. But if you seesaw. With great effort, they all sorts of problems will emerge: elephants instead of two little kids, phants are consumed balancing the seesaw, instead of being ■ First, the enormous potential energies of the two ele able to do something more useful, like mowing the lawn or paying the bills. This is equivalent to diverting energy from various long-term building projects in orde r to solve short-term stressful emergencies. ccur just because of how larg and unsubtle e, lumbering, By using two elephants to do the job, damage will o ■ e flowers in the process of en elephants are. They squash th tering the playground, they strew leftovers and garbage all ey must eat while balancing the seesaw, they wear out the seesaw faster, and over the place from the frequent snacks th so on. This is equivalent to a pattern of stress-related diseas e that will run through many of the subsequent chapters: it is hard to fix one major problem in the body without knocking something else out of balance (the very essence of allostasis spreading across systems throughout the body). Thus, you may be able to solve one bit of imbalance brought on during stress by using your elephants (your massive levels of various stress hormones), but such great quantities of those hormones can make a mess of something else in the process. And a long history of doing this produces wear and allostatic load. tear throughout the body, termed A final, subtle problem: when two elepha for them to get off. Either one hops nts are balanced on a seesaw, it's tough ■ extremely delicate task of coordinating their comes crashing to the ground, or there's the off and the other the same time. This is delicate, lithe leaps at a metaphor for another theme that will run through subseq uent chapters—sometimes stress-related disease can arise from turning off the stress-response too slowly, or turning off the different components of the stress-response at stress-response returns to normal yet another etion rate of one of the hormones of the different speeds. When the secr of the hormones is still being secreted like mad, it can be the equivalent of one elephant suddenly being left alone on the seesaw, crashing to earth.* The preceding pages should allow you to begin to appreciate the two punch lines of this book: The first is that if you plan to get st ressed like a normal mammal, dealing with an acute physical challenge, and you see this, all you have to do is examine the stress-response, you're in big trouble. To turn on cannot appropriately someone who cannot activate the stress-response. As will be explained in the coming chapters, two critical classes of one disorder, Addison's disease, you ar hormones are secreted during stress. In e unable to secrete one class of these Shy-Drager syndrome, it is hormones. In another, called e second class of hormones that is the secretion of th Shy-Drager syndrome are not more at risk for cancer or diabetes or any impaired. People with Addison's disease or treated Addison's di other such disorders of slow accumulatio n of damage. However, people with un sease, when faced nt or an infectious illness, fall into an "Addisonian" crisis with a major stressor such as a car accide , where their blood pressure drops, they cannot maintain circulation, they go into shock. In Shy-Drager syndrome, it is hard enough simply to stand up, let alone go sprinting after a zebra for dinner—mere standing causes a severe drop in blood zziness, all sorts of unpleasantness. These two diseases pressure, involuntary twitching and rippling of muscles, di teach something important, na es. Addison's and Shy- ng physical challeng mely, that you need the stress-response duri Drager represent catastrophic failures of turning on the stress-response. In coming chapters, I will discuss some disorders that involve subtler undersecretion of stress hormones. These include chronic fatigue syndrome, critically ill patients, and possibly individuals with post- fibromyalgia, rheumatoid arthritis, a subtype of depression, traumatic stress disorder. locked up together at a stress conferen * If you find this analogy silly, imagine wh at it is like to have a bunch of scientists ce working with it. I was at a meeting where this analogy first factions pushing analogies about ele- emerged, and in no time there were onkey bars and merry-go-rounds, sumo phants on pogo sticks, elephants on m wrestlers on seesaws, and so on. tical, especially for the zeb ra who occasionally has to run for its life. But the That first punch line is obviously cri ated in traffic jams, worrying about expenses, mulling over second punch line is far more relevant to us, sitting frustr cannot turn off the stress- the stress-response, or if you repeatedly turn on tense interactions with colleagues. If you 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

12 Pa g e 12 of 212 response at the end of a stressful even . A large percentage of t, the stress-response can ev entually become damaging excessive stress-responses. diseases are disorders of what we think of when we talk about stress-related ry concerning that last statement, whic h is one of the central ideas of this A few important qualifications are necessa you sick or, as emphasized to be that stressors make book. On a superficial level, the message it imparts might seem actually more accurate to say that chronic in the last few pages, that chronic or repeated stressors make you sick. It is potentially of being sick. Stressors, even if massive, or repeated stressors can risk make you sick or can increase your illness. And the theme of the last section of this book is to repetitive, or chronic in nature, do not automatically lead to make sense of why some people develop stress-related diseases more readily than others, despite the same stressor. ssors can increase your risk of being An additional point should be emphasized. To state that "chronic or repeated stre sick" is actually incorrect, but in a subtle way that will initia lly seem like semantic nit-picking. It is never really the diseases . Stress increases your risk of getting en increases your risk of being sick case that stress makes you sick, or ev that make you sick, or if you have such a disease, stress increases the risk of your defenses being overwhelmed by the disease. This distinction is important in a few ways. Firs t, by putting more steps between a stressor and getting sick, vidual differences— why only some pe ople wind up actually getting sick. there are more explanations for indi Moreover, by clarifying the progression be tween stressors and illness, it becomes easier to design ways to intervene in the process. Finally, it begins to explain why the stress concept often seems so suspect or slippery to many medical atements like "You feel sick practitioners—clinical medicine is traditionally quite good at being able to make st why you got disease X in the first place. lly quite bad at being able to explain because you have disease X," but is usua ve disease X, not because of some in effect, "You feel sick because you ha Thus, medical practitioners often say, nonsense having to do with stress; however, this ignores the stressors' role in bringing about or worsening the disease in the first place. can now begin the task of under-standing the individual steps in this With this framework in mind, we system. Chapter 2 introduces the hormones and brain systems involved in the stress-response : which ones are activated during stress, which ones are stems of your body that are inhibited? This leads the way to chapters 3 through 10, which examine the individual sy es enhance cardiovascular tone during stress, and how does chronic stress cause heart affected. How do those hormon disease (chapter 3)? How do those hormones and neural sy stems mobilize energy during stress, and how does too much stress cause energetic diseases (chapter 4)? And so on. Chapter 11 examines the in teractions between stress and how stress can disrupt sleep and how sleep deprivation is a stressor. Chapter 12 sleep, focusing on the vicious circle of process and the disturbing r examines the role of stress in the aging ecent findings that sustaine d exposure to certain of the brain. As will be seen, these processes are actually accelerate the aging of the hormones secreted during stress may and subtle than they may seem from the simple picture presented in this chapter. often more complicated Chapter 13 ushers in a topic obviously of central importance to understanding our own propensity toward stress- remaining chapters. Chapter 14 serves as a prelude to the related disease: why is psychological stress stressful? This flicts vast numbers of us and is often closely related to reviews major depression, a horrible psychiatric malady that af differences have to do with individual differences in psychological stress. Chapter 15 discusses what personality patterns of stress-related disease. This is the world of anxiety disorders and Type A-ness, plus some surprises about puzzling issue that lurks unexpected links between personality and the stress-resp onse. Chapter 16 considers a good, throughout reading this book—sometimes stress feels good enough that we'll pay good money to be stressed by is a good thing, and the interactions us, the chapter considers when stress a scary movie or roller-coaster ride. Th d by some stressors and the process of addiction. between the sense of pleasure that can be triggere d the type of society in Chapter 17 focuses above the level of the individual, looking at what your place in society, an which you live, has to do with patterns of stress-related disease. If you plan to go no further, here's one of the punch oiding stress-related diseases, make sure you don't lines of that chapter: if you want to increase your chances of av inadvertently allow yourself to be born poor. In many ways, the ground to be covered up to the final ch apter is all bad news, as we are regaled with the evidence stress. The final chapter is meant about new and unlikely parts of our bodies and minds that are made miserable by certain bodies and certain psyc hes deal with stress to give some hope. Given the same external stressors, those folks doing right, and what can the rest of us learn from them? We'll look at the better than others. What are ey have been applied with and exciting realms in which th main principles of stress management and some surprising stunning success. While the intervening chapters document our numerous vulnerabili ties to stress-related disease, the them. Most certainly, all is protect ourselves from many of final chapter shows that we have an enormous potential to not lost. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

13 Pa g e 13 of 212 2 GLANDS, GOOSEFLESH, AND HORMONES In order to begin the process of learning how stress can make us sick, there is something about the workings of ppreciate. It is perhaps best the brain that we have to a illustrated in the following rather technical paragraph from an early invest igator in the field: him, all his blood-v As she melted small and wonderful in hi essels seemed to s arms, she became infinitely desirable to scald with intense yet tender desire, for her, for her softness , for the penetrating beauty of her in his arms, passing into his blood. And softly with that marvelous swoon-like caress of his hand in pure soft desire, softly he stroked the silky slope of her loins, down, down between her soft, warm buttocks, coming nearer and nearer to the very quick of her. lt herself melting in the flam And she felt him like a flame of desire, yet tender, and she fe e. She let herself go. She felt and she let herself go to him. She yielded with a amazing force and assertion, his penis risen against her with silent quiver that was like death, she went all open to him. there may be some interestin Now think about this. If D. H. Lawrence is to your taste, g changes occurring in your body. You haven't just run up a flight of stairs, but maybe your heart is beating faster. The temperature has not changed in the room, but you may have ju nd even though certain rather sensitive st activated a sweat gland or two. A suddenly very aware of them. parts ofyour body are not being overtly stimulated by touch, you are You sit in your chair not moving a muscle, and simply think a thought, a thought having to do with feeling angry or pancreas? sad or euphoric or lustful, and suddenly your pancreas secretes some hormone. Your How did you manage to do that with your pancreas? You don't even know where your pancreas is. Your liver is making an enzyme that wasn't there before, your spleen is text-messaging somethin g to your thymus gland, blood flow in little capillaries in your ankles has just changed. All from thinking a thought. We all understand intellectually that the brain can regulate functions throughout the rest of the body, but it is still r is to learn a bit about The purpose of this chapte eaching those effects can be. surprising to be reminded of how far-r the lines of communication be s are activated and which are in order to see which site tween the brain and elsewhere, quieted when you are sitting in your chair and feeling severely stressed. This is a prerequisite for seeing how the stress -response can save your neck during a sprint across the savanna, but make you sick during months of worry. STRESS AND THE AUTONOMIC NERVOUS SYSTEM The principal way in which your brain can tell the rest of the body what to do is to send messages through the nerves that branch from your brain down your spine and out to the periphery of your body. One dimension of this communication system is pretty straightforward and familiar . The voluntary nervous system is a conscious one. You decide to move a muscle and it happens. This part of the nervous system allows you to shake hands or fill out your tax sides skeletal muscle, and this em that projects to organs be forms or do a polka. It is another branch of the nervous syst lushing, getting gooseflesh, having an orgasm. In general, part controls the other interesting things your body does—b we have less control over what our brain says to our sweat glands, for example, than to our thigh muscles. (The r; biofeedback, for example, workings of this automatic nervous system are not entirel y out of our control, howeve consists of learning to alter this automatic function consciously. Potty training is another example of us gaining mastery. On a more mundane level, we are doing the same thing when we repress a loud burp during a wedding messages that are relatively involuntary ceremony.) The set of nerve projections to places like sweat glands carry and automatic. It is thus 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

14 Pa g e 14 of 212 ( Outline of some of the effects of the sympathetic and parasympathetic nervous systems on various organs and glands. termed the autonomic nervous system, and it has everything to do with your response to stress. One half of this system stress, one half is suppressed. is activated in response to em that is turned on is called the sympathetic nervous system* Originating in The half of the autonomic nervous syst the brain, sympathetic projectio ns exit your spine and branch out to nearly every organ, every bl ood vessel, and every sweat gland in your body. They even project to the scads of tiny little muscles attached to hairs on your body. If you on end; gooseflesh results when the ate those projections, your hair stands are truly terrified by something and activ parts of your body are activated where those muscles exist but lack hairs attached to them. The sympathetic nervous system kicks into action during emergencies, or what you think are emergencies. It helps ivation, mobilization. To generations of first-year medical students, it is described mediate vigilance, arousal, act through the obligatory lame joke about the sympathetic nervous system mediating the four F's of behavior—flight, fight, fright, and sex. It is th when life gets exciting or alarming, such as e archetypal system that is turned on at times during stress. The nerve endings of this system release adrenaline. When someone jumps out from behind a door and startles you, it's your sympathetic nervous system re leasing adrenaline that causes your stomach to clutch. and noradrenaline Sympathetic nerve endings also release the closely related substance noradrenaline. (Adrenaline 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

15 Pa g e 15 of 212 and are actually British desi epinephrine gnations; the American terms, which will be used from now on, are lt of the actions of the sympathe Epinephrine is secreted as a resu norepinephrine.) tic nerve endings in your adrenal r sympathetic nerve endings your kidneys); norepinephrine glands (located just above is secreted by all the othe throughout the body. These ar e the chemical messengers that kick vari ous organs into gear, within seconds. opposing role. This parasympathetic component mediates The other half of the autonomic nervous system plays an calm, vegetative activities—everything but the four F's. If you are a growing kid and you have gone to sleep, your parasympathetic system is activated. It ist Seymour Levine, this goes back to Galen, who beli to the eminent stress physiolog * Where did this name come from? According eved that the brain was responsible for rational thought and the peripheral vis cera for emotions. Seeing this co llection of neural pathways l inking the two suggested that it allowed your brain to sympathize with your visc era. Or maybe for your viscera to sympathize with your brain. As we'll see shortly, longside," refers to the not nervous system. Para, meaning "a the other half of the autonomic nervou s system is called the parasympathetic the sympathetic alongside those of projections sit the parasympathetic neural very exciting fact that "Oh, that's Edward and his fight-or-flight mechanism." promotes growth, energy storage, and other optimistic pro cesses. Have a huge meal, s it there bloated and happily drowsy, and the parasympathetic is going like gangbusters. Sprint for your life across the savanna, gasping and trying to control the panic, and you've turned the parasympathetic component down. Thus, the autonomic system works in opposition: sympathetic and parasympathetic projec-tions from the brain course their way out to a particular organ bring about opposite results. The sympathetic system speeds up the heart; the where, when activated, they parasympathetic system slows it down. The sympathetic system diverts blood flow to your muscles; the parasympathetic does the opposite. It's no surprise that it woul d be a disaster if both bran ches were very active at the same time, kind of like putting your foot on the gas and brake simultaneously. Lots of safety features exist to make sure that does not happen. For example, at activate one of the two branches typically inhibit the parts of the brain th the other, YOUR BRAIN: THE REAL MASTER GLAND which the brain can mobilize waves of The neural route represented by the sy mpathetic system is a first means by ssor. There is another way as well—through the secretion of hormones. If a neuron (a cell activity in response to a stre of the nervous system) secretes a chemi cal messenger that travels a thousandth of an inch and causes the next cell in line (typically, another neuron) to do something different, that messenger is called a neurotransmitter. Thus, when the heart muscle to work differently, t secrete norepinephrine, which causes sympathetic nerve endings in your hear neuron (or any cell) secretes a messenger that, instead, norepinephrine is playing a neurotransmitter role. If a percolates into the bloodstream and af fects events far and wide, that messenge r is a hormone. All sorts of glands of some of them is turned on during stress, and the secretion of others is turned off. secrete hormones; the secretion 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

16 Pa g e 16 of 212 What does the brain have to do with all of these glands secreting hormones? People used to think, "Nothing." The assumption was that the peripheral glands of the body—your pancreas, your adrenal, your ovaries, your testes, and so on—in some mysterious way "knew" what they were doing, had "minds of their own." They would "decide" when to gan. This erroneous idea gave rise to a rather silly fad secrete their messengers, without directions from any other or d that men's sexual drive declined with age, and assumed during the early part of the twentieth century. Scientists note that this occurs because the testicles of aging men secrete less male sex hormone , testosterone. (Actually, no one knew in the testes. And in fact, about the hormone testosterone at the time; they just referred to mysterious "male factors" age. Instead, the decline is moderate and highly variable from one male to the testosterone levels do not plummet with does not have much of an effect on next, and even a decline in testosterone to perhaps 10 percent of normal levels sexual behavior.) Making another leap, they then ascribed ag ing to diminishing sexual drive, to lower levels of male nage to grow old, but the female half of the population factors. (One may then wonder why females, without testes, ma didn't figure much in these ideas back then.) How, then, to reverse aging? Give the aging males some testicular extracts. Soon, aged, monied gentlemen were check ing into impeccable Swiss sanitariums and getting injected daily in their rears with testicu-lar extracts from dogs, from roosters, from monkeys. You could even go out to the stockyards of the sanitarium and pick out the goat of Advertisement, New York Therapeutic Review, 1893. your choice—just like picking lobsters in a restaurant (and more than one gentleman arrived for his appointment with his own prized animal in tow). This soon led to an offshoot of n therapy," namely, such "rejuvenatio rn the "monkey gland" craze, the term "organotherapy"—the grafting of little bi ts of testes themselves. Thus was bo testes. Captains of industry, heads of state, gland being used because journalists were forbidden to print the racy word War I, there was such a shortage of the aftermath of the carnage of World at least one pope—all signed up. And in young men and such a surfeit of marriages of younger women to older men, that therapy of this sort seemed pretty important. Naturally, the problem was that it didn't work. There wasn't any testosterone in the testicular extracts—patients would not go into solution in water. And the smidgens of organs be injected with a water-based extract, and testosterone does die almost immediately, with the scar tissu that were transplanted would e being mistaken for a healthy graft. And testosterone, it is not because the —if aging testes are secreting less even if they didn't die, th ey still wouldn't work testes are fail-nig, hul because another orga n (stay tuned) is no longer telling them to do so. Put in .1 brand-new sel of testes and they should fail also, for lack ol .1 stimulatory signal. Uui nol a problem, Nearly everyone reported wondrous results anyway. If you're paying a fortun e for painful daily injections of extracts of some beast's you feel like a young bull. One big placebo effect. testicles, there's a certain incentive to decide 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

17 Pa g e 17 of 212 With time, scientists figured out that the testes and othe r peripheral hormone-secreting glands were not autonomous, to the pituitary gland, sitting just underneath the brain. but were under the control of something else. Attention turned It was known that when the pituitary was damaged or diseased, hormone secretion throughout the body became part of the century, careful expe riments showed that a peripheral gland releases its hormone disordered. In the early rmone that kicks that gland into action. The pituitary contains a whole array of only if the pituitary first releases a ho hormones that run the show throughout the rest of the body; it is the pituitary that actually knows the game plan and rise to the memorable cliche that the pituitary is the regulates what all the other glands do. This realization gave master gland of the body. Reader's Digest, This understanding was disseminated far and wide, mostly in the which ran the "I Am Joe's" series of Am Joe's Ovaries," and so on). By the third paragraph of "I articles ("I Am Joe's Pancreas," "I Am Joe's Shinbone," "I ster gland business. By the 1950s, howev Am Joe's Pituitary," out comes that ma er, scientists were already learning the master gland after all. that the pituitary wasn't The simplest evidence was that if you removed the pituitary from a body and put it in a small bowl filled with ally secrete were no longer s hormones that it would norm pituitary nutrients, the gland would act abnormally. Variou secreted. Sure, you might say, remove any organ and throw it in some nutrient soup and it isn't going to be good for much of anything. But, interestingly, while this "explanted " pituitary stopped secreting cer tain hormones, it secreted others at immensely high rates. It wasn't just that the pituitary was traumatized and had shut down. It was acting e hormonal game plan. It erratically because, it turned out , the pituitary didn't really have the whol would normally be following orders from the brain, and there was no brain on hand in that small bowl to give directions. The evidence for this was relatively easy to obtain. Destroy the part of the br ain right near the pituitary and the pituitary stops secreting some of others. This tells you that the brain controls certain hormones and secretes too much pituitary hormones by stimulating their release and controls others by inhibiting them. The problem was to figure out how the brain did this. By all logic, you would look for nerves to pro- ject from the brain to the pi tuitary (like the nerve projecti ons to the heart and elsewhere) , and for the brain to release neurotransmitters that called the shots. But no one could find these projections. In 1944, the physiologist Geoffrey traveled to the pituitary and Harris proposed that the brain was also a hormonal gland, that it released hormones that directed the pituitary's actions . In principle, this was not a crazy idea; a quarter-century before, one of the godfathers of the field, Ernst Scharrer, had shown that some other hormones, thought to originate from a peripheral gland, were actually made in the brain. Nevertheless, lots of scientis ts thought Harris's idea was bonkers. You can get hormones from peripheral glands like ovaries, testes, pancreas— but your brain oozing hormones? Preposterous! This seemed not only scientifically implausible but somehow also an unseemly and indecorous thing for your brain to be doing, as opposed to writing sonnets. began looking for these brain hormones. This was a Two scientists, Roger Guillemin and Andrew Schally, stupendously difficult task. The brain rculatory system, only tuitary by a minuscule ci communicates with the pi ce. You couldn't search for thes slightly larger than the period at the end of this senten e hypothetical brain "releasing hormones" and "inhibiting hormones" in the general circulation of blood; if the hormones existed, by the time they reached the voluminous general circulation, they would be diluted beyond detection. Instead, you would have to search in the tiny bits of tissue at the base of the brain containing those blood vessels going from the brain to the pituitary. ey were highly motivated by the abstract intellectual puzzle Not a trivial task, but these two scientists were up to it. Th of these hormones, by th eir potential clinical a pplications, by the acclaim waiting at the end of this scientific rainbow. late 1950s, Guillemin and quest. Initially, in the r, which invigorated the Plus, the two of them loathed each othe Schally collaborated in the search for th ese brain hormones. Perhaps one tired even ing over the test tube rack, one of them dissed the other in some way—the actual events have sunk into historical obscurity; in any case a notorious at least on a par with the Greeks versus the Tro-jans, maybe animosity resulted, one enshrined in the annals of science g the first to isolate ys, each intent on bein Guillemin and Schally went their separate wa even with Coke versus Pepsi. the puta-tive brain hormones. How do you isolate a hormone that may not exist or that, even if it does, occurs in tiny amounts in a minuscule hit on the same strategy. They Started circulation system to which you can't gain access? Roth Guillemin and Schally collecting animal brains from slaughterhouses. Cut out the part at the base of the brain, near the pituitary. Throw a bunch of those in a blender, pour the resulting brain chemicals that purify the mash, collect th e droplets that come out the other end. mash into a giant test tube filled with pituitary changes its pattern of hormone release. If it does, Then inject those droplets into a rat and see if the rat's maybe those brain droplets contain one of those imagined releasing or inhibiting hormones. Try to purify what's in the version of it, and see if that regulates pituitary function. structure, make an artificial droplets, figure out its chemical Pretty straightforward in theory. But it took them years. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

18 Pa g e 18 of 212 One factor in this Augean task was th e scale. There was at best a minuscule amount of these hormones in any one eat slaughterhouse war was on. of brains at a time. The gr brain, so the scientists wound up dealing with thousands re collected; chemists pour ed cauldrons of brain into monumental chemical- Truckloads of pig or sheep brains we separation columns, while others pondered the thimblefuls of liquid that dribbled out the bottom, purifying it further ine work. New types of chemistry had to be xt... But it wasn't just mindless assembly-l in the next column and the ne invented, completely novel ways of testing the effects in the living body of hormones that might or might not actually exist. An enormously difficult scientific problem, made worse by the fact that lots of influential people in the field tions and that these two guys were wasting a lot of time and money. believed these hormones were fic Guillemin and Schally pi oneered a whole new corporate ap proach to doing science. One of our cliches is the lone scientist, sitting there at two in the morning, trying to figu re out the meaning of a result. Here there were whole teams of chemists, biochemists, physiologists, and so on, coordina ted into isolating these putative hormones. And it worked. t releasing hormone was published.* Two e, the chemical structure of the firs A "mere" fourteen years into the ventur years after " The answer depends on how you define "getting * "So," asks the breathless spor ts fan, "who won the race—Guillemin or Schally? there first." The ectly regulates the release of controls the way in which thyroid hormone (that is, it the pituitary regulates first hormone isolated was one that indir ormone in the brain that rst to submit a paper for publication saying, the thyroid). Schally and crew were the fi in effect, "There really does exist a h hing the identical regulates thyroid hormone release, and its chemical structure is X." In a photo finish, Guillemin' s team submitted a paper reac min and friends had been the first to publ conclusion five weeks later. But as a comp lication, a number of months before, Guille ish a paper saying, in effect, "If you synthesize a chemical with structure X, it and does so in a way similar to the way hypothalamic regulates thyroid hormone release in the (continued) if whatever it is brain mash does; we don't know yet that, in 1971, Schally got there with the sequence for the next hypothalamic hormone, and Guillemin published two ing Schally to the next hormone by a solid three years. months later. Guillemin took the next round in 1972, beat Everyone was delighted, the by correct, and Guillemin and Schally got the -then-deceased Geoffrey Harris was proved Nobel Prize in 1976. One of them, urbane and knowing what would sound right, proclaimed that he was motivated only by science and the impulse to help mankind; he noted how stimulating and productive his interactions with his co -winner had been. The other, less polis tion was all that drove him for decades hed but more honest, said the competi any years of vicious attack s and bitter retaliation." and described his relationship with his co-winner as "m So hooray for Guillemin and Schally; the brain turned out to be the master gland. It is now recognized that the base of contains a huge array of those releasing an the brain, the hypothalamus, d inhibiting hormones, which instruct the pituitary, which in turn regulates the secretions of the peri pheral glands. In some cases, the brain triggers the release easing hormone. Sometimes it halts the release of pituitary of pituitary hormone X through the action of a single rel some cases, a pituitary hormone is controlled by the hormone Y by releasing a single inhibiting hormone. In coordination of both a releasing and an inhibiting hormone from the brain—dual control. To make matters worse, in y confusing system that I study) th ere is a whole array of hypothalamic some cases (for example, the miserabl hormones that collectively regulate the pituitary, some as releasers, others as inhibitors. ay, "This structure rised if it did." So Guillemin was the first to s s structure X, but we wouldn't be one bit surp (continued) hypothalamus also ha works like the real thing," and Schally was d many decades afterward, real thing." As I have discovered firsthan the first to say, "This structure is the Schally prizefight years are still willing to get worked up as to which counts as the battle-scarred veterans of the Guillemin- the knockout. alth sitting the like the National Institutes of He into this insane competition, vious wasn't done a few years One might wonder why something ob two down and saying, "Instead of us giving you all of this extr gether?" a taxpayers' money to work separately, why don't you two work to Independent all that great for scientif ic progress. The competition se rved an impo Surprisingly, this wouldn't necessarily be rtant purpose. nce. Years into a chase, a scientist triu replication of results is essential in scie ormone or brain chemical. mphs and publishes the structure of a new h incentive on earth to prove that Two weeks later the other gu y comes forward. He has every the first guy was wrong. Instead, he is forced to say, "I solid, from nce is really have to admit he's right. We get the identical structure." That is how you know that your evide hate that son of a bitch, but I independent confirmation by a hostile competito ther, things usually do go faster, but everyone winds up sharing the r. When everyone works toge can grow into big ones. same assumptions, leaving th em vulnerable to small, unexamined mistakes that HORMONES OF THE STRESS-RESPONSE and activate componen As the master gland, the brain can expe rience or think of something stressful ts of the stress- response hormonally. Some of the hypothalamus-pituitary-per ipheral gland links are activ ated during stress, some inhibited. Two hormones vital to the stress-respon rine, released by the se, as already noted, are epinephrine and norepineph of hormones in the response to stress are called sympathetic nervous system. Another important class glucocorticoids. By the end of this book you will be astonishingly informed about glucocorticoid trivia, since I am in love with these is used to describe the genera l chemical structure of five hormones. Glucocorticoid s are steroid hormones. (Steroid classes of hormones: androgens—the famed "anabolic" steroids like testosterone that get you thrown out of the adrenal gland, they often Olympics—estrogens, progestins, mineralocor-ticoids, and gluc ocorticoids.) Secreted by the hrine acts within seconds; glucocorticoids back this activity act, as we will see, in ways similar to epinephrine. Epinep up over the course of minutes or hours. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

19 Pa g e 19 of 212 Because the adrenal gland is basically witless, glucocorticoid release must ulti mately be under the control of the hormones of the brain. When something stressful happens or you think a stressful thought, the hypothalamus secretes an array of releasing hormones into the hypothalamic-pit uitary circulatory system that gets the ball rolling. The H (corticotropin releasing hormone), while a variety of more minor players principal such releaser is called CR econds or so, CRH triggers the pituitary to release the hormone ACTH (also synergize with CRH.* Within fifteen s renal gland and, within a few known as corticotropin). After ACTH is released into the bloodstream, it reaches the ad ocorticoids and the secretions minutes, triggers glucocorticoid release. Together, gluc of the sympathetic nervous ) account for a large percentage of what system (epinephrine and norepinephrine * For the three people on ea rth who are reading this book, read the prior edition, and remember anything from it, you may be wondering why the s of endocrinology, a putative hormone previously known as CRF (corticotro pin releasing factor) has been transformed into CRH. By the rule int it graduates into being a "hormo ructure is confirmed, at which po actor" until its chemical st hormone is referred to as a "f ne." CRF achieved that status in the mid-1980s, and my continued mpt on my part to n was merely a nostalgic and pathetic atte use of "CRF" as recently as the 1998 editio hold on to those reckless days of my youth before CRF was tamed. After much painful th this and will psychological work, I have come to terms wi use "CRH" throughout. Outline of the control of glucocorticoid secretion. A stressor is sensed or anticipated in the brain, triggering the release of CRH (and related hormones) by the hypothalamus. These hormones enter the private circulatory system linking the hypothalamus and the anterior pituitary, causing the release of ACTH by the anterior pituitary. ACTH enters the general circulation and triggers the release of glucocorticoids by the adrenal gland. e are the workhorses of the stress-response. happens in your body during stress. Thes 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

20 Pa g e 20 of 212 Gluc ocorticoids, In addition, in times of stress your pancreas agon. is stimulated to release a hormone called gluc gluc As we will see, these ose. agon, gluc and the sympathetic nervous system raise circulating levels of the sugar hormones are essential for mobilizing energy during stre ss. Other hormones are activat ed as well. The pituitary h, among other effects, plays a role in suppressing reproduction during stress. Both the secretes prolactin, whic pituitary and the brain also s rphine-like substances called endorphins and ecrete a class of endogenous mo which help blunt pain perception, among other things. Finally, the pituitary also secretes vasopressin, enkephalins, which plays a role in the antidiuretic hormone, also known as cardiovascular stress-response. response to stress, various hormonal systems are inhibited during stress. The Just as some glands are activated in secretion of various reproductive hormones such as estrog en, progesterone, and testosterone is inhibited. Hormones as is the secretion of insuli n, a pancreatic hormone that related to growth (such as growth hormone) are also inhibited, normally tells your body to store energy for later use. (Are you overwhelmed and intimidated by these terms, wondering if you should have bought some Deepak Chopra morizing these names of horm self-help book instead? Pl ant ones are ease, don't even dream of me ones. The import tably and accurately slipping them into ming pages that you will soon be comfor going to appear so regularly in the co everyday conversation and birthday cards to favorite cousins. Trust me.) A FEW COMPLICATIONS the neural and hormonal messen This, then, is an outline of our current understanding of gers that carry the brain's news that something awful is happening. Cannon was the first to recognize the role of epinephrine, norepinephrine, and the sympathetic nervous system. As no ted in the previous chapter, he coined the phrase "fight-or-flight" response, which is a way of conceptualizing the stress-response as preparing the body for that sudden burst of energy demands. Selye pioneered the glucocorticoid component of the story. Since then the roles of the other hormones and neural the dozen years since this book systems have been recognized. In first came out, various new minor hormonal players have been added to the picture, and, undoubtedly, more are ye t to be discovered. Collectively, these shifts in secretion and activation form the primary stress-response. Naturally there are complications. As will be reiterated throughout the following chapters, the stress-response is about preparing the body for a major expenditu re of energy—the canonical (or, perh aps, Can-nonical) "fight-or-flight" people to rethink this. She suggests Shelley Taylor of UCLA has forced response. Recent work by the psychologist that the fight-or-flight response is what dealing with stress is about in males, and that it has been overemphasized as a to study males rather than females. bias among (mostly male) scientists phenomenon because of the long-standing response can be quite different in females, built around Taylor argues convincingly that the physiology of the stress- are typically less aggressive than males, the fact that in most species, females and that having dependent young often precludes the option of flight. Showing that she can match the good old boys at coming up with a snappy sound bite, Taylor suggests that rather than the female stress-response being about fight-or-flight, it's about "tend and befriend"— taking care of her young and seeking social affiliation. As will be seen in the fi nal chapter of the book, there are some striking gender differences in stress management styles that support Taylor's view, many of them built around the propensity toward social affiliation. monal mechanism that helps co Taylor also emphasizes a hor ntribute to the "tend and befriend" stress-response. While the sympathetic nervous system, glucocorticoids, and the other hormones just reviewed are about preparing the body for major physical demands, the hormone oxytocin seems more related to the tend and befriend themes. The pituitary hormone plays a role in causing the fe male of various mammalian species to imprint on her child after birth, to stimulate milk production, and to stimulate maternal behavior. Moreover, oxytocin may be critical for a female to ly few mammalian species that are monogamous).* And the form a monogamous pair bond with a male (in the relative rts the idea that responding to stress may not just consist of fact that oxytocin is secreted during stress in females suppo preparing for a mad dash across the savanna, but may also involve feeling a pull toward sociality. A few critics of Taylor's influential work have pointed out that sometimes the stress-respon se in females can be about fight-or-flight, biological criteria. But that's another book. bly should not include humans, by a number of * A list of species that proba rather than affiliation. For ex wildly aggressive (oft en in the context of ample, females are certainly capable of being protecting their young), and often sprint for their lives or for a meal (among lions, for example, females do most of the hunting). Moreover, sometimes the stress-response in males can be about affiliation rather than fight-or-flight. This e coalitions with other males or, in those rare monogamous species (in which can take the form of creating affiliativ males typically do a fair amount of the child care), some of the same tending and befriending behaviors as seen among females. Nevertheless, amid these criticisms, there is a widespread acceptance of the idea that the body does not 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

21 Pa g e 21 of 212 respond to stress merely by preparing for aggression or escap differences in the e, and that there ar e important gender physiology and psychology of stress. when considering the classic stress-response built around fight-or-flight, not all Some more complications arise. Even s. For example, while stress cau ses a prompt decline in the of its features work quite the same way in different specie hormone secretion in humans (this puzzle causes a transient increase in growth secretion of growth hormone in rats, it n for humans are discussed in the chapter on growth). and its implicatio e time course in actions of epinephrine a Another complication concerns th nd glucocorticoids. A few paragraphs back, activity over the course of latter backs up epinephrine's I noted that the former works within seconds, while the ace of an invading army, sometimes the minutes to hours. That's great—in the f defensive response can take the form of handing out guns from an armory (epinephrine working in seconds), and a defense can also take the form of beginning construction of new tanks (glucocorticoids working over hours). But within the framework of lions chasing s? What good are glucocorticoids if some of zebras, how many sprint s across the grasslands actually go on for hour cal dawn-on-the-savanna stressor is over with? Some glucocorticoid actions do their actions occur long after your typi help mediate the stress-response. Others help mediate the recovery from the stress-response. As will be described in number of autoimmune diseas es. And some glucocorticoid chapter 8, this probably has important implications for a actions prepare you for the next stressor. As will be discussed in chapter 13, this is critical for understanding the ease es can trigger glucocorticoid secretion. with which anticipatory psychological stat response when it is activated. Central to Selye's Another complication concerns consistency of the stress- , or are that zebra or that lion whether you are too hot or too cold conceptualization was the belief that activate the same pattern of s (or simply stressed by the repetitiveness of that phrase), you ecretion of glucocorticoids, estrogen, and so forth for each of those epinephrine, growth hormone, stressors. This is mostly true, and this the stress-response into a package deal starts at the brain, where the same intertwining of the various branches of c nervous system. ate the sympatheti ease from the hypothalamus and activ pathway can both stimulate CRH rel Moreover, epinephrine and glucocortico ids, both secreted by the adrenal, can potentiate each other's release. However, it turns out that not all stressors produce the exact same stress-response. Th e sympathetic nervous system ually all stressors. But the speed and magnitudes of the and glucocorticoids play a role in the response to virt branches can vary depending on the stressor, and not all of the other endocrine sympathetic and glucocorticoid components of the stress-respo g of hormone release estration and patternin nse are activated for all stressors. The orch , with there being a particular hormonal "signature" for a tend to vary at least somewhat from stressor to stressor particular stressor. the sympathetic stress-responses. James tude of the glucocorticoid versus One example concerns the relative magni stressors such as subordinan ce to cause heart disease in Henry, who has done pioneering work on the ability of social ticularly activated in a socially subordinate rodent that is rodents, has found that the sympathetic nervous system is par vigilant and trying to cope with a challenge. In contrast, it is the glucocorticoid system that is relatively more activated in a subordinate rodent that has given up on coping. Studies of humans have shown what may be a human analogue of y and vigilance, while heavy secretion of hetic arousal is a relative marker of anxiet that dichotomy. Sympat glucocorticoids is more a marker of depression. Furthermore, all stressors do not cause s ecretion of both epinephrine and norepinephrine, nor of norepinephrine from all branches of the sympathetic system. In some cases, the stress signature sneak s in through the back door. Two stressors can produce identical profiles of stress hormone release into the bloodstr eam. So where's the signature that differ entiates them? Tissues in various parts one stressor, but not the other. to a stress hormone in the case of sensitivity of the body may be altered in their r 13, two identical stressors can cause very different stress signatures, depending Finally, as will be the topic of chapte t generate exactly the same stress-response. the stressors. Thus, every stressor does no on the psychological context of This is hardly surprising. Despite the dimensions common to various stressors, it is still a very different physiological challenge to be too hot or too cold, to be extremely anxious or deeply depressed. Despite this, the ned in this chapter, which occur pretty reliably hormonal changes outli vely different stressors, in the face of impressi still constitute the superstructure of the neural and endo crine stress-response. We are now in a position to see how these responses collectively save our skins during acute emergencies but can make us sick in the long run. 3 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

22 Pa g e 22 of 212 STROKE, HEART ATTACKS, AND VOODOO DEATH It's one of those unexpected emergencies: you're walking meet a friend for dinner. down the street, on your way to You're already thinking about what you'd like to eat, savoring your hunger. Come around the corner and—oh no, a lion! As we now know, activities throughout your body shift immediately to meet the crisis: your digestive tract shuts down and your breathing rate skyrockets. Secretion of sex hormones is inhibited, while epinephrine, norepinephrine, and glucocorticoids pour into the bloodstream. And if your legs are going to save you, one of the most important additional things that better be going on is an increase in your cardiovascular output, in order to deliver oxygen and energy to those ex ercising muscles. THE CARDIOVASCULAR STRESS-RESPONSE long as you have a sympathetic nervous system plus some Activating your cardiovascular system is relatively easy, so glucocorticoids and don't bother with too many details. The first thing you do is shift your heart into higher gear, get it rn activating the sympathetic mplished by turning down pa to beat faster. This is acco rasympathetic tone, and in tu by activating neurons in the brain stem that stimulate nervous system. Glucocorticoids add to this as well, both e effects of epinephrine sympathetic arousal, and by enhancing th t muscle. You also want and norepinephrine on hear a trick with the veins that return blood to increase the force with which your heart beats. This involves to your heart. Your sympathetic nervou s system causes them to constrict, to get more rigid. And that causes the returning blood to blast through those veins with more force. Blood returns to your heart with more force, slamming into your heart walls, distending them more than usual... and those heart walls, like a stretched rubber band, snap back with more force. So your heart rate and blood pressure have gone up. The next task is to distribute the blood prudently throughout that sprinting body of yours. Arteries are relaxed—dilated—that lead to your muscles, increasing blood flow and energy ease in blood flow to nonessential parts of your body, like delivery there. At the same time, there is a dramatic decr ing that will be discussed in blood flow to your brain, someth your digestive tract and skin (you also shift the pattern of ood flow to the gut was first noted in 1833, in an extended study of a Native American chapter 10). The decrease in bl When the man sat quietly, his gut tissues were ter a gunshot wound there. who had a tube placed in his abdomen af bright pink, well supplied with blood. sa would blanch, because Whenever he became anxiou s or angry, the gut muco of decreased blood flow. (Pure speculation, perhaps, but one suspects that his transients of anxiety and anger might have been related to those white folks sitting around experimenting on him, instead of doing something useful, like sewing him up.) response to stress, involving the kidneys. As that zebra with its belly ripped There's one final cardiovascular trick in open, you've lost a lot of blood. And you're going to need th at blood to deliver energy to your exercising muscles. Your body needs to conserve water. If blood volume go es down because of dehydra tion or hemorrhage, it doesn't matter what your heart and veins are doing; your ability to deliver glucose and oxygen to your muscles will be the source of the water in urine is the be losing water? Urine formation, and impaired. What's the most likely place to bloodstream. Thus, you decrease blood flow to your kidney s and, in addition, your brain sends a message to the kidneys: stop the process, reabsorb th e water into the circulat ory system. This is accomplished by the hormone ine formation), as well as a host of for its ability to block diuresis, or ur antidiuretic hormone vasopressin (known as related hormones that regulate water balance. A question no doubt at the forefront of ev ery reader's mind at this point: if one of the features of the cardiovascular stress-response is to conserve water in the circulation, an d this is accomplished by inhibitio n of urine formation in the 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

23 Pa g e 23 of 212 kidneys, why is it that when we are really terrified, we wet our pants? I congratulate the reader for homing in on one of the remaining unanswered questions of modern science. In trying to Why do we have bladders? They are dandy answer it, we run into a larger one. if you are a hamster or a dog, because adders up until they are just about to burst and then run around their territories, species like those fill their bl demarcating the boundaries—odoriferous little "keep out" signs to the neighbors.* A bladder is logical for scent- + For humans, it is a myst ery, just a boring storage marking species, but I presume that you don't do that sort of thing. site. The kidneys, now those are someth rectional organs, which means you can ing else. Kidneys are reabsorptive, bidi spend your whole afternoon happily putting water in from the circulation and getting some back and regulating the s south to the bladder, you whole thing with a collection of hormones. But once the urin e leaves the kidneys and head can kiss that stuff good-bye; the bladder is unidirectional. When it comes to a stressful emergency, a bladder means a ss the savanna. The answer is obvious: empty that bladder.++ lot of sloshy dead weight to carry in your sprint acro * One of my intrepid research assistants, Michelle Pearl, called up some of America's leading urologists to ask them why bladde rs evolved. One rodents having bladders ter) took the findi comparative urologist (as well as Jay Kaplan, whose research is discussed in this chap ngs about territorial d leave a scent to make scent trails and inverted the argument—maybe we have bladders so that we can avoid continual dr ibble of urine that woul however, that a weakness with his idea is that fish also have bladders, and they trail so some predator could track us. The same urologist noted, mber of urologists suggested that maybe the bladder acts as a bu ffer between the presumably don't have to worry about leaving scent trails. A nu for the purpose of e chance of kidney infections. However, it kidney and the outside world, to reduce th seems odd to develop an organ exclusively protecting another organ from infection. Pearl suggested that it may have evolved for male reproduction—the acidity of urine is n't very healthy for e urine. A sperm (in ancient times, women would use half a lemon as a diaphr agm), so perhaps it made sense to evolve a storage site for th ave a bladder," before d be an extreme social liability to not h stioned said something like, "Well, it woul remarkable percentage of the urologists que adders tens of millions of year s ago so that we humans wouldn 't inadvertently pee realizing that they had just suggested that vertebrates evolved bl on our party clothes. Mostly, however, the urologists said things I don't know and I like, "To be honest, I've never thought about this before," " talked to everyo ne here and they don't know a nything either," and "Beats me." The strangest thing about it all is that ma ny animals may not actually take advantag e of their bladder's storage capacity. In m y vast experience , there's a lot of work ld it in when they have to go. Clearly watching baboons go about their urinary business, it is apparent that they very rarely ho to be done in this area. + Well, maybe some humans do. When the A llies breached the Rhine River in Germany during World War II by putting up a pontoon b ridge, "I've been waiting a General George Patton apparently walked across it, stopped in the middle, and, w ith cameras blazing, took a piss in the Rhine. scent-marking, during the Korean ntinuing this intersection of m ilitarism, bodies of water, and long time for that," he said. Co War, American troops would line up along the Yalu River, across from Chinese so ate en masse into the river. ldiers facing them, and urin stress can increase the occurrence of enures kids who have nocturnal ++ It should be noted that in kids, while is (loss of control of the bladder), most tting) (continued) enuresis (bed-we "So! Planning on roaming the neighborhood with some of your buddies today?" 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

24 Pa g e 24 of 212 Everything is great now—you have kept your blood volume up, it is roaring through the body with more force and speed, delivered where it is most needed . This is just what you want when running away from a lion. Interestingly, go and Laurel Fisher of the Marvin Brown of the University of California at San Die University of Arizona have shown that a different picture emerges when one is being vig ilant—a gazelle crouching in the grass, absolutely quiet, as a lion passes nearby. The sight of a lion is obviously a stressor, but of a subtle sort; while having to remain as still grasslands with the briefest as possible, you must also be prepared, physiologically, for a wild sprint across the es that mysterious problem for guys as to why it is so diffi (continued) are psychologically normal. This entire discussion rais cult to urinate at a he movie starts. g to get back to their seats before t iting in line behind you, all impatiently waitin urinal when you are stressed by a crowd wa of warnings. During such vigilance, heart rate and blood flow tend to slow down, and vascular resistance throughout scles. Another example of the compli the body increases, including in the mu cating point brought up at the end of r every type of stressor. identical stress-response fo chapter 2 about stress signatures—you don't turn on the Finally, the stressor is over, the lion pursues some other pedestrian, you can return to your dinner plans. The various hormones of the stress-response turn off, your parasympathetic nervous system begins to slow down your heart via something called the vagus nerve, and your body calms down. CHRONIC STRESS AND CARDIOVASCULAR DISEASE So you've done all the right things during your lion encounter. But if you put your heart, blood vessels, and kidneys to work in this way every time someone irritates you, y ou increase your risk of h eart disease. Never is the e case of the cardiovascular maladaptiveness of the stress-response during psychological stress clearer than in th system. You sprint through the restaurant district terrified, and you alter cardiovascular functions to divert more blood flow to your thigh muscles. In such cases, there's a wonderful match between blood flow and metabolic demand. In next week, driving yourself into a hyperventilating panic, contrast, if you sit and think about a major deadline looming you still alter cardiovascular function to divert more bl s. Crazy. And, potentially, ood flow to your limb muscle eventually damaging. How does stress-induced elevation of blood pressure during chronic psychological stress wind up causing er one killer in the United States and the developed wo cardiovascular disease, the numb rld? Basically, your heart is just a dumb, simple mechanical pump, and your blood vessels are nothing more exciting than hoses. The nsists of making them work harder for a while, and if you do that on a cardiovascular stress-response essentially co regular basis, they will wear out, just like any pump or hose you'd buy at Sears. lated disease is developing hypertension, chronically elevated blood pressure.* The first step in the road to stress-re This one seems reflecting the force with wh * Resting blood pressure where sy stolic pressure—the upper number, ich blood is leaving your heart— which blood returns to your heart—is above he lower number, reflecting the force with is above 140, or when diastolic pressure—t 90, is considered elevated. obvious: if stress causes your blood pressure to go up, then chronic stress causes your blood pressure to go up chronically. Task accomplished , you've got hypertension. point. The little blood vessels roughout your cious cycle emerges at this It's a bit messier because a vi distributed th body have the task of regulating blood flow to the local neighborhoods as a means of ensuring adequate local levels of oxygen and nutrients. If you chronically raise your blood pressure—chronically increase the force with which blood is coursing through those small vessels—those vessels have to work harder to regulate the blood flow. Think of the ease it takes to control a garden hose spritzing water versus a firehose with a hydrant's worth of force gushing through it. precisely what happens at these sma ll vessels. They build a thicker muscle The latter takes more muscle. And that's layer around them, to better control the increased force of blood flow. But as a result of these thicker muscles, these vessels now have become more rigid, more resistant to the force of blood flow. Which tends to increase blood e vascular resistance. Which tends ... pressure. Which tends to further increas So you've gotten yourself chronically high blood pressure. This isn't great for your heart. Blood is now returning to your heart with more force and, as mentioned, this ma kes for a greater impact upon the heart muscle wall that n with more muscle. This is termed "left ventricular encounters that tsunami. Over time, that wall will thicke ricle, the part of the heart hypertrophy," which means increasing the mass of the left vent in question. Your heart is now lopsided, in a sense, being overdeveloped in one quadrant. This increases the risk of developing an irregular d wall of ventricular heart muscle may now require more heartbeat. And more bad news: in addition, this thickene blood than the coronary arteries can supply. It turns out that after controlling for age, having left ventricular hypertrophy is the single best predictor of cardiac risk. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

25 Pa g e 25 of 212 The hypertension isn't good for your blood vessels, either. A general feature of the circulatory system is that, at various points, large blood vessels (your descending aorta, ler vessels, then into even for example) branch into smal of capillaries. This process of splitting into smaller and smaller ones, and so on, down to tiny beds of thousands bifurcation. ed bifurcation is in the inarily efficient this repeat smaller units is called (As a measure of how extraord circulatory system, no cell in your body is more than five cells away from a blood vessel—yet the circulatory system takes up only 3 percent of body mass.) One feature of systems that branch in this way is that the points of bifurcation are particularly vulnerable to injury. The branch points of the fluid pressure slamming into them. Thus, a simple cation occurs bear the brunt in the vessel wall where bifur rce with which the fluid is moving throu gh the system, turbulen ce increases and those rule: when you increase the fo outposts of wall are more likely to get damaged. ns to occur at branch points anies repeated stress, damage begi ood pressure that accomp With the chronic increase in bl in arteries throughout the body. The smooth inner lining of the vessel begins to tear or form little craters of damage. Once this layer is damaged, you get an inflammatory response—cells of the immune system that mediate jured site. Moreover, cells full of fatty nu inflammation aggregate at the in trients, called foam cells, begin to form there, too. In addition, during stress the sympathetic nervous system makes your blood more viscous. Specifically, epinephrine makes circulating platelets (a type of blood cell that promotes clotting) more likely to clump together, and these clumped platelets can get gummed up in these aggregates as well. As we'll see in the next chapter, during stress glucose, and the "bad" type of cholesterol, and these can you're mobilizing energy into the bloodstream, including fat, e. All sorts of fibrous gunk builds up there, too. You've now made yourself an atherosclerotic also add to the aggregat plaque. Therefore, stress can promote plaque formation by increasing the odds of blood vessels being damaged and inflamed, ulating crud (platelets, fat, cholesterol, and so on) sticks to those inflamed and by increasing the likelihood that circ ovascular disease by measuring injury sites. For years, clinicians have tried to get a se nse of someone's risk of cardi there is in the bloodstream. This is, of course, cholesterol, leading to such a how much of one particular type of crud ge us to give their cholesterol-filled products a break. High skittishness about cholesterol that the egg industry has to ur r cardiovascular disease. But certainly increase the risk fo levels of cholesterol, particularly of "bad" cholesterol, they're not a great predictor; a surpri sing number of folks can tolerate high levels of bad cholesterol without ack victims have elevated cholesterol levels. about half of heart att cardiovascular consequences, and only clear that the amount of damaged, inflam ed blood vessels is a better predictor of In the last few years, it is becoming cardiovascular trouble than is . This makes sense, in that you can eat eleventy eggs a the amount of circulating crud day and have no worries in the atherosclerosis realm if there are no damaged vessels for crud to stick to; conversely, plaques can be forming even amid "healthy" levels of cholesterol, if there is enough vascular damage. A healthy blood vessel (left), and one with an atherosclerotic plaque (right). of inflammatory damage? A great marker is turning out to be something called C- How can you measure the amount gnal indicating an injury. It migrates to liver and is secreted in response to a si reactive protein (CRP). It is made in the the damaged vessel where it helps amplify the cascade of in flammation that is developing. Among other things, it helps trap bad cholesterol in the inflamed aggregate. terol, even years in advance CRP is turning out to be a much better predictor of cardiovas cular disease risk than choles of disease onset. As a result, CRP has suddenly become qu ite trendy in medicine, and is fast becoming a standard endpoint to measure in general blood work on patients. ension and atherosclerosis— the accumu Thus, chronic stress can cause hypert lation of these plaques. One of the own lives, is to be found in the work of the physiologist clearest demonstrations of this, with great application to our Jay Kaplan at Bowman Grey Medical Sc hool, Kaplan built on the landmark work of an earlier physiologist, James Henry (who was mentioned in the previous chapter), who showed that purely social stress caused both hypertension and atherosclerosis in mice. Kaplan and colleagues have shown a similar phenomenon ir primates, bringing the story much closer home to us humans. Establish male monkeys in a social group, and over the course of days tc months 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

26 Pa g e 26 of 212 they'll figure out where they chy has emerged, the stand with respect to one another. Once a stable dominance hierar to the most physical st m: not only are you subject las place you want to be is on the botto ressors but, as will be stress, to the most psychological stre reviewed in chapter 13 on psy-chological ssors as well. Such sub-ordinate males show a lot of the physiological indices of chronically turning on their stress-re sponses. And often these animals wind at the atherosclerosis arises from the ries are all clogged up. As evi-dence th up with atherosclerotic plaques—their arte overactive sympathetic ent of the stress-response, if Kaplan gave the monkeys at risk drugs th at prevent sympathetic nervous system compon ey didn't form plaques. activity (beta-blockers), th keep the dominance system unstable by animals is also at risk. Suppose you Kaplan showed that another group of l the animals are perpetually in the tense, uncertain stage shifting the monkeys into new groups every month, so that al rcumstances, it is generally the animals of figuring out where they stand with respect to everyone else. Under those ci st fighting and at the top of the shifti chy who do the mo precariously holding on to their places ng dominance hierar show the most behavioral and hormonal indices of stress. And, as it turns out, they have tons of atherosclerosis; some of the monkeys even have heart attacks (abrupt blockages of one or more of the coronary arteries). n. Kaplan showed that this at risk for plaque formatio In general, the monkeys under the most social stress were most et, which makes sense, since, as will be described in the next chapter, a lot of the fat can even occur with a low-fat di body, rather than coming from the cheeseburger the monkey that forms plaques is being mobilized from stores in the high-fat diet, the effects synergize, and ate just before the tense conference. But if you couple the social stress with a plaque formation goes through the roof. lerosis. Form enough atherosclerotic plaques to seriously obstruct flow to the So stress can increase the risk of atherosc est hurt like hell for lack of oxygen which means that your legs and ch claudication, lower half of the body and you get and glucose whenever you walk; you are th e same thing happens to the arteries en a candidate for bypass surgery. If th nary heart disease, myocardial isch emia, all sorts of horrible things. going to your heart, you can get coro But we're not done. Once you've formed those plaques, continued stress can get you in trouble another way. Again, ease the chances of ith enough force, incr ood pressure, and, as the blood moves w increase stress and increase bl tearing that plaque loose, rupturing it. So maybe you've had a plaque form in a huge aqueduct of a blood vessel, with and that e. But tear it loose now, the plaque being way too small to cause any troubl thrombus, form what is called a og up a coronary artery and l, clogging it completely. Cl mobile hairball can now lodge in a much smaller blood vesse you've got a myocardial infarct, a heart attack (and this thrombus route accounts fo r the vast majority of heart attacks). Clog up a blood vessel in the brain and you have a brain infarct (a stroke). individual new stressor is But there's more bad news. If chronic stress has made a me ss of your blood vessels, each even more damaging, for an additional insidious reason. This has to do with myocar arises when the arteries dial ischemia, a condition that feeding your heart have become sufficiently clogged that your heart itself is partially deprived of blood flow and thus is happening, and your cardiovascular system is in great of oxygen and glucose.* Suppose something acutely stressful t speeds up in a strong, shape. You get excited, the sympathe tic nervous system kicks into action. Your hear 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

27 Pa g e 27 of 212 coordinated fashion, and its contractiv e force increases. As a result of work ing harder, the heart muscle consumes more energy and oxygen and, conveniently, the arteries going to your heart dilate in order to deliver more nutrients and oxygen to the muscle. Everything is fine. ffering from chronic myocardial ischemia, you're in But if you encounter an acute stressor with a heart that has been su trouble. The * It may initially seem illogical for the h le—require the energy When the walls of th eart to need special arteries feeding it. e heart—the heart musc d simply be absorbed from the vast amounts of blood passing th and oxygen stores in the blood, you might imagine that these coul rough the ogy, consider people le is fed by arteries coursing from the main aorta. As an anal chambers of the heart. But instead it has evolved that heart musc oir. Every time they get thirsty, they might go over to the edge of the reservoir with a bucket working at a city's water reserv and pull up some water .) that reservoir just outside the office, fed indirectly by have a water fountain in to drink. (Instead, the usual solution is to A necrotic heart. vasodilating in response to the sympathetic nervous system, vaso constrict. coronary arteries, instead of This is very different from the scenario described at the beginning of the chapter, where you are constricting some big blood vessels that deliver blood to unessential parts of your body. Instead, these are the small vessels diverting blood right to ese already clogged vessels, your heart. Just when your heart needs more oxygen and glucose delivered through th acute stress shuts them down even more, producing a shortage of nutrients for the heart, myocardial ischemia. This is to hurt like crazy—angina pectoris. And it turns out that it exactly the opposite of what you need. Your chest is going vasoconstrictive problem. Ther efore, chronic myocardial takes only brief periods of hypertension to cause this ischemia from atherosclerosis sets you up for, at the least, terrible chest pain whenever anything physically stressful ening a preexisting problem. extremely effective at wors occurs. This is the perfect demonstration of how stress is ts were surprised to discover that we are even more When cardiology techniques improved in the 1970s, cardiologis an had been guessed. With the old techniques, you would take someone with vulnerable to trouble in this realm th than women) up to some massive ECG en are more prone to heart disease myocardial ischemia and wire him (m machine (same as EKG), focus a huge X- ray camera on his chest, and then send him running on a treadmill until he uld decrease and his chest would hurt. uld expect, blood flow to the heart wo was ready to collapse. Just as one wo Some engineers invented a miniature ECG machine that can be strapped on while you go about your daily business, and se. There were little ischemic crises was invented. Everyone got a rude surpri ambulatory electrocardiography occurring all over the place in people at risk. Most ischemic episodes turned out to be "silent"—they didn't give a warning signal of pain. Moreover, all sorts of rviews, exams. According to the old psychological stressors could trigger th em, like public speaking, pressured inte dogma, if you had heart disease, you had better worry when you were undergoing physical stress and getting chest someone at risk, trouble is occurring under pains. Now it appears that, for all sorts of circumstances of psychological t even know it. Once the cardiovascular system is da maged, it appears to be stress in everyday life, and you may no immensely sensitive to acute stressors, whether physical or psychological. One last bit of bad news. We've been focusing on the st ress-related consequences of activating the cardiovascular noted earlier, your heart system too often. What about turning it off at the end of each psychological stressor? As the parasympathetic nervous sy stem. Back to the autonomic slows down as a result of activation of the vagus nerve by nervous system never letting you put your foot on the gas and brake at the same time—by definition, if you are turning on the sympathetic nervous system all the time, you're chronically shutting off the parasympathetic. And this makes it harder to slow things down, even during those rare moments when you're not feeling stressed about something. to calm down the cardiovascula How can you diagnose a vagus nerve that's not doing its part r system at the end of a stressor? A clinician could put someone through a stressor, say, run the person on a treadmill, and then monitor the speed of recovery afterward. It turns out that there is a subtler but easie r way of detecting a problem. Whenever you inhale, you turn on the sympathetic nervous system slightly, minutely speeding up your heart. And when you exhale, 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

28 Pa g e 28 of 212 the parasympathetic half turns on, activating your vagus nerve in order to slow things down (this is why many forms of meditation are built around extended exhalations). Theref een heartbeats tends to be ore, the length of time betw shorter when you're inhaling than exhaling. But what if chronic stress has blunted the ability of your parasympathetic nervous system to kick the vagus nerve into action? When you exhale, your heart won't slow down, won't increase the time intervals between beats. Cardiologists use sensitive mo intervals. Large amounts of nitors to measure interbeat variability (that is to say, short interbeat intervals during inhalation, long during exhalation) mean you have strong parasympathetic tone counteracting your sympathetic tone, a good thing. Minimal variability means a parasympathetic component that has trouble putting its foot on the brake. This is th e marker of someone who not only turns on the cardiovascular stress-response too often but, by now, has trouble turning it off. SUDDEN CARDIAC DEATH the cardiovascular system, with each chronic stress will gradually damage The preceding sections demonstrate how en more vulnerable. But one of the mo succeeding stressor making the system ev st striking and best-known features of heart disease is how often that cardiac catastrophe hits during a stressor. A man gets shocking news: his wife has died; he's lost his job; a child long thought to be dead appears at the door; he wins the lottery. The man weeps, rants, exults, staggers about gasping and hyperventilating with the force of the news. Soon afterward, he suddenly grasps at his sudden cardiac arrest. A str chest and falls over dead from ong, adverse emotion like anger doubles the risk of a heart ng the O. J. Simpson trial, Bill Hodgman, one of the attack during the subsequent two hours. For example, duri prosecutors, got chest pains around th ect to something Johnnie Cochran was e twentieth time he jumped up to obj saying, and collapsed afterward (he survived). This sort of cardiac vulnerability to strong emotions has led Las Vegas casinos to keep defibrillators handy. It also is thought to have a lot to do with why exposure to New York City is a risk factor for a fatal heart attack.* The phenomenon is quite well documented. In one study, a physician collected newspaper clippings on sudden He identified a number of ev cardiac death in 170 individuals. ents that seemed to be asso ciated with such deaths: the collapse, death, or thr eat of loss of someone iversity of California blished in 1999 by Nicholas Christenfeld and colleagues at the Un * This is for real, as was reported in a widely cited study pu superb job of ruling out various confounding factors. They show ed that this at San Diego (what, you were expecting NYU?). The authors did a increased risk didn't occur in other urban areas in the country. disease-prone crazies It wasn't due to self-selection (i.e., who but stressed, heart people happening to tion of socioeconomic status, race, ethnicity choose to live in NYC?). It was not a func , or immigrant status. It was not due to get more heart attacks (i.e., commuters during work hours). It wasn't due to New York doctors having a be in NYC at the time of day when people d more disruption of a function of stress, excitement, fear, an eart attacks. Instead, it was most plausibly tendency to mislabel other maladies as h sleep/wake cycles than in most other pla ces. And this was before 9/11. Naturally, li ke all the other native New Yorkers I know, I find this paper to be perversely pleasing and affirming. of an injury, or close; acute grief; loss of status or self-esteem; mourning, on an anniversary; pe rsonal danger; threat recovery from such a threat; triumph or extreme joy. Other studies have shown the same. During the 1991 Persian cardiac death among frightened Gulf war fewer deaths in Israel were due to SCUD missi le damage than to sudden elderly people. During the 1994 L. y a big jump in heart attacks.* A. earthquake, there was similarl The actual causes are obviously tough to study (since you can't predict what's going to happen, and you can't interview the people afterward to find out what they were feeling), but the general consensus among cardiologists is extreme version of acute stress causing ve ntricular arrhythmia or, even worse, that sudden cardiac death is simply an + As you would guess, it involves the sympathetic nervous system, ventricular fibrillation plus ischemia in the heart. can suffer sudden cardiac death and it is more likely to happen in damaged heart tissue than in healthy tissue. People without a history of heart disease and despite increased blood flow in the coronary vessels; autopsies have generally still occur, however, of shown, however, that these people had a fair amount of at herosclerosis. Mysterious cases seemingly healthy thirty-year-olds, victims of sudden car diac death, who show little evidence of atherosclerosis on autopsy. n which, for example, Fibrillation seems to be the cr itical event in sudden cardiac death, as judged by animal studies (i ten hours of stress for a rat makes its heart more vulnerable to fibrillation for days afterward). As one cause, the ble, making it prone to fibrillation. In addition, activation muscle of a diseased heart becomes more electrically excita ecomes disorganized during a massive st tic nervous system of stimulatory inputs to the heart b ressor. The sympathe sends two symmetrical nervous projections to the heart; it is theorized that during extreme emotional arousal, the two that they become uncoordinated—major fibrillation, clutch your chest, keel over. inputs are activated to such an extent * I once received a letter from the chief medi cal examiner of Vermont describing his inve stigation of what he concluded to be a case of stress- beloved tractor, while induced cardiac arrest: an eighty-eight-year-old man with a history of heart disease, lying dead of a heart attack next to his was his eighty-seven-year-old wife, more r ecently dead of a she could have seen him prone in the barn, just outside the house, at an angle where obviously wrong found at autopsy). At her side was the bell she had used to summon heart attack (but with no history of heart disease and nothing him to lunch for who knows how many years. begins to contract in a ra pid, disorganized way that + Don't panic at the jargon. In ventricular fi brillation the half of your heart called the ventricles accomplishes nothing at all in terms of pumping blood. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

29 Pa g e 29 of 212 FATAL PLEASURES Embedded in the list of categories of precipitants of sudden cardiac death is a particularly interesting one: triumph or ario of the man dying in the aftermath of the news of his winning the lottery or the extreme joy. Consider the scen proverbial "at least he died happy" instance of someone dying during sex. (When these circumstances apparently claimed the life of an ex-vice presiden t a few decades back, the medical minuti ae of the incident received especially n because he was not with his wife at the time.) careful examinatio ure seems crazy. Isn't stress-related dis The possibility of being killed by pleas ease supposed to arise from stress? How can joyful experiences kill you in the sa because they share some similar traits. me way that sudden grief does? Clearly erent effects on reproductive physiology, on growth, most probably on the Extreme anger and extreme joy have diff r system, they have fairly si immune system as well; but with regard to the cardiovascula milar effects. Once again, we deal with the central concept of stress physiology in explaining similar responses to being too hot or too cold, a prey or a predator: some parts of our body, including the heart, do not care in which direction we are knocked out of iling and pounding the walls in grief or leaping about and allostatic balance, but rather simply how much. Thus wa another way, your sympathetic nervous rge demands on a diseased heart. Put shouting in ecstasy can place similarly la system probably has roughly the same ef fect on your coronary arteries whethe r you are in the mi ddle of a murderous rage or a thrilling orgasm. Diametrically opposite emo tions then can have surprisingly similar physiological underpinnings (reminding one of the oft-quoted statement by Elie Wiesel, the Nobel laureate writer and Holocaust survivor: "The opposite of love is not hate. The oppo site of love is indifference."). When it comes to the , grief and triumph all represent ch cardiovascular system, rage and ecstasy allenges to allostatic equilibrium. WOMEN AND HEART DISEASE nonetheless the leading cause Despite the fact that men have heart attacks at a higher rate than women, heart disease is of death among women in the United St ,000 deaths a year for breast cancer). ates—500,000 a year (as compared to 40 And the rate is rising among women have been declining for decades. Moreov er, for the same severity of heart while cardiovascular death rates in men as men to be left disabled. attack, women are twice as likely ttack seems to be an epidemiological rate of being disabled by a heart a What are these changes about? The increased fluke. Women are still less subject to heart attacks than are men, with the onset of vulnerability delayed about a decade in women, relative to men. Ther efore, if a man and woman both have h eart attacks of the same severity, the is, she is statistically less likely to ears older than the man. And because of th woman is statistically likely to be ten y bounce back afterward. But what about the increasing incidence of s are likely to be contributing to it. heart disease in women? Various factor heart disease (as discussed in d this increases the risk of Obesity is skyrocketing in this country, more so in women, an the next chapter). Moreover, th they are declining more slowly among ing in the country, ough smoking rates are declin women than men. Naturally, stress seems to have something to do with it as well. Kaplan and Carol Shively have studied female monkeys in dominance hierarchies and observe that animals chronically stuck in subordinate positions have twice the low-fat diet. Findings with a similar theme of social atherosclerosis as dominant females, even when on a period of increasing rates of cardiovascular disease in women corresponds subordination emerge among humans. This to a time when increasing percentages of women are working outside the home. Could the stressfulness of the latter shown that working outside have something to do with the former? Careful studies have the home does not increase cal work. Or has an unsupportive boss. Go sease for a woman. Unless she is doing cleri the risk of cardiovascular di men working outside the home causes a shift toward men figure. And just to show what a myth it is that wo shouldering more of the burden of work at home, the other predictor of cardiovascular disease for women working outside the home is having kids back home. male primates, human or otherwise? The answer is So why does stress increase the risk of cardiovascular disease in fe hetic nervous system arousal, too much secretion of glucocorticoids. But all the usual suspects—too much sympat another factor is relevant, one that is wildly controversial, namely estrogen. edition of this book, estrogen was boring news. People had known for decades that At the time of the previous estrogen protects against cardiovascular di and possibly Alzheimer's disease), sease (as well as stroke, osteoporosis, mostly thanks to estrogen working as an antioxidant, getting rid of damaging oxygen radicals. This explained why women didn't start to get significant am ounts of heart disease until after estrogen levels dropped with menopause. This ogen replacement therapy. for post-menopausal estr was widely known and was one of the rationales 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

30 Pa g e 30 of 212 The importance of estrogen in protectin g against cardiovascular disease came no t just from statistics with human 7, stress causes a decline in will be discussed in chapter populations, but from careful experimental studies as well. As estrogen levels as low as you would find in a monkey estrogen levels, and Kaplan's low-ranking female monkeys had that had had her ovaries removed. In contrast, subject a female to years of subordinance but treat her with estrogen, ears. And remove the ovaries the atherosclerosis risk disapp raising her levels to those seen in dominant animals, and atherosclerosis. Studies like these seemed definitive. of a high-ranking female, and she was no longer protected from Health Initiative, a study of Then in 2002 came a landmark paper, based on the Women's thousands of women. The erapy with estrogen plus post-menopausal replacement th of eight years of goal had been to assess the effects progestin. The expectation was that this was going to be th of the protective effects of e gold-standard demonstration orosis. And five years into it, the codes as to who was such therapy against cardiovascul ar disease, stroke, and osteop ed, and the ethics panel overseeing getting hormone and who placebo were crack the mammoth project brought it to a so clear that it was unethi halt. Because the benefits of estrogen plus progestin were cal to give half the women the risk of heart disease and stroke (while increasing us progestin was so clearly placebo? No—because estrogen pl still protecting against osteoporosis) that it was unethical to continue the study. page news everywhere. Similar trials were halted in Europe. This was a bombshell. Front- Pharmaceutical stocks plummeted. And zillions of perimenopausal women wonde red what they were supposed to do about estrogen replacement therapy. Why such contradictory findings, with year s of clinical statistics and careful laboratory studies on one side, and this e of Kaplan's involv one important factor, studies like thos ed estrogen, while huge and excellent study on the other? As plus progestin. This could well make a big di fference. Then, as an example of the this clinical trial was about estrogen nit-picking that scientists love and which drives everyone else mad, the doses of hormones used probably made a difference, as did the type of estrogen (estradiol versus estriol versus estrone, and synthetic versus natural hormone). Finally, and this is an important point, the laboratory studies suggest that estrogen protects against the formation of atherosclerosis, rather than reverses atherosclero sis that is already there. This is quite relevant because, given our Western diets, people are probably just starting to form atherosclerotic plaques in their thirties, not in their post-menopausal fifties or sixties. The jury is still out on this one. And though it may not turn out that post- e that estrogen secreted by women ovascular disease, it seems plausibl menopausal estrogen protects against cardi themselves at much younger ages does. And stress, by suppressing such estrogen levels, could be contributing to cardiovascular disease through that route. VOODOO DEATH The time has come to examine a subject fa r too rarely discussed in our public schools. Well-documented examples of voodoo death have emerged from all sorts of traditional non-westernized cultures. So meone eats a forbidden food, t or blasphemous. ing unacceptably violen he or she shouldn't have, does someth insults the chief, sleeps with someone The outraged village calls in a shaman who waves some ritualistic gewgaw at the transgressor, makes a voodoo doll, or in some other way puts a hex on the person. Convincingly soon, the hexed one drops dead. The Harvard team of ethnobotanist Wade Davis and cardiologist Regis DeSilva reviewed the subject.* Davis and DeSilva object to the use of the term voodoo death, since it reeks of West ern condescension toward non-Western noting psychophysiological death, ey prefer the term d all that. Instead, th societies—grass skirts, bones in the nose, an that in many cases even that term is some instances, the shaman may spot people who are probably a misnomer. In already very sick and, by claiming to have hexed them, gain brownie points when the person kicks off. Or the shaman may simply poison them and gain kudos for his cursing powers. In the confound (that is, the source of confusion) that in effect, "Voodoo I found most amusing, the sh aman visibly puts a curse on someone, an d the community says, cursing works; this esearch uncovered a of horror movie fans far and wide. As detailed in the reference section, his prior r * Wade Davis is the favorite ethnobotanist possible pharmacological basis of how zombies (people in a death own) are made in Haiti. Davis 's Harvard doctoral like trance with no will of their The Serpent and the Rainbow, and then a schlocky horror movie of the same name—a dissertation about zombification was first turned into a book, distracted committee member or t ed to be skimmed briefly by a student whose thesis is destin dream come true for every graduate wo. person is a goner, so don't waste good food and water on him." The individual, denied food and water, starves to true, the shaman's fees go up. death; another voodoo curse come Nevertheless, instances of psychophysiological death do occur, and they have been the focus of interest of some great physiologists in this century Cannon (the man who came up with the fight-or-flight . In a great face-off, Walter concept) and Curt Richter (a grand old man of psychosomatic medicine) differed in thei r postulated mechanisms of psychophysiological death. Cannon thought it was due to overactivity of the sympathetic nervous system; in that em kicks into gear and vasoconstricts being cursed that the sympathetic syst scheme, the person becomes so nervous at blood vessels to the point of rupturing them, causing a fatal drop in blood pressure. Richter thought death was due to 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

31 Pa g e 31 of 212 too much parasympathetic activity. In this surprising formul ation, the individual, realizin g the gravity of the curse, t down to the point of stopping—death e, slowing the hear gives up on some level. The vagus nerve becomes very activ m." Both Cannon and Richter kept their theories unsullied by never examining due to what he termed a "vagal stor anyone who had died of psychophysiological death, voodoo or otherwise. It turns out that Cannon was probably right. Hearts almost never stop outright in a vagal storm. Inst ead, Davis and DeSilva suggest that these cases are simply sympathetic tone driving the heart into ischemia and dramatic versions of sudden cardiac death, with too much fibrillation. All very interesting, in that it explains why psychophysiological death might occur in individuals who already have some degree of cardiac damage. But a puzz ling feature about psychophysiological death in traditional societies is that y latent cardiac disease. This mystery remains it can also occur in yo ung people who are extremely unlikely to have an ing within us than we ever would have guessed, perhaps unexplained, perhaps implying more silent cardiac risk lurk testifying to the power of cultural belief. As Davis and DeSilva note, if faith can heal, faith can also kill. PERSONALITY AND CARDIAC DISEASE: A BRIEF INTRODUCTION Two people go through the same stressful social situation. Only one gets hypertensive. Two people go through a fe's ups and downs. Only one gets cardiovascular disease. decade's worth of li These individual differences could be due to one person already having a damaged cardiovascular system—for example, decreased coronary blood flow. They could also be due to genetic factors that influence the m echanics of the system—the norepinephrine receptors, and so on. Th lt of differences ey could be the resu elasticity of blood vessels, the numbers of experiences—does the person smoke, eat a diet teeming with saturated fats? in how many risk factors each individual lf the variability in patterns of heart (Interestingly, individual differences in these risk factors explain less than ha disease.) Faced with similar stressors, whether larg e or small, two people may also differ in their risk for cardiovascular disease I will review some of these— how the risk of cardiovascular as a function of their personalities. In chapters 14 and 15 d by clinical depression. The bad news is that these disease is increased by hostility, a Type-A personality, an personality risk factors are substantial in their impact. But the good news is that something can often be done about them. ysis that will dominate This discussion has served as the first ex the coming chapters. In the ample of the style of anal face of a short-term physical emergency, the cardiovascular stress-response is vita l. In the face of chronic stress, those verse effects are particular ly deleterious when they interact with the adverse same changes are terrible news. These ad consequences of too much of a metabolic stre ss-response, the subject of the next chapter. 4 STRESS, METABOLISM, AND LIQUIDATING YOUR ASSETS So you're sprinting down the street with the lion after you. Things looked grim for a moment there, but—your system kicked into gear, good luck—your cardiovascular and now it is delivering oxygen and energy to your energy? There's not enough exercising muscles. But what time to consume a candy bar and derive its benefits as you sprint to digest food already in the along; there's not even enough time gut. Your body must ge t energy from its places of storage, like fat or liver or non-exercising muscle. To understand how you mobilize how that mobilization can make you energy in this circumstance, and 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

32 Pa g e 32 of 212 sick at times, we need to learn ho w the body stores energy in the first place. PUTTING ENERGY IN THE BANK so that they can then be unks of animals and vegetables The basic process of digestion consists of breaking down ch e chunks exactly as they are; transformed into chunks of human. We can't make use of th we can't, for example, make lex food matter is broken muscle we ate. Instead, comp our leg muscles stronger by grafting on the piece of chicken down into its simplest parts (molecules): amino acids (the building blocks of protein), simple sugars like glucose (the building blocks of more complex sugars and of starches [carbohydrates]), and free fatt y acids and glycerol (the constituents of fat). This is s that can degrade more complex molecules. The act by enzymes, chemical accomplished in the gastrointestinal tr simple building blocks thus produced are absorbed into th e bloodstream for delivery to whichever cells in the body use those building blocks to construct the proteins, fats, need them. Once you've done that, the cells have the ability to ness. And just as important, those simp le building blocks (especially the fatty and carbohydrates needed to stay in busi acids and sugars) can also be burned by the body to provide the energy to do all that construction and to operate those new structures afterward. Your bloodstream is teeming with amino acids, fatty acids, It's Thanksgiving, and you've eaten with porcine abandon. glucose. It's far more than you need to power you over to the couch in a pos does your body do tprandial daze. What with the excess? This is crucial to understand because, basi cally, the process gets reversed when you're later sprinting for your life. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

33 Pa g e 33 of 212 To answer this question, it's time we talked finances, the works-savings acco unts, change for a dollar, stocks and s— because the process of transporting rates, shaking coins out of piggy bank bonds, negative amortization of interest energy through the body bears some striking similarities to the movement of money. It is rare today for the grotesquely wealthy to walk aro und with their fortunes in their pockets, or to hoard their wealth as cash stuffed inside mattresses. Instead, surplus wealth is al funds, tax-free lex than cash: mutu stored elsewhere, in forms more comp government bonds, Swiss bank accounts. In the same way, surplus energy is not kept in the body's form of cash— Enzymes in fat cells can ed in more complex forms. circulating amino acids, glucose, and fatty acids—but stor ). Accumulate enough of these in the triglycerides (see the table on page 60 combine fatty acids and glycerol to form stick series of glucose molecules together. These long fat cells and you grow plump. Meanwhile, your cells can Most glycogen formation occurs in your glycogen. chains, sometimes thousands of gl ucose molecules long, are called muscles and liver. Similarly, enzymes in cells throughout the body can combine long strings of amino acids, forming them into proteins. es the transport and storage of these building bloc ks into target cells is insulin. Insulin is The hormone that stimulat . Eat a huge meal and insulin pours out of the pancreas this optimistic hormone that plans for your metabolic future ulating glycogen and protein synthesis. into the bloodstream, stimulating the tran sport of fatty acids into fat cells, stim It's insulin that's filling out the deposit slips at your fat banks. We even secrete insulin when we are about to fill our ve building blocks: if ock, by five forty-five you're you eat dinner each day at six o'cl bloodstream with all those nutriti already secreting insulin in anticipation of the rising gl ucose levels in your bloodstream. Logically, it is the imulates the anticipatory s ecretion, and this ability parasympathetic nervous system that st to secrete insulin in the anticipatory quality of allostatic e about to rise is a great example of preparation for the glucose levels that ar balance. What you stick in your How it gets stored if you How it gets mobilized in How it winds up in your stressful emergency have a surplus bloodstream mouth > Proteins— Protein— Amino acids > Amino acids—> Starch, sugars, Glucose Glycogen—> Glucose—> > carbohydrates — Fatty acids and glycerol— Fatty acids, glycerol, ketone Fat—> Triglycerides —> bodies > EMPTYING THE BANK ACCOUNT: ENERGY MOBILIZATION DURING A STRESSOR This grand strategy of breaking your food down into its simplest parts and reconverting it into complex storage forms is precisely what your body should do when you've eaten plenty. And it is precisely what your body should do in not ergy storage. Turn up the activity of the the face of an immediate phys ical emergency. Then, you want to stop en sympathetic nervous system, turn down the parasympathetic, a nd down goes insulin secreti on: step one in meeting an emergency accomplished. ll. With the onset of the stressful The body makes sure that energy storag e is stopped in a second way as we sport of nutrients into fat cells. This counteracts the emergency, you secrete glucocorticoids, which block the tran effects of any insulin still floating around. So you've made sure you don't do anything as irrational as store away new energy at this time. But in addition, you want your body to gain access to the energy already stored. You want to dip into your bank account, liquidate some of your assets, turn stored nutrients into your body's equivalent of cash to get you through this crisis. Your body reverses all of the storage steps through the release of the stress hormones glucocorticoids, glucagon, epinephrine, and norepinephrine. These cause tr iglycerides to be broken down in the fat ce lls and, as a result, free fatty acids and glycerol pour into the circulatory system. The same hormones trigger the degradation of glycogen to glucose in cells throughout the body, and the glucose is then flushed into the bloodstream. These hormones also cause protein in non- exercising muscle to be converted back to individual amino acids. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

34 Pa g e 34 of 212 The stored nutrients have now been converted into simpler forms. Your body makes another simplifying move. Amino acids are not a very good source of energy, but glucose is. Your body shunts the circulating amino acids to the gluconeogenesis, rate new glucose, a process called glucose. The liver can also gene liver, where they are converted to and this glucose is now readily available for energy during the disaster. As a result of these processes, lots of There's a burst of act ivity; you leave the energy is available to your leg muscles. lion in the dust and arrive at the restaurant only a smidgen late for your five forty-five anticipatory insulin secretion. cally a strategy to shunt energy from storage sites like fat to muscle during an The scenario I've been outlining is basi cally fuel, say, your arm muscles while you're running emergency. But it doesn't make adaptive sense to automati away from a predator if you happen to be an upright human. It turns out that the body has solved this problem. Glucocorticoids and the other hormones of the stress-response also act to block energy uptake into muscles and into gency have a means to override this fat tissue. Somehow the individual muscle s that are exercising during the emer blockade and to grab all the nutrients floating around in the circulation. The net result is that you shunt energy from fat and from non-exercising muscle to the exercising ones. disease, where people cannot what occurs in Addison's And what if you can't mobilize energy during a crisis? This is secrete adequate amounts of glucocorticoids, or in Shy- Drager syndrome, where it is epinephrine and norepinephrine that are inadequate, having an inability to mobilize the body during energetic demands. Obviously, the lion is more likely to feast. And in a more subtle scenario, if you li ve in a westernized society and tend to have a somewhat underactive stress-response? Just as obviously, you'll have trouble mobilizing energy in response to the demands of which is characterized by, daily life. And that is precisely what is seen in individuals with chronic fatigue syndrome, among other things, too low levels of glucocorticoids in the bloodstream. SO WHY DO WE GET SICK? You most definitely want to have a metabolic stress-response if you're evading a lion, and even if you are doing anything as taxing as walking up a flight of stairs (or even getting up in the morning, the time of day when our glucocorticoid levels normally peak). But what about the more typical scenario for us, one of turning on the stress-response too often, for months on end? We get into metabolic trouble for many of the same reasons that consta ntly running to the bank and drawing on your account is a foolish way to handle your finances. On the most basic level, it's inefficien t. Another financial metaphor helps. Suppose you have some extra money and decide to put it away for a while in a high-interest account. If you agree not to touch the money for a certain period ), the bank agrees to give you a higher-than-normal rate of interest. And, typically, if (six months, two years, whatever you request the money earlier, you will pay a penalty for the early withdrawal. Suppose, then, that you happily deposit ncial jitters, withdraw your money, and pay the penalty. your money on these terms. The next day you develop the fina The day after, you change your mind again, put the money back in, and sign a new agreement, only to change your nother penalty. Soon you've squandered half your money on mind again that afternoon, withdraw the money, and pay a penalties. In the same way, every time you store en n and then return it, you lose a fair chunk of the ergy away from the circulatio , to power the enzymes that s in and out of the bloodstream potential energy. It takes energy to shuttle those nutrient glue them together (into proteins, triglycerides, and glycoge then break them apart, to n) and the other enzymes that ect, you are penalized if you activate the stress-response too fuel the liver during that gluconeogenesis trick. In eff often: you wind up expending so much energy that, as a first consequence, you tire more readily—just plain old everyday fatigue. As a second consequence, your muscles can waste away, alth ough this rarely happens to a significant degree. Muscle is chock-full of proteins. If you are stressed chronically, constantly triggering the breakdown of proteins, your muscles ates this component of each time your body activ atrophy ever so slightly never get the chance to rebuild. While they the stress-response, it requires a really ex traordinary amount of stress for this to happen to a serious extent. As we will see in later chapters, sometimes clinicians give patients ma ssive doses of synthetic glucocorticoids. In this scenario, similar to that seen in people who are significant amounts of myopathy — atrophy of muscle—can occur, of a type bedridden for long periods. at in the last chapter. Finally, another problem with constantly mobilizing the meta bolic stress-response was hinted d glucose perpetually circulating in your You don't want to have tons of fat an bloodstream because, as we saw, that omming on to some damaged blood vessel and worsening atherosclerosis. increases the chances of the stuff gl Cholesterol also plays into this. As is well understood, there ein-associ-ated cholesterol (L DL) and "good" cholesterol is "bad" cholesterol, also known as low-density lipoprot LDL-cholesterol is the type that gets added to an (high-density lipopro-tein-associated cholesterol, HDL). 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

35 Pa g e 35 of 212 atherosclerotic plaque, whereas HDL-chol esterol is cholesterol that has been removed from plaques and is on its way tion, your total level of cholesterol in the bloodstream is not to be degraded in the liver. As a result of this distinc type you have, and lo ts of LDL and minimal to know how much of each actually a meaningful number. You want inflammation, as measured that the amount of vascular HDL are independently bad news. We saw in the last chapter ar disease risk. Nonetheless, you don't want to have tons by CRP levels, is the best predictor out there of cardiovascul of LDL-cholesterol floating around and not enough HDL to counteract it. And during stress, you increase LDL- cholesterol levels and decrease HDL.* Therefore, if you are stressed too often, the metabolic f can increase your risks of eatures of the stress-response rticularly relevant with diabetes. cardiovascular disease. This becomes pa JUVENILE DIABETES The first is known as juvenile diabetes (or There are multiple forms of diab etes, and two are relevant to this chapter. r reasons that are just being sorted ou type 1, insulin-dependent diabetes). Fo t, in some people the immune system reign invaders and attacks them (such that secrete insulin are, in fact, fo decides that the cells in the pancreas "autoimmune" diseases will be discussed in chapter 8). This destroys those cells, leaving the person with little ability to secrete insulin. For equally mysterious reasons, this tends to hit people relatively early in life (hence the "juvenile" e mystery, in recent decades, the rate at which adults, even middle-aged adults, part of the name) although, to add to th are getting diagnosed with juvenile diabetes is climbing. ability to promote the Because the person can no longer secrete adequate amounts of insuli n (if any), there is little uptake of glucose (and, indirectly, fatty acids) into target cells. Cells starve—big trouble, t a good sign if, for t LDL levels because of frequent stressors * So it can be bad news to frequently boos . But, independent from that, it is also no large any given stressor, you have a particularly g of people with heart disease tend to have LDL increase. Studies have shown that the offsprin ress, suggesting a vulnerab ility factor that has been passed on to them. atypically large LDL responses to st ght. In addition, there's now all that glucose and fatty acid circulating in the not enough energy, organs don't function ri oodlums with no place to go, bloodstream-oleaginous h c trouble there as well. The and soon there's atheroscleroti same can occur in the eyes, causing them to fail. The circulating stuff gums up the blood vessels in the kidneys, causing blindness. Blood vessels elsewhere in the body are clogged, causing little strokes in those tissues and, often, chronic pain. With enough glucose in the circulation, it begins to stick to proteins, begins to Velcro proteins together that have no business being connected, knocking them out of business. None of this good. odating that dependency And what is the best way to manage insulin-dependent diabetes? As we all know, by accomm your insulin levels to get too low—cells are deprived of with insulin injections. If you're diabetic, you never want want to take too much insulin. For complex reasons, this energy, circulating glucose levels get too high. But you don't deprives the brain of energy, potentially putting you into shock or a coma and damaging neurons. The better the ectancy. Thus, there's a major and the longer the life exp metabolic control in a diabetic, the fewer the complications keep food intake and insulin dos task for this type of diabetic to keep things just right, to ages balanced with respect to logical progress enabling been extraordinary techno an area where there has activity, fatigue, and so on. And this is diabetics to monitor blood glucose levels minute by minute and make minuscule changes in insulin dosages accordingly. How does chronic stress affect th is process? First, the hormones of the st ress-response cause ev en more glucose and bloodstream. For a juvenile diabetic, this increases the likelihood of the now- fatty acids to be mobilized into the in the wrong places. tty acids gumming up familiar pathologies of glucose and fa Another, more subtle problem occurs with chronic stress as well. When something stressful happens, you don't just block insulin secretion. Basically, the brai n doesn't quite trust the pancreas not to keep secreting a little insulin, so a second step occurs. As noted earlier, du ring stress, glucocorticoids act on fat cells throughout the body to make them around. Fat cells then rel ease some newly discovered less sensitive to insulin, just in case there's some still floating stop responding to insulin as well. Stress promotes insulin hormones that get other tissues, like muscle and liver, to this diabetic state because they ar resistance. (And when people get into e taking large amounts of synthetic glucocorticoids [to control any of a variety of diseases that will be discussed later in the book] they have succumbed to "steroid diabetes.") ey have everything nice and Why is this stress-induced insulin resistance bad for someon e with juvenile diabetes? Th good sensitivity to their body's signals as to when a little insulin needs to be injected, balanced, with a healthy diet, a and so on. But throw in some chronic stress, and suddenly insulin doesn't work quite as well, causing people to feel of the stuff... which can make cells even more resistant to terrible until they figure out that they need to inject more riod of stress is over with, at which point it's not clear insulin, spi-raling the insulin requirements upward ... until the pe sulin sensitivity at when to start getting the insuli n dose down ... because different parts of the body regain their in nced system is completely upended. different rates... The perfectly bala 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

36 Pa g e 36 of 212 Stress, including psychological stress, can wreak havoc wi th metabolic control in a juvenile diabetic. In one demonstration of this, diabetics were exposed to an experimental stressor (speaking in public) and their glucocorticoid ose circumstances were the rgest stress-response under th secretion was monitored. Those who tended to have the la es well controlled. Moreover, in related studies, those who had the strongest ones least likely to have their diabet emotional reactions to an experimental stressor tended to have the highest blood glucose levels. eful studies have shown higher rates of major stressors suffered by people Stress may sneak in another way. Some car by chance. Does this mean during the three years before the onset of their juvenile diab etes than would be expected more likely to attack the pancreas? Th that stress can make the immune system ere is a little bit of evidence for this, ound the fact that once the likely explanation is built ar which will be discussed in chapter 8 on immunity. A more once the diabetes has started), it takes a while before the immune system begins to attack the pancreas (that is, stress can speed up the whole process, symptoms become apparent. By having al l the adverse effects just talked about, making the person notice sooner that he or she is just not feeling right. crease the odds of getting juve nile diabetes, accelerate the Thus, frequent stress and/or big stress-responses might in development of the diabetes, and, once it is established, cause major complicati ons in this life-shortening disease.* Therefore, this is a population in which successful stress management is critical. r attempt to keep the disease under contro abetes is often occurring * A major challenge for diabetologists in thei l in their patients is that juvenile di getting enough sleep. skipping meals, not in juveniles who stress their system by beha ving in ways that are, well, juvenile. Ea ting the wrong things, A major management headache. ADULT-ONSET DIABETES In adult-onset diabetes (type 2, non-insulin-dependent diabetes ), the trouble is not too little insulin, but the failure of diabetes. The problem here resistant respond the cells to to insulin. Another name for the disorder is thus insulin- arises with the tendency of many people to put on weight as they age. (However, if people do not put on weight as ed risk of this disease. This is the case among people in non-westernized populations. they age, they show no increas ity and fat surplus, conditions stead, it is a disease of inactiv a normal feature of aging; in The disease is not, therefore, that just happen to be more common with t stored away, the fat cells essentially age in some societies.) With enough fa get full; once you are an adolescent, the number of fat cells you have is fixed, so if you put on weight, the individual fat cells are distended. Yet another heav y meal, a burst of insulin trying to prom ote more fat storage by the fat cells, sulin; we're completely full." No room at the inn. The luck, I don't care if you are in and the fat cells refuse—"Tough fat cells become less responsive to insulin trying to promote more fat storage, and less glucose is taken up by these release hormones that trigger other fat cells and muscle into becoming insulin cells.* The overstuffed fat cells even resistant. e source of the trouble in the Do the cells now starve? Of course not, the abundant amounts of fat stored in them was th ecause of all that circulating glucose and fatty acids, damaging blood vessels. first place. The body gets into trouble b Same old problem. And if the adult-onset diabetes goes on for a while, an additional, miserable development can occur. Your body has become insulin-resistant. Your pancr eas responds by secreting even more insulin than usual. as pumping out ever higher You're still resistant. So th e pancreas secretes even more . Back and forth, your pancre levels of insulin, trying to be heard. secreting cells in the pancreas, actually Eventually, this burns out the insulin- destroying them. So you finally get your adult-onset diabetes under control, thanks to losing weight and exercising, and you discover you've now got juvenile diabetes, thanks to that damage to your pancreas. * The careful reader may be confused at this point—if insulin regulates glucose uptake, why does it influence the amount of fat being stored in fat es requires glucose cells? For immensely complex reasons that I once understood for a few hours for a fina l exam, the storage of fat as triglycerid uptake. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

37 Pa g e 37 of 212 Photomicrograph of bloated fat cells. How does chronic stress affect n, constantly mobilizing glucose and fatty acids into adult-onset diabetes? Once agai the bloodstream adds to the atherosclerotic glomming. And there's that problem of the stress-response involving your fat cells being instructed to become less responsive to insulin. Suppose that you're in your sixties, overweight, and just chronic stress with those stre on the edge of insulin resistance. Along comes a period of ss hormones repeatedly telling your cells what a great idea it is to be insulin-resistant. Enough of this and you pass the threshold for becoming overtly diabetic. worldwide epidemic of adul ion to? Because there is a t-onset diabetes going on, Why is any of this worth paying attent ve had adult-onset diabetes. of Americans over age sixty-fi especially in our country. As of 1990, about 15 percent then. As of a decade later, there's been a 33 percen t increase above that, and That was considered a health disaster ng is suddenly hitting far younger people as well—in the among middle-aged adults as well. And this disease of agi In addition, so mething like 20 g thirty-year-olds. crease in its incidence amon last decade, there's been a 70 percent in million Americans are "pre-diabetic"—b arreling toward a formal diagnosis. Ad ult-onset diabetes has even become more prevalent among kids than juvenile diabetes, which is pretty horrifying. Moreover, as people in the developing world are first being exposed to westernized diets, not only do they develop faster rate than do westerners, for reasons cultural and genetic. diabetes, they develop it at a that are probably both This once nonexistent disease afflicts an estimated 300 mi llion people worldwide and killed 200,000 Americans last year. ession that everyone spe What's this about? It's obvious. Despite the impr nds their days eating low- fat/carb/cholesterol/cardboard diets and power walking uphill while loudly reciting the writings of Atkins or Ornish, with each passing year, we are eating mo re food—more junk food—and exercising less. Tw enty percent of Americans s 44 percent then). To ent are "overweight" (versu rcent in 1990), and 54 perc are now technically "obese" (versus 12 pe er, prosperity has become a cause of death.* paraphrase the allostasis theorist Joseph Ey METABOLIC SYNDROME/SYNDROME X e's a whole set of things that can go wrong in you In the well-entrenched tradition of medi cal compartmentalizing, ther that would get you sent to a cardiologist, whereas a bunch of different problems would get you turfed to an internal with each other now and then. What es. With any luck, they'd even confer medicine doc who specializes in diabet should be obvious over the last two chapters is that cular systems are intimately your metabolic and cardiovas yndrome" (also known as Syndrome X) is a new term recognizing this interconnection. interconnected. "Metabolic s It's actually not so new, having been formalized in the late 1980s by Gerald Reaven of Stanford University. It's just few years (so trendy that it's even b een described in a population of wild become tremendously trendy in the past baboons who forage through the desserts in a garbage dump at a tourist lodge in East Africa). es gaining all this Cannon, none of this makes sense: "What's the deal with our bodi * If you learned your physiology sitting on the knee of Walter weight, what happened to that 'Wisdom of the body' business?" you would ask. Peter Ster ling points out that if the body worked by classical imple regulatory homeostatic principles of low-leve l, local feedback control, adult-onset diabetes shouldn't exist. It would be avoided with a s hungry. But it doesn't w issue—put on a certain amount of weight and fat cells tell appetite centers in the brain to stop being ork that way—as we collectively keep putting on more there is a lot more to erling points out the allo-static fact that weight, we collectively keep getting hungrier. St regulating appetite than simply how s of higher level factors, including numerous so cietal ones, tend to much fat you have stored, and that all sort ppetite. This will be returned to in chapter 16. override the efforts of fat cells to decrease a 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

38 Pa g e 38 of 212 Make a list of some of the things that can go wrong from th e last two chapters: elevated insulin levels in the blood. LDL-cholesterol. resistance. Too much lic and diastolic blood pressure. Insulin Elevated glucose levels. Elevated systo Suffer from a subset of thes Too little HDL. Too much fat or cholesterol in the blood. e, and you've got Metabolic syndrome (the formal diagnosis involves "one or more" from a list of some of these problems, and "two or more" from a list of the others).* The syndrome-ness is a way of st ating that if you have a subset of those symptoms, you're em, since they're all one or probably heading toward the rest of th two steps away from each other. Have elevated etty good you're going to get insulin resistance. insulin levels, low HDL, and abdominal obe sity and the chances are pr Elevated LDL-cholesterol, high blood pressure, and insulin resistance, and you're likely to be obese soon. Another bunch and they predict hypertension. ely predict major disease outcomes, like only predict each other, they collectiv Subsets of these clusters of traits not and mortality rates. This was shown with particul ar subtlety in an impressive study carried out heart attacks or stroke, by a team headed by Teresa Seeman of UCLA. Medicine normally works in diagnostic categories: have glucose levels above X, and it's official, you have hyperglycemia. Have blood pressure levels above Z, you're hypertensive. But how about if your glucose levels, blood pressure, HDL-cholesterol, and so on, are all in the normal range, but all of them are getting near the r words, no measure is abnormal, but there's an edge of where you have to start worrying? In othe wrong, amid it being obvious abnormally large number of meas ures that are almost abnormal. Technically, nothing is that things are not right. Take more than a thousand study none of whom are certifiably subjects, all over age seventy, w, see how they're doing on all those hose measures are technically abnormal. No sick—that is to say, where none of t row in some other measures as well—inclu ding resting levels of glucocorticoids, Metabolic syndrome measures. Th and, collect ively, this epinephrine, norepinephrine. Combine the insights into th ese measures mathematically information was significantly predictive of who was going to have heart disease, a decline in cognitive or physical functioning, and mortality, far more predictive than subsets of those variables alone. concept, of keeping things This is the essence of that "allostasis" in balance through interactions among different, far- flung systems in the of use there doesn't seem to be a consensus, as far as I can tell, as to which are the exact set * I'm being a bit vague here beca symptoms to choose from to diagnose Metabolic syndrome. body. This is also the essence of the w " a formal demonstration that even if ear-and-tear concept of allostatic "load, there's no single measure that's certifiably wrong, if there are enough things that are not quite right, you're in trouble. of what stress does. No single disastrous effect, no lone And, as the final, obvious point, this is also the essence that a bit less effective. gunman. Instead, kicking and poking and impeding, here and th ere, make this a bit worse, Thus making it more likely for the roof to cave in at some point. 5 ULCERS, THE RUNS, AN D HOT FUDGE SUNDAES Not having enough food or water definitely counts as a stressor. If you're a human, having enough food and water for this meal, but not being sure where the next meal is coming from is a ma jor stressor as well, one of the defining experiences of life outside the westernized world. And not to eat to the point of starvation—anorexia—is choosing odd endocrine signature, harking a stressor as well (and one with an ticoids tend to be elevated while the back to chapter 2, in that glucocor sympathetic nervous system is unexpectedly inhibited). None of this is stress changes eating patterns. This surprising. Nor is it surprising that 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

39 Pa g e 39 of 212 is well established. The questi on, of course, is in what way. STRESS AND FOOD CONSUMPTION rms of appetite. You're the zebra running for perfectly obvious where we're heading in te From the previous chapter it's your life, don't think about lunch. That's the reason why we lose our appetites when we'r e stressed. Except for those of way. And those who claim they're not in sight, in a mindless mechanical us who, when stressed, eat everything hungry, are too stressed to eat a thing, and just happen to ni bble 3,000 calories' worth of food a day. And those of us thing. Except for chocolate-choc who really can't eat a olate chip hot fudge sundaes. With whipped cream and nuts. (eating more) and the rest hyperphagic makes about two-thirds of people The official numbers are that stress Weirdly, when you stress lab rats, you get the same confusing picture, where some become hyperphagic, hypophagic* alter appetite. Which doesn't teach us a others hypophagic. So we can conclude wi th scientific certainty that stress can whole lot, since it doesn't tell us wh ether there's an increase or decrease. It turns out that there are ways to explain why some of us become hyper- and others hypophagic during stress. To unter. During the stresso r, appetite and energy cenario to the point of it surviving its enco start, we extend the zebra s storage were suppressed, and stored energy was mobilized. Thus, what's th e logic during the post-stress period? Obvious—recover from that, reverse th ose processes. Block the energy mobilization, store the nutrients in your bloodstream, and get more of them. Appetite goes up. eally elegant. The This is accomplished through some endocri nology that is initially fairly confusi ng, but is actually r imulates appetite, while another inhibits it. the critical hormones of the stress-response st confusing issue is that one of er chapters that the hormone CRH is released by the hypothal You might recall from earli amus and, by stimulating the adrenal release of glucocorticoids. Evolution ts the cascade of events that culminates in pituitary to release ACTH, star emical messengers, and CRH is has allowed the development of efficient use of the body's ch no exception. It is also used in parts of the brain to regulate other features of the stress-response. It helps to turn on the sympathetic nervous increasing vigilance and arousal during stress. It also suppresses system, and it plays a role in appetite. (Unsuccessful dieters should be warned against running to the neighborhood pharmacist for a bottle of CRH. It will probably help you lose weight, but you'll feel awful—as if you were always in the middle of an anxiety-provoking emergency: your l, irritable. Probably better to just opt for a few more sit-ups.) heart racing; feeling jumpy, hyposexua On the other side of the picture are glucocorticoids. In addition to the actions already outlined in response to stress, they appear to stimulate appetite. This is typically demonstrated in rats: gl ucocorticoids make these animals more willing to run mazes looking fo r food, more willing to press a lever fo r a food pellet, and so on. The hormone stimulates appetite in humans as well (although, to my knowledge, no one so develop a specific craving for carbohyd * The jury remains out as to whether the folks who become hyperphagic after stress al rates. Clinical lore lly easier to eat than there's a problem here, which is that high-carb foods are typica me laboratory studies. However, supports this picture, as do so be snacks. So it's not clear if people really get a craving for carbohydrates, or if t low-carb foods, since the former tend to hey get a craving for easy, mindless eating. antified them scurrying up and down supermarket aisles). has stoked human volunteers on glucocorticoids and then qu Scientists have a reasonably good idea where in the brain glucocorticoids stimulate appetite, which type of are involved, and so on.* What is glucocorticoid receptors ocorticoids don't just stimulate really fascinating is that gluc erentially for foods that are st archy, sugary, or full of fa appetite—they stimulate it pref t—and we reach for the Oreos and not the celery sticks. + Yet they are both Thus, we appear to have a problem here. CRH inhibits appetite, glucocorticoids do the opposite. e is a burst of CRH hormones secreted during stress. ssful event occurs, ther Timing turns out to be critical. When a stre fteen seconds to go up, while it takes many minutes for secretion within a few seconds. ACTH levels take about fi glucocorticoid levels to surge in the bloodstream (dependi ng on the species). Thus, CRH is the fastest wave of the so seen in the speed at which these t. This difference in time course is al adrenal cascade, glucocorticoids the slowes hormones work on various parts of the body. CRH makes its effects felt within seconds, while glucocorticoids take minutes to hours to exert their actions. Finally, when the st ressful event is over, it takes mere seconds for CRH to be hours for glucocorticoids to be cleared. cleared from the bloodstream, while it can take Therefore, if there are large amounts of CRH in your bloodstream, yet almost no glucocorticoids, it is a safe bet that ressful event. Good time to turn off ap petite, and the combination of high CRH you are in the first few minutes of a st s accomplishes that. and low glucocorticoid Next, if there are large amounts of CRH and glucocorticoids in the bloodstream, you are probably in the middle of a d. You can pull this off only if the appetite-suppressing sustained stressor. Also a good time to have appetite suppresse ppetite-stimulating effects of glucocorticoids. And that's exactly how it works. effects of CRH are stronger than the a 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

40 Pa g e 40 of 212 Finally, if there are substantial amounts of glucocorticoids in the circulation but little CRH, you have probably started the recovery period. That's exactly when digestion starts up again and your body the brain to decrease d hormone called leptin. Very full fat cells * The effect involves a recently discovere secrete a lot of leptin, which works in ng people leptin was of pharmaceutical companies thinking that givi appetite. This fact caused entrep reneurial hysteria a while back, with all sorts worked, for some r going to be the perfect diet drug. Hasn't eason. In any case, glucocorticoids make the brain less sensitive t o leptin, blunting its satiation signal. So you eat more. + ss, also increase appetite, but we're go Beta-endorphins, released during stre ing to ignore that for the moment. Appetite is stimulated. In can begin to replenish those stores of energy consumed in th at mad dash across the savanna. chapter 4, we saw how glucocorticoids help to empty out the bank account of stored energy during a stressor. In this recovering ress-response, but as the means of ch serve as the mediator of the st case, glucocorticoids would not so mu from the stress-response. Things now begin to make sense when you consider both the duration of a stressor and the recovery period combined. mal signal to secrete CRH, AC TH, and glucocorticoids is Suppose that something truly stressful occurs, and a maxi initiated. If the stressor ends after, sa y, ten minutes, there will cumulatively be perhaps a twelve-minute burst of CRH ear the CRH afterward) exposure (ten minutes during th e stressor, plus the seconds it takes to cl and a two-hour burst of exposure to glucocorticoids (the roughly eight minutes of secretion during the stressor plus the much longer time to oid levels are high and thos clear the glucocorticoids). So the period where glucocortic e of CRH are low is much A situation that winds up stimulating appetite. longer than the period of CRH levels being high. In contrast, suppose the stressor lasts for days, nonstop. In other words, days of elevated CRH and glucocorticoids, followed by a few hours of high glucocorticoids and low CRH, as the system recovers. The sort of setting where the most likely outcome is suppression of appetite. hyper- or hypophagia. Take so The type of stressor is key to whether the net result is me crazed, maze-running rat of a human. He sleeps through the alarm clock first thing in the morning, total panic. Calms down when it looks like the after all. Gets panicked al commute isn't so bad today, maybe he won't be late for work l over again when the commute e boss is away for the day and she didn't notice he was late. then turns awful. Calms down at work when it looks like th Panics all over again when it becomes clear the boss is there and did notice. So it goes throughout the day. And how would that person describe his life? "I am like, SO stressed, like totally, nonstop stressed, 24/7." But that's not really like totally nonstop stressed. Take a whole body burn. That's like totally nonstop stressed, 24/7. What this first person lly in that scenario? Frequent stressors. And what's going on hormona frequent intermittent is actually experiencing is ed from the bursts of CRH release through ticoids are clear e slow speed at which glucocor out the day. As a result of th ticoid levels are close to n circulation, elevated glucocor onstop. Guess who's going to be scarfing up Krispy Kremes all day at work? So a big reason why most of us become hyperphagic during stress is our westernized human capacity to have intermittent psychological stressors throughout the day. The type of stressor is a big factor. Another variable that helps predict hyperphagia or hypophagia during stress is how your body responds to a particular a session on an exercise stressor. Put a bunch of subjects through the same experime ntal stressor (for example, bicycle, a time-pressured set of math questions, or having to speak in public) and, not surprisingly, not everyone secretes the exact same amount of gluc ocorticoids. Furthermore, at the end of the stressor, everyone's glucocorticoid levels don't return to baseline at the same rate. The sources of these individual differen ces can be psychological—the and no big deal for another. experimental stressor may be an utter misery for one person Differences can also arise from physiology—one person's liver may be pokier at breaking down glucocorticoids than the next person's. Elissa Epel of UCSF has shown that the glucocorticoid hyper-secreters are the ones most likely to be hyperphagic period, they also atypically after stress. Moreover, when given an array of foods to choose from during the post-stress crave sweets. This is an eff ect that is specific to stress. The people wh o secrete excess glucocorticoids during stress eir resting, non-stressed levels of ects in the absence of stress, and th don't eat any more than the other subj glucocorticoids aren't any higher than the others. What else separates the stress hyperphagics from the stress hypo-phagics? Some of it has to do with your attitude toward eating. Lots of people eat not just out of nutritional need, but out of emotional need as well. These folks tend ere's a fascinating literature concerning the majority of us, both to be overweight and to be stress-eaters. In addition, th for whom eating is a regulated, disciplined task. At any given point, about two-thirds of us are "restrained" eaters. These are people who are actively trying ements like, "In a typical meal, I'm to diet, who would agree with stat conscious of trying to restrict the amount of food that I consume." Mind you, these are not people who are necessarily overweight. Plenty of heavy people are not dieting, plenty of everyone else is at any point. Restrained eaters are actively restricting their food intake. What the studies consistently show is that during stress, people who are normally an others to become hyperphagic. restrained eaters are more likely th 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

41 Pa g e 41 of 212 This makes lots of sense. Things are a bit stressful—cor porate thugs have looted your retirement savings, there's anthrax in the mail, and you've realized that you hate how your hair looks. That's exactly the The Sin of Gluttony, Mark Daughhetee, oil on silver print, 1985. time when most people decide that, as a coping device, as a means of be ing nice to themselves during a tough time, they need to ease up on something abou t which they're normally pretty regimented. So if you normally force yourself Survivor XII. instead of reality TV as some sort of gesture of self-improvement, on goes Masterpiece Theater to watch And if it's food intake that you're normally regimented about, out come the fudge brownies. appetite, and this has something to do with the type and So we differ as to whether stress stimulates or inhibits our pattern of stressors, how reactive our glucocorticoid system is to stress, and whether eating is normally something that also differ as to how readily we store food away after a we keep a tight, superegoish lid on. It turns out that we where stressor. And in the body we store it. APPLES AND PEARS means to recover from the stress-response, also Glucocorticoids not only increase appeti te but, as an additional during that mad dash across the savanna, and you're od. Mobilize all that energy increase the storage of that ingested fo going to have to do a lot of energy storage during your recovery period. In order to have this effect, glucocorticoids trigger fat cells to make an enyzme that breaks down the circulating nutrients in to their storage forms, ideal fo r storing them for next winter. orticoids stimulate. Time for one of the great dichotomies revered by fat cell It's not just any fat cells that glucoc dominal area, around your belly, are known as "visceral" fat. Fill up those fat aficionados: fat cells located in your ab cells with fat, without depositing much fat elsewhere in your body, and you take on an "apple" shape. In contrast, fat cells around your rear end form "gluteal" fat. Fill those up preferentially with fat and you take on a "pear" shape, being round-bottomed. The fo rmal way to quantify these different types of fat deposition is to measure the circumference of your waist (which tells you about the amount of abdominal fat) and the circumference of your hips (a measure of gluteal fat). Apples have waists that are bigger than hips, producing a "waist-hip ratio" (WHR) that hips that are bigger than waists, pr oducing a WHR that is less than 1.0. is bigger than 1.0, while pears have It turns out that when glucocorticoids stimulate fat deposi tion, they do it preferentially in the abdomen, promoting fat cells are more sensitive ttern arises because abdominal apple-shaped obesity. This ev en occurs in monkeys. The pa glucocorticoids by to glucocorticoids than are gluteal fat cells; the former have more recep tors that respond to ids only do this in the presence of high insulin levels. activating those fat-storing enzymes. Furthermore, glucocortico es it mean if you have high glucocorticoid levels and low insulin levels in And once again, this makes sense. What do the bloodstream? As we know from chapter 4, you're in the middle of a stressor. High glucocorticoids and high recover from the grassland sprint. phase. Pack away those calories to insulin? This happens during the recovery 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

42 Pa g e 42 of 212 This stimulation of visceral fa t deposition by glucocorticoids is not good news . This is because if you have to pack on a pear, not an apple. As we saw in the chapter on metabolism, lots of fat is a some fat, you definitely want to become ictor of trouble than being predictor for Syndrome X. But it turns out that a large WHR is an even better pred overweight is. Take some extremely ap plish people and some very peary ones. Match them for weight, and it's the r reasons, this is probably because fat tabolic and cardiovascular disease. Among othe apples who are at risk for me readily finds its way to the liver (in contrast to fat from gluteal fat stores, released from abdominal fat cells more which gets dispersed more equally throughout the body), where it is converted into glucose, setting you up for and insulin resistance. elevated blood sugar for the same stressor, if you tend to secrete more These findings lead to a simple prediction, namely that glucocorticoids than most, not only are you going to have a bigger appetite post-stressor, you're going to go apple, t cells. And that's precise preferentially socking aw ay more of those calories in your abdominal fa ly what occurs. Epel has studied this in women and men across a range of ages, and she finds that a prolonged glucocorticoid response to novelty is a feature of applish people, not pears. So with lots of stress, you get cravings for starchy comfort food and you pack it in the abdomen. One final distressing some fascinating recent work by Mary Dallma n from the University of California at piece of information, based on San Francisco: consuming lots of those comfort foods and bulking up on abdominal fat are stress-reducers. They tend to decrease the size of the stress-respon se (both in terms of glucocorticoid secretion and sympathetic nervous system good as well. activity). Not only do the Oreos taste good, but by reducing the stress-response, they make you feel sity can occur—too much or too little of this or that There seems to be a huge number of routes by which obe hormone; too much or too little sensitivity to this or that hormone.* But another route appears to involve being the o many stressors, too many perceived glucocorticoids, either because of to sort of person who secretes too many stressors, or trouble turning off the stress-response. A nd thanks to that weird new regulatory loop discovered by Dallman, it appears as if abdominal fat is one route for trying to tone down that overactive stress-response. BOWEL MOVEMENT AND BOWEL MOVEMENTS what you ingest, apter and to chapter 4, we've now sorted Thanks to the preceding part of this ch out how stress alters how it gets stored and mobilized. We have one last piece to fill in, which is getting food from your mouth to its digested form in your circulation. This is the other players like * The hormones involved obviously include the ones we've already heard of, like insulin, leptin, CRH, and glucocorticoids, plus stosterone. But there's also an array of brand-new appetite-rela ted hormones and neurotransmitt ers with names growth hormone, estrogen, and te ng hormone. that are so hideous that I have no choice but to bury them in a footnote. Neuropeptide Y. C holecystokinin. Melanocyte-stimulati lly how you spell it; however, I otein. Ghrelin (yes, that's actua ectin. Hypocretin. Agouti-related pr Oleylethanolamide. Adipon have no idea how you pronounce it). stomach, small intestines and large intestines (also known purview of the gastrointestinal (GI) tract—your esophagus, as the colon or the bowel). there's no such thing as a free lunch. You' When it comes to your GI tract, ve just finished some feast, eaten like a a bare minimum of vegetables to a's famous mashed potatoes and gravy, hog—slabs of turkey, somebody's grandm r drumstick and some corn on the cob, a slice or two of give a semblance of healthiness, and—oh, why not— anothe pie for dessert, ad nauseam. You expect your gut to magically convert all that into a filtrate of nutrients in your bloodstream? It takes energy huge amounts of it. Muscular work. Your stomach not only breaks down food chemically, it does so mechanically as we ll. It undergoes systolic contractions: the muscle walls contract violently on one side of your stomach, and hunks of food are flung against the far wall, breaking them down in a cauldron of acids racting the muscular nal contraction), cont tines do a snake dance of peristalsis (directio and enzymes. Your small intes walls at the top end in order to squeeze th e food downstream in time for the next stretch of muscle to contract. After that, your bowels do the same, and you're destined for the bathroom soon. Circular muscles called sphincters located en and close, serving as locks to make sure that things don't move to the at the beginning and end of each organ op next level in the system until the previous stage of digesti on is complete, a process no less complicated than shuttling ships through the locks of the Panama Canal. At your mout h, stomach, and small intestines, water has to be poured into the system to keep everything in solution, to make sure that the sweet potato pie, or what's left of it, doesn't turn large intestines, which have to extract the water and return into a dry plug. By this time, the action has moved to your it to your bloodstream so that you don't inadvertently excrete all that fluid and desiccate like a prune. All this takes energy, and we haven't even considered jaw fatigue. All told, your run-of-the-mill mammals, including us, expend 10 to 20 percent of their energy on digestion. So back to our by-now-familiar drama on the savanna: if you are that zebra being pursued by a lion, you can't waste energy on your stomach walls doing a rumba. There isn't time to get any nutritional benefi ts from digestion. And if you are that lion running after a meal, you haven't just staggered up from some all-you-can-eat buffet. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

43 Pa g e 43 of 212 Digestion is quickly shut down during stress. We all know the first step in that process. If you get nervous, you stop secreting saliva and your mouth gets dry. Your stomach gr stop, enzymes and digestive inds to a halt, contractions eted, your small intestines stop peristalsis, nothing is absorbed. The rest of your body acids are no longer secr even knows that the digestive tract has been shut down—as we saw two chapters ago, blood flow to your stomach and gut is decreased so that the blood-borne oxygen and gluc e, where they're needed. The ose can be delivered elsewher , normally mediates the actions of for all that calm, vegetative physiology parasympathetic nervous system, perfect digestion. Along comes stress: turn off the parasympathetic, turn on the sympathetic, and forget about digestion.* End d the digestive process resumes. of stress; switch gears again, an for the zebra or the lion. An d as usual, it is in the face of chronic stress that As usual, this all makes wonderful sense diseases emerge instead. BOWELS IN AN UPROAR n is, we're not likely to soil our pants. Nevertheless, we Regardless of how stressful that board meeting or examinatio ely terrified people—for example, sold iers amid horrifying battle—to defecate are all aware of the tendency of immens spontaneously. (This reaction is consistent enough that in many states, prisoners are clothed in diapers before an execution.) The logic as to why this occurs is similar to why we lose control of our bladders if we are very frightened, as get your mouth, stomach, bile ducts, and so forth to work described in chapter 3. Most of digestion is a strategy to together to break your food down into its constituent parts by the time it reaches th e small intestines. The small intestines, in turn, are responsible for absorbing nutrients out of this mess and delivering them to the bloodstream. As is apparent to most of us, not much of what we eat is act ually nutritious, and a large percentage of what we consume is through it. In the large intestines, the leftovers are converted to feces and left over after the small intestines pick stage left. eventually exit in your large intestines, from which the nutritive potential Yet again, you sprint across the veld. All that stuff sitting has already been absorbed, is just dead weight. You have the choice of sprinting for for a living, if you * Back to stress turning off salivation, an inhibition mediated by the sympathetic nervous system. What if you have to salivate eed musicians wind up spittle. Thus, many r comes along, good and nervous and—disaster—no are, say, an oboe player? Big audition using drugs e big arpeggi in time for th in order to slobber just the sympathetic nervous system o. like beta-blockers that block the action of your life with or without a couple of pounds of excess baggage in your bowels. Empty them. The biology of this is quite well understood. The sympathetic nervous system is responsible. At the same time that it is sending a signal to your stomach to stop its contractions and to your small intestine to stop peristalsis, your ovement in your large intestine. Inject into a rat's brain sympathetic nervous system is actually stimulating muscular m hetic nervous system, and suddenly the small intestine stops contracting and the the chemicals that turn on the sympat large intestine starts contracting like crazy. But why, to add insult to injury, is it so frequently diarrhea when you are truly frightened? Relatively large amounts of water are needed for digestion, to keep your food in solution as you break it down so that it will be easy to absorb into the circulation when digestion is done. As noted, a job of the large intestine is to get that water back, and that's why your bowels have to be so long—the leftovers slowly inch their way through the large intestine, starting as a soupy gruel and ending up, ideally, as reasonably dry stool. Disaster strikes, run for your life, increase that large intestinal motility, and everything gets pushed through too fast for the water to be absorbed optimally. Diarrhea, simple as that. STRESS AND FUNCTIONAL GASTROINTESTINAL DISORDERS the first, you feel terrible, something isn't working right, Broadly, there are two types of gastrointestinal disorders. In and the doctors find something wrong. These are "organic" GI disorders. A gaping hole in the wall of your stomach, there being something demonstrably wron in other words, a peptic ulcer, counts as g. We'll consider ulcers shortly. Out which is what inflammatory bow el disease is, also counts -of-control inflammation of tissue throughout your GI tract, as demonstrably wrong. This disorder will be briefly touched on in chapter 8. But suppose you feel terrible, something isn't working right, and the docs can't find a thing wrong. Congratulations, you now have a "functional" GI disorder. These are immensely sensitive to stress. And this is not just the touchy-feely psychologists saying this. Papers about stress and functional GI disorders are even published in tough-guy meat-and- Gut. potato scientific journals with names like 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

44 Pa g e 44 of 212 The most common functional GI disorder (IBS), which , which will be considered here, is irritable bowel syndrome involves abdominal pain constipation, passage of (particularly just after a meal) that is relieved by defecating and sympto ms such as diarrhea or mucus, bloating, and abdominal distention. Despite physicians checking you from every which end, they can't find common of stress-sensitive er. IBS is among the most anything wrong, which qualifies IBS as a functional disord passage in my life have been marked disorders. Personally, all the major rites of cases of the runs by pretty impressive a few days before—my bar mitzvah, going away to college, my doctoral defense, proposing marriage, my wedding. books these days. Now if I can only name some ne obligatory to successful (Finally, here's that confessional to Hollywood starlet with whom I've taken diuretics, this may become a bestseller.) the first symptoms of IBS Carefully conducted studies show that major chronic stre ssors increase the risk of crease the contractions what stress does is in appearing, and worsen preexisting cases. This makes sense. As we saw, so known as "spastic colon"—involves the colon being too in the colon, getting rid of that dead weight. And IBS—al contractile, an excellent way of producing diarrhea. (It is not clear why lots of st ress-induced contractions of the colon can lead to constipation. As a possible explanation, the stress-indu ced contractions in the co lon are directional, which colon from the small intestinal end to the anus. And if they do that a lot, things is to say, they push the contents of the ble scenario, with long en get accelerated, resulting in diar rhea. However, in one plausi ough periods of stress, the contractions begin to get disorganized, lo se their directionality, so that not mu ch of anything moves toward the anus). riencing a lot of stressors. So people with IBS are disproportionately likely to be expe But in addition, IBS can be a disorder of too much gastrointestinal sensitivity to stress. This can be shown in experimental situations, where a person with IBS is subjected to a controlled stressor (keepin g her hand in ice water for a while, trying to make sense of two recorded conversations at once, participating in a pressured interv iew). Contractions in the colon increase in IBS patients than in control subjects. response to these stressors more in l see in chapter 9, stress can blunt the sort of pain and IBS concerns pain. As we'l Another connection between stress you feel in your skin and skeletal muscles while increasing the sensitivity of internal organs like the intestines to pain (something called "visceral" pain). And th at is the profile seen in IBS patients—less sensitivity to skin ("cutaneous") pain, and more visceral pain. Even more support for the stress/IBS link is that people with IBS don't typically have they are asleep. Gut spasticity is not hypercon-tractility of their bowels when something that's going on all the time—only when the person is awake, amid the opportunities to be stressed. the sympathetic nervous system is What's the physiology of this gut that is too contractile? As we saw earlier, responsible for the increased large intestinal contractions during stress. And as would be expected, people with IBS have overactive sympathetic nervous systems (though it is less clear whether glucocorticoid levels are abnormal in of that gassy, distended, hypersensitive gut can stimulate IBS). And just to make the whole process worse, the pain r, making for a vicious circle. sympathetic activation even furthe buse, for example) ss early in life (a with IBS. Interestingly, traumatic stre So ongoing stress can be closely associated greatly increases the risk of IBS in adulthood. This implie e an echo of vu lnerability, a s that childhood trauma can leav to stress, long afterward. Animal st udies have shown that this occurs. large intestine that is hyperreactive to the link between stress and Despite these findings, there is a great deal of resistance IBS (prompting some semi- ers of earlier editions of this book). One reason for this is the linkage between IBS and irate letters to me from read certain personality types. In the cases of lier linkages seem pretty e connection is solid, but ear depression or anxiety, th suspect. These studies tended to focus on a lot of psychoanalytic gibberish (there, now I'll get myself into trouble with anal stage of development, a regression to the period of that crowd)—some hoo-ha about the person being stuck in the toilet training where going to the bath room gained great acclaim and, sudden ly, diarrhea was a symbolic reach for parental approval. Or the approval of the doctor as a parental surrogate. Or something or other. I'm not sure how they factored in constipation, but I'm sure they did. Few gastroenterologists take these ideas seriously anymore. However, in less scientific circles, some still cling to one suffering from IBS, who has just managed to clear up the perception that these views. It is easy to see how some they're still having some potty-training issues, isn't enthus ed about getting fingered for not dealing well with stress. Another reason why the stress /IBS connection is often vi n is because there have been many ewed with suspicio studies that have failed to find a link. Why should this be? First, both the severity of IBS symptoms and the intensity of stressors that someone is experiencing tend to wax and uctuating patterns takes some very fancy statistics. wane over time, and detecting a link between two such fl ced than the statistics that most (Typically, a technique called time-series analysis, a subject four classes more advan biomedical scientists have sort of learned. When my wife had to do a 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

45 Pa g e 45 of 212 time-series analysis as part of her doctor al research, it made me nervous just to have a textbook on the subject in the of symptoms is particularly difficul waning of stress and house.) Such waxing and t to track because most studies are retrospective (they look at people who already have IBS and ask them to identify stressors in their past) rather than prospective (in which people who do not have a disease are followed to see if stress predicts who is going to get it). rs and symptoms that are The problem here is that people are te rribly inaccurate at recalli ng information about stresso more than a few months old, a point we're going to return to often in this book. Moreover, as was mentioned above, s prior to the emergence of symptoms, the sorts of stressors that can increas e the risk of IBS can occur many year making the link hard to detect even in prospective studies. Finally, "IBS" is probably a hodgepodge of diseases with multiple causes, and stress may be relevant to only some of them, and it takes some additional fancy statistics to random noise in the data. ole, instead of as just detect those folks as a meaningful subset of the wh links between stress and some di sease, and be in the same At later junctures in this book, we will see other supposed quandary—there definitely is a link in some patients, or clinical impressions strongly support a stress-disease link, yet hard-nosed studies fail to show the same thing. As we w ill see repeatedly, the trouble is that the supposedly hard- does stress cause the disease in the nosed studies are often asking a fairly unsophisticated, straightforward question: preexisting disease, majority of sufferers? The far more sophisticated questions to ask are whet her stress worsens whether patterns of symptoms and of stressors fluctuate in pa rallel over time, and whether these links occur only in a duals. When asked in those ways, the st subset of vulnerable indivi ress-disease link becomes far more solid. ulcers At last we arrive at the medical proble m that started the stress concept on the road to fame and fortune. An ulcer is a immediately bordering it are the stomach or in the organs hole in the wall of an organ, and ulcers originating in those a bit higher up than the stomach are termed gastric ulcers; peptic ulcers. The ones within the stomach are called (the most common of peptic ulcers). duodenal esophageal, and those at the border of the stomach and the intestine are Photomicrograph of a stomach ulcer. symptoms Selye noted more th an sixty years ago when he As will be recalled, peptic ulcers were among the trio of antness. Since then, stomach ulcers ha exposed his rats to nonspecific unpleas ve emerged as the disorder most recognized by the lay public as a stress-related disease: in this view, you have upsetting thoughts for a long period of time and holes appear in the walls of your stomach. ubtype of ulcers that forms relatively rapidly (sometimes over the course of days) Most clinicians agree that there is a s in humans who are exposed to immensel y stressful crises—hemorrhag e, massive infection, trauma due to accident or surgery, burns over large parts of the body, and so on. Such "stress ulcers" can be life threatening in severe cases. emerging ulcers. This used to be a ed has been with the issue of gradually But where a lot of contention has appear physicians, would immediately think stress. But a revolution has dramatically changed realm where people, including thinking about ulcers. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

46 Pa g e 46 of 212 That revolution came with the discov This obscure ery in 1983 of a bacterium called Helicobacter pylori. microorganism was discovered by an obscure Australian pathologist named Robert Warren. He, in re obscure younger colleague named Barry Marshall, who documented that this bacterium turn, interested an even mo consistently turned up in biopsies of the stomachs of people with duodenal ulcers and stomach inflammation (gastritis). He theorized that it actually announced this to the caused the inflammation and ulcers, the room. Ulcers were caused by diet, a conference, and was nearly laughed out of (gastroenterological) world at is so incredibly acidic, owing to genetics, stress—not bacteria. Everyone kn ew that. And besides, because the stomach , no bacteria could survive in there. the hydrochloric acid in stomach juices People had known for years that the t turn up were just due to contamination by some at any bacteria that migh stomach was a sterile environment, and th sloppy pathologist. sed gastritis and ulcers in mice. That's great, but mice work differently than Marshall showed that the bacteria cau bilge and Helicobacter humans, everyone said. So, in a heroic, soon-to-be-a-movie gesture, he swallowed some tually, some folks in the field got tired of hearing him go caused gastritis in himself. Still, they ignored Marshall. Even on about the damn bacteria at meetings , decided to do some experiments to prove him wrong, and found that he was absolutely right. Helicobacter pylori turns out to be able to live in the acidic stomach environment, protecting itself by having a a coat of protective bicarbonate. And this structure that is particular ly acid-resistant and by wrapping itself in t of ulcers in Western populations (as well as with stomach bacterium probably has a lot to do with 85 to 100 percen —it is probably the most Helicobacter world are infected with of people in the developing cancer). Nearly 100 percent fect cells in the lining of the stomach, causing gastritis, common chronic bacterial infection in humans. The bacteria in ing the duodenum to defend themselves against stomach which somehow compromises the ability of those cells lin acids. Boom, under the right conditions, you've got a hole in that duodenal wall. Many of the details remain to be sorted out, but th e greatest triumph for Marshall and Warren has been the crobial drugs, such as antibiotics, turn out to be the greatest things since sliced bread for demonstration that antimi dealing with duodenal ulcers—th ey are as good at getting rid of the ulcers as are antacids or antihistamine drugs (the stay away (or at least until of other treatments, ulcers now main prior treatments) and, best of all, unlike the aftermath the next Helicobacter infection). Once everybody in the field got used to the idea of Marshall and Warren being carried around on sedan chairs for their discovery, they embraced Helicobacter with a vengeance. It makes perfect sense, given ease, rather than that wimpy nosed, reductive models of dis the contemporary desire of medicine to move toward hard- psychosomatic stuff. The Center for Di y physician in America, sease Control sent out edu cational pamphlets to ever advising them to try to disabuse their patients of the obsolete notion that stress has anything to do with peptic ulcers. Clinicians celebrated at never having again to sit down with their ulcer patients, make some serious eye contact, and ask them how their lives were going. In what one pair of investigators has termed the "Helicobacterization" of stress research on ulcers, the number of papers on stress as a component of the ulcer story has plummeted. Don't bother with eal science here, complete with this psychological stuff when we finally have gotten some r a bacterium that's got its own Latin name. the whole story. For starters, up to 15 percent of duodenal ulcers form in The trouble is that one bacterium can't be infected with or with any other known bacterium related to it. More damning, only people who aren't Helicobacter, about 10 percent of the people infected with the bacteria get ulcers. It's got to be Helicobacter pylori plus something a lifestyle risk factor—alcohol, smoking, skipping breakfast habitually, taking else. Sometimes, the something else is Maybe the something else is a genetic tendency to secrete a a lot of nonsteroidal anti-inflammatory drugs like aspirin. lot of acid or to make only minimal amounts of mucus to protect stomach linings from the acid. But one of the additional factors is stress. Study after st udy, even those carried out after the ascendancy of the bacteria, show that duodenal ulceration is more likely to occur in people who are anxious, depressed, or undergoing natural disasters). An analysis of the entire literature shows that somewhere severe life stressors (imprisonment, war, factors (i.e., stress) involved. The problem is that stress between 30 and 65 percent of peptic ulcers have psychosocial creases the risk of an ulcer causes people to drink and smoke more. So maybe stress in merely by increasing the incidence of those lifestyle risk factors. But no—after you c ontrol for those variables, stress itself still causes a two- to e risk of an ulcer. threefold increase in th Helicobacter is relevant to ulcers, but it is only in the context of its interactions with these other factors, including stress. You can show this statistically if you study a zillio n ulcer patients. Then, do a fanc y mathematical analysis that multivariate analysis). takes into account bacterial load, lifestyle risk factors, and st ress (something aptly called a , stress, or lifestyle e factors (bacterial load ise if you only have a little bit of one of th You'll observe that ulcers can ar risks), so long as you have a lot of one or two of the others. As an example of that, if you expose 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

47 Pa g e 47 of 212 lab rats to psychological stressors, they get ulcers—but not if they live in a germ -free environment that lacks Helicobacter. n? Some sixty years after Se So how does stress exacerbate the process of ulcer formatio lye first noticed his rats' te clear. There are some fa ulcers, it is still not qui vorite scenarios, however. y of what bizarre things we are ve to grapple with the grim realit To understand this mechanism, we ha Acid Rebound willing to eat and expect our stomachs to digest. The only way that the stomach is going to be able to handle some of but the main weapon is the contractions certainly help, this stuff is if it has powerful degradative weapons. The hydrochloric acid that pours into your stomach from the cells lining it. Hydrochloric acid is immensely acidic; all well and good, but it raises the obvious question of why your stomach is not itself digested by the digestive acids. Eat somebody else's stomach and your stomach disintegrates it. How do your own stomach walls remain unscathed? stomach wall and coats them Basically, your stomach has to spend a fortune protecting itself . It builds many layers of bicarbonate is secreted into with thick, soothing mucus that buffers the acid. In addition, the stomach to neutralize the acid. This is a wonderful solution, and you happily go about digestion. Along comes a stressful period that lasts months. Your body cuts down on its acid secretion—there are now frequent times when digestion is being inhibited. During this period, your stomach essentially decides to save itself some energy by cutting corners. It cuts back a bit on the constant thickening of the stomach walls, undersecretes mucus and bicarbonate, and pockets the difference. Why not? There isn't much acid around during this stressful period anyway. celebrate by eating a large chocolate cak e inscribed for the occasion, stimulate End of stressful period; you decide to your parasympathetic nervous system, st art secreting hydrochloric acid, and ... your defenses are down. The walls bicarbonate is overwhelmed. A have thinned, there isn't as thick a protective mucous laye r as there used to be, the couple of repeated cycles of stress an d rebound with a bacterial infection that is already compromising the defenses and you've got an ulcer. Suppose you are in the middle of a very stressful period, an sk for an ulcer. What's the d you worry that you are at ri solution? You could make sure that you remain under stress every second for the rest of your life. You definitely will avoid ulcers caused by hydrochloric acid secretion, but of course you'll die for a zillion other reasons. The paradox is that, in this scenario, ulce rs are not formed so much during the stressor as durin g the recovery. This idea predicts that several periods of transient stress should be more ulcerative than one long, continuous period, and animal experiments have generally shown this to be the case. As we know, in an emergency, you want to deliver as much blood as possible to the muscles Decreased Blood Flow that are exercising. In response to stress, your sympathetic nervous system diverts blood from the gut to more important places—remember the man with a gunshot wound in the stomach, whose guts would blanch from decreased blood flow every time he became angry or anxious. If your stressor is one that involves a dramatic decrease in blood flow to the gut (for example, following a hemorrhage), it begins to cause little infarcts—small strokes—in your tic (dead) tissue, which are the building stomach walls, because of lack of oxyge n. You develop small lesions of necro blocks of ulcers. ss of the acid that ecreased blood flow, le es for at least two reasons. First, with d This condition probably aris e second reason involves another accumulates is being flushed away. Th paradoxical piece of biology. We all obviously need oxygen and would turn an unsightly blue without it. However, running your cells on oxygen can oxygen radicals. Normally, another group of sometimes produce an odd, dangerous class of compounds called me evidence, however, that compounds (free radical quenchers, or scavengers) dispose of these villains. There is so during periods of chronic stress, when blood flow (and thus oxygen delivery) to the gut decreases, your stomach stops making the scavengers that protect you from the oxygen radicals. Fine for the period of stress (since the oxygen ly); it's a clever way to save radicals are also in shorter supp energy during a crisis. At the end of stress, however, when blood flow chock-full of oxygen resumes and the normal amount of oxygen radicals is generated, the stomach has its oxidative pants down. Without sufficient scavengers, the oxygen radicals start killing cells in the stomach walls; ulcer. Note how similar this in trouble thanks to bacteria couple that with cells already l infection and you've got an mechanism: in both cases, the damage occurs not during the period of stress but in its scenario is to the acid-rebound of acid secreted or or example, the amount ecause stress increases the size of an insult (f aftermath, and not so much b produced), but because, during the stressful emergency, the gut scrimps on defenses the amount of oxygen radicals against such insults. Immune Suppression as a bacterium triggers your immune system into trying to defend against it.* As Helicobacter you will soon learn in sickening detail (chapter 8), chronic stress suppresses immunity, and in this scenario, lowered reproducing happily. immune defenses equals more Helicobacters In this scenario, micro-ulcers begin now and then in your gut, as part of the Insufficient Amounts of Prostaglandins ge by secreting a class of chemicals . Normally your body can repair the dama expected wear and tear on the system 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

48 Pa g e 48 of 212 called prostaglandins, thought to aid the healing process by increasing blood flow through the stomach walls. During orticoids. In bited by the actions of glucoc stress, however, the synthesis of these prostaglandins is inhi this scenario, rm as impair your body's ability to catch stress does not so much cause ulcers to fo them early and repair them. It is not yet established how often this is the route for ulcer formation during stress. (Aspirin also inhibits prostaglandin synthesis, which is why aspiri n can aggravate a bleeding ulcer.) For unknown reasons, stress causes the stomach to initiate slow, rhythmic contractions (about Stomach Contractions one per minute); and for unknown reasons, these seem to add at during the contractions, to ulcer risk. One idea is th ch evidence for this, however. blood flow to the stomach is disrupted, causing little burs ts of ischemia; there's not mu jury is still out on that mechanism. Another idea is that the contractions m echanically damage the stomach walls. The well documented routes by which ulcers can form; of those credible Most of these mechanisms are pretty More than one mechanism may occur mechanisms, most can occur during at least certain types of stressors. eemingly differ as to how lik r in their gut during stress, simultaneously, and people s ely each mechanism is to occu and how likely it is to interact with bacterial infection. Ad ditional mechanisms for stress's role in ulcer formation will no doubt be discovered, but for the moment these should be quite sufficient to make anyone sick. Peptic ulcers are what the physician Susan Levenstein, the wittiest person on earth writing about gastroenterology, has + Stress doesn't cause peptic ulcers to termed "the very model of a modern etiology." neficial insofar as it stimulates immunity. Helicobacter, * And some scientists even think that amid its disease-causing potential, is also be + cal school, the Admittedly, there's a small sample size of such writers. In one of my favorite essays of hers, she begins, "When I was in medi : interrogate, palpate, pontificate." al, the veterinary, and the priestly nt combined the patern reigning approach to the patie form. But it makes the biological villains that do cause ulcers to form more likely to occur, or more virulent, or teraction between the organic ains. This is the classic in impairs your ability to defend yourself against those vill (bacteria, viruses, toxins, mutations) and the psychogenic components of disease. 6 DWARFISM AND THE IMPORTANCE OF MOTHERS It still surprises me that organisms grow. Maybe 1 don't believe in biology as much as I claim. Eating and digest- ing a meal seems very real. You put a massive amount of something or other in your mouth, and, as a result, all sorts of tangible things happen—your jaw gets tired, your stomach distends, eventually so mething comes out the other end. Growth seems pretty tangible, too. Long bones get longer, kids weigh more when you heft them. My difficulty is with the steps that connect digestion with growth. I know how it works; my university even allows me untain of spaghetti, salad, to teach impressionable studen ts about it. But it just seem s implausible. Someone ate a mo dessert—and that has been transformed and is now partially inside this test garlic bread, and two slices of cake for tube of blood? And somehow it's going to be reconstructed into bone? Just thin k, your femur is made up of tiny pieces of your mother's chicken potpie that you ate throughout yo ur youth. Ha! You see, you don't really believe in the primitive to comprehend the transmogrification of material. process either. Maybe we're too HOW WE GROW lt of eating. And in a kid, it's not a trivial process. The brain gets bigger, the Nevertheless, growth does occur as a resu shape of the head changes. Cells divide, grow in size, and synthesize new proteins. Long bones lengthen as cartilaginous cells at the ends of bones migrate into 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

49 Pa g e 49 of 212 the shaft and solidify into bone. Baby fat melts away and is replaced by muscle. The larynx thickens and the voice easts develop, testes enlarge. s of unlikely places on the body br deepens, hair grows in all sort From the standpoint of understanding the effects of stress on growth, the most important feature of the growth process is that, of course, growth doesn't come are needed for all cheap. Calcium must be obtained to bu ild bones, amino acids that protein synthesis, fatty acids build cell walls—and it's glucose that pays for the building costs. Appetite soars, and nutrients pour in from the intestines. A large part of what various hormones do is to mobilize the energy and the material needed for all these civic ex pansion projects. Growth hormone dominates the process. Sometimes it works directly on cells in the body—for example, growth hormone helps to break down fat stores, flushing them into the circulation so they can be diverted to the growing cells. Alternatively, sometimes growth hormone must first trigger somatomedins, which actually do the job, such as promoting cell the release of another class of hormones called division. Thyroid hormone plays a role, promoting growth hormone release, making bones more responsive to somatomedins. Insulin does something similar as well. Th e reproductive hormones come into play around puberty. Estrogen promotes the growth of long bones, both by acting directly on bone and by increasing growth hormone secretion. Testosterone does similar things to long bones and, in addition, enhances muscle growth. Adolescents stop growing when the ends of the long bones meet and begin to fuse, but for complex reasons, ng bones, can actually speed th testosterone, by accelerating th e growth of the ends of lo e cessation of growth. Thus, pubescent boys given testosterone will, paradoxically, wind up having their adult stature blunted a bit. Conversely, boys castrated before puberty grow to be quite tall, with lanky bodies and particularly long limbs. Opera history buffs will recognize this morphology , as castrati were fame d for this body shape. NEUROTIC PARENTS: BEWARE! ent. As we'll see, this not only involves impairing skeletal It is time to look at how stress disrupts normal developm growth (that is, how tall you grow to be), but also how stress early in life can alter yo ur vulnerabilit y to disease throughout your lifetime. Now, before I launch into this, I have to issue a warning to anyone who is a parent, or who plans to be a parent, or who had parents. There's nothing like parenthood to make you really neurotic, as you worry about the consequences of your every act, thought, or omission. I have young children, and here are some of the heinous things that my wife and I have done to irreparably harm them: there wa s the time we were desperate to placate them about something and allowed them to eat went to when our firstborn there was the loud concert we some sugar-bomb breakfast cereal we'd normally ban; then was a third-trimester fetus, causing him to kick throughout, no doubt in pained protest; and there was the time we messed up with our otherwise ceasele a violent cartoon to show on the ss vigilance and allowed ten seconds of television while we fumbled with the Kumbaya-esque video we were attempting to insert. You only want perfection for the ones you love beyond words, so you get nu tsy at times. This section will make you nutsier. So keep this warning in mind, a point I will return to at the end. PRENATAL STRESS ents about the nature of the What is childhood about? It is a time when you make assessm world. For example, "If you let go of something, it falls down, not up." Or, "If somethin g is hidden underneath something else, it still exists." Or, mmy always comes back." ideally, "Even if Mommy disappears for a while, she w ill come back because Mo of the world forever. For example, as w ill be discussed in chapter 14, if you Often, these assessments shape your view lose a parent to death while you are a child, your risk of major depression has increased for the rest of your life. I will suggest that this arises from having learned at a premature age a deep emotional lesson about the nature of life, namely, that this is a world in which awful things can happen over which you have no control. It turns out that during development, beginning with fetal life, your body is also learning about the nature of the world and, metaphorically, making lifelong decisions about how to respond to the outside world. And if development involves certain types of stresso rs, some of these "decisions" cause a lifelong increase in the risk of certain diseases. getting enough calories, nor is her fetus. It turns out that Consider a female who is pregnant during a famine. She's not during the latter part of pregnancy, a fetus is "learning" about how plentiful food is in that outside world, and a famine winds up "teaching" it that, jeez, e, better store every smidgen of it. Something about the metabolism of that fetus there's not a whole lot of food out ther shifts permanently, a feature called meta bolic "imprinting" or "programming." Forever after, that fetus will be 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

50 Pa g e 50 of 212 particularly good at storing the food it consumes, at retaini ng every grain of precious salt from the diet. Forever after, that fetus develops what has been termed a "thrifty" metabolism. in the middle of chapters 3 and 4. of that? Suddenly we find ourselves back And what are the consequences Everything else being equal throughout life, even late in life , that organism is more at risk for hypertension, obesity, adult-onset diabetes, and cardiovascular disease. Remarkably, things work precisely this way in rats, pigs, and sheep. And humans as well. The most dramatic and d of World War II. The occupying Nazis were being Hunger Winter at the en most cited example concerns the Dutch pushed back on all fronts, the Dutch were trying to aid th e Allies coming to liberate them, and, as punishment, the on, the Dutch starved. People consumed less than 1,000 calories For a demarcated seas Nazis cut off all food transport. starved to death. Fetuses, going about their lifelong a day, were reduced to eating tulip bulbs, and 16,000 people metabolic programming, learned some severe lessons about food availability during that winter of starvation. The rome a half-century later. result is a cohort of people with thrifty metabolisms and incr eased risks of Metabolic synd Seemingly, different aspects of metabolism and physiology ge t programmed at different points of fetal development. of heart disease, obesity, and ograms you for a greater risk If you were a first-trimester fetus during the famine, that pr an unhealthy cholesterol prof ile, whereas if you were a second- or third- trimester fetus, that programs you for a greater diabetes risk. The key to this phenomenon seems to be not only that you we re undernourished as a fetus, but that after birth you had plenty of food and were able to recover from the deprivation quickly. Thus, from early in childhood, you not only were highly efficient at storing nutrients, bu t had access to plentiful nutrients.* So avoid starving a fetus while you're pregnant. But this ph enomenon also applies to less dramatic situations. Within the normal range of birth weights, the lower the weight of a baby (when adjusted for body length), the greater the risk of those Metabolic syndrome that winter, people had the benefit of plentifu * The Dutch example was ideal for l food. In contrast, the this, in that once the country recovered from same has not been seen among people who we ward. World War II—food was not plentiful after re fetuses during the Siege of Leningrad in problems in adulthood. Even after you control for adult body weight, low birth weight still predicts an increased risk of diabetes and hypertension. those who were heaviest versus lighte st at birth, you These are big effects. When you compare see an approximate ce in the risk of Metabolic out an eighteen-fold differen risk of pre-diabetes, and ab eight-fold difference in the syndrome. Among both men and women, compare those whose birth weights were in the lowest 25 percent versus those in the highest 25 percent, and the former have a 50 percent higher rate of death from heart disease. ng risks of metabolic and cardiovascular disease was first This relationship between fetal nutritional events and lifelo described by the epidemiologist David Barker of Southampton Hospital in England, and now goes by the name Fetal Origins of Adult Disease (FOAD). And we're not done with this yet. Starvation is clearly a stressor, raisi programming occurs because of the ng the question of whether the metabolic of calories, and/or because of the stre ssfulness of the shortage of calories. nutritional consequences of the shortage Asked another way, do non-nutritional stressors during pregnancy also induce FOAD-like effects? The answer is, yes. ways while she is rat in any number of hing back decades, shows that stressing a female An extensive literature, stretc pregnant will cause lifelong changes in the physiology of her offspring. Predictably, one set of changes involves ce again, think of the fetal body "learning" a bout the outside world, this time along the glucocorticoid secretion. On lines of, "How stressful is it out th ere?" Fetuses can monitor signals of stress from the mother, insofar as ids "teach" the fetus that it is ation, and lots of glucocortico y pass through to the fetal circul glucocorticoids readil indeed a stressful world out there. The result? Be prepared for that stressful world: tend toward secreting excessive amounts of glucocorticoids. Prenatally stressed rats grow into adults with elevated glucocorticoid levels—depending ress-response. The on the study, elevated basal levels, a larg er stress-response, and /or a sluggish recovery from the st e number of receptors for glucocorticoids in one ng seems to be due to a permanent decrease in th lifelong programmi part of the brain. The brain region is involved in turni ng off this stress-response by inhibiting CRH release. Fewer glucocorticoid receptors s less effective reining in of the hormone's signal, which mean there mean less sensitivity to subsequent glucocorticoid secretion. The result is a lifelong tendency toward elevated levels. female that gives rise to th ese permanent changes in the Is it the glucocorticoid secretion by the stressed pregnant offspring? Seemingly yes—th e effect can be replicated in a number of species, including nonhuman primates, by injecting the pregnant female with high glucocorticoid levels, instead of stressing her. A smaller but fairly solid literature shows that prenatal stress programs humans for higher glucocorticoid secretion in adulthood as well. In these studies, low birth weight (corrected for body length) is used as a surrogate marker for 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

51 Pa g e 51 of 212 stressors during fetal life, and the lower the birth weight, the higher the basal glucocorticoid levels in adults ranging from age twenty to seventy; this rela pronounced when low birth weight is coupled with tionship becomes even more premature birth.* posure of a stressful fetal life seems to contri The excessive glucocorticoid ex bute to the lifelong increase in the risk of or nonhuman primate to lots of synthetic evidence, if you expose a fetal rat, sheep, Metabolic syndrome as well. As ll be more at risk for the glucocorticoids during late gestational life (by injecting the moth er with them), that fetus wi arise? A plausible sequence is that the prenatal exposure symptoms of Metabolic syndrome as an adult. How does this to high glucocorticoid levels leads to the elevated glucocorticoid levels in adulthood, which increases the risk of ve no trouble recalling exactly how have memorized the book so far will ha Metabolic syndrome. Those readers who an excess of glucocorticoids in adul y, insulin-resistant diabetes, and thood can increase the odds of obesit hypertension. Despite those potential links, the elevated glucocorticoid levels in adulthood are probably only one of the routes linking prenatal stress with the adult Metabolic syndrome. d excess in this picture. So now we have hypertension, diabetes, cardiovascular dis ease, obesity, and glucocorticoi extensive literature shows th Let's make it worse. How about the reproductive system? An at if you stress pregnant xually active as adults, and have less developed genitals. rats, you "demasculinize" the male fetuses. They are less se ress decreases testosterone secretion, a As we will see in the next chapter, st nd it seems to do so in male fetuses as well. Furthermore, glucocorticoids and testosterone have similar chemical structures and. As we will see at a couple of points in the book, studies like this one could * The seventy-year-olds were studied in Finl only be carried out in aginable, including birth w Scandinavia, whose countries have a traditio n of obsessively good record keeping about everything im eights for large populations of people. block receptors for (they are both "steroid" hormones), and a lot of glucocorticoids in a fetus can be gin to gum up and testosterone, making it impossible for the testosterone to have its effects. More FOADish problems. Seriously stress a pregnant rat and her offspring will grow up to be anxious. Now, how do t; how long does it take for by definition, scary) environmen you tell if a rat is anxious? You put it in a new (and thus, it to explore? Or take advantage of the fact that rats, being nocturnal, don't like bright lights. Take a hungry rat and put til the rat goes for the food? How readily can the rat learn some food in the middle of a brightly lit cage; how long un w much does the rat defecate in a novel setting?* Prenatally in a novel setting, or socially interact with new rats? Ho ecate like crazy. Sad. As earn in novel settings, def und bright lights, can't l stressed rats, as adults, freeze up when aro we will see in chapter 15, anxiety revolves around a part of the brain called the amygd ala, and prenatal stress programs the amygdala into a lifelong profile that has anxi ety written all over it. The amygdala winds up with more receptors for (that is, more sensitivity to) glucocorticoids, mo re of a neurotransmitter that mediates anxiety, and fewer + Does prenatal stress in humans make for anxious adults? It's receptors for a brain chemic al that reduces anxiety. difficult to study this in humans, in that it is hard to find mothers who are anxious during pregnancy, or anxious while their child is growing up, but not both. So there's not a huge amount of evidence for this happening in humans. Finally, chapter 10 will review how an excess of stress can have bad effects on the brain, particularly in the developing brain. Prenatally stressed rodents grow up to have fewer connections between the neurons in a key area of old age, while prenatally impairments of memory in the brain involved in learning and memory, and have more stressed nonhuman primates have memory problems and form fewer * I kid you not, and this should make perfect sense after chapte t? Increase large intestinal mo tility, defecate, and r 5. Anxious in a new environmen ative measure of the grad student doing a thesis on rat anxi ety counts the number of fecal pellets in the cage afterward for a remarkably inform anxiety. + none other than , the neurotransmitter that mediat Just to give away some of the informa tion coming in chapter 15 es anxiety via the amygdala is eceptor for the e stress-response than merely releasing ACTH). Meanwhile, the r CRH (recall from chapter 5 that CRH mediates other aspects of th brain chemical that inhibits anxiety is called a benzodiazepine re e? No one is exactly sure what the anxiety- ceptor. What is a benzodiazepin about the synthetic benzodiazepine s—these are Valium reducing benzodiazepine is in the brain that normally binds to the receptor, but we all know and Librium, the anxiety-reducing tranquilizers. to that of those examining neurons as well. The human studies have been very hard to carry out for reasons similar of anxiety. With that caveat, a number of studies have shown that such stress whether prenatal stress increases the risk fits in with the picture of being results in children born with a smal ler head circumference (which certainly not clear whether head circumference at birth predicts how many academic underweight in general). However, it's degrees the kid is going to have after her name thirty years later. One final piece of the FOAD story is so intrinsically fascinating th at it made me stop thinking like a worried parent I just marveled at biology. for a few minutes and instead malnutrition, and who thus programs a thrifty metabolism. Suppose you have a fetus exposed to lots of stress, say, Later, as an adult, she gets pregnant. She consumes normal has that thrifty metabolism, amounts of food. Because she is so good at storing away nutrients in case that fetal fami r body grabs a disproportionate ne ever comes back again, he 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

52 Pa g e 52 of 212 share of the nutrients in her bloodstream for herself. In ot her words, amid consuming an average amount of food, her it, producing mild malnutrition. And thus programs a milder version of a thrifty fetus gets a less than average share of metabolism. And when that fetus eventually becomes pregnant... can be transmitted across generations, without the benefit of genes. It's not In other words, these FOADish tendencies due to shared genes, but to shared environment, namely, the intimately shared blood supply during gestation. in the Dutch Hunger Winter population, in that their grandchildren are born Amazing. This is precisely what is seen This is seen in other realms as well. Pick some rats at random and feed them with lower than expected birth weights. on a diet that will make them become obese at the time of pregnancy. As a result, their offspring, despite being fed a milarly, in humans, having insulin-resistant normal diet, have an increased risk of obesity. As will their grandkids. Si risk of the disorder in your offspring, after controlling for weight. Wait a diabetes while pregnant increases the second—going through a famine means less nutrients in the bloodstream, while having insulin-resistant diabetes means more. How can they produce the sa me thrifty metabolism in the fetus? Remember, you have elevated levels of e you can't store the stuff. R glucose in the bloodstream in the case of diabetes becaus ecall a one-sentence factoid from chapter 4—when overstuffed fat cells begin to become insulin- resistant, they release hormone s that urge other fat cells and muscle to do the same. And those hormones get into the fetal circulation. So you have Mom, who is in sulin-resistant because she has too much energy stored away d at energy storage as well releasing hormones that make the normal-weight fetus ba ... and the fetus winds up underweight and with a thrifty metabolic view of the world. So expose a fetus to lots of glucocorticoids and you are increasing its risk for obesit y hypertension, cardiovascular ybe reproductive impairments, maybe anxiety, and impaired brain development. disease, insulin-resistant diabetes, ma And maybe even setting up that fetus's eventual offspring for the same. Aren't you sorry now that the two of you had that argument over whether to videotape the de livery? Now on to the next realm of worries. postnatal strEss The obvious question to begin this section is, does postnatal stress have lifelong adverse effects on development as well? Of course it can. To begin, what's the most stressful thing that could happen to an infant rat? Being deprived of its mother (while still receiving adequate Emory University shows that maternal nutrition). Work done by Paul Plotsky at deprivation causes similar consequences in a rat as prenatal stress: increased le vels of glucocorticoids during stress the end of stress. More anxiet y, and the same sorts of chan and an impaired recovery at ges in the amygdala as were seen in pre-natally stressed adults. And impaired development of a part of the brain relevant to learning and memory Separate an infant rhesus monkey from its mother and it grows up to have elevated glucocorticoid levels as well. How about something more subtle? What if your rat mom is around but is simply inattentive? Michael Meaney of McGill University has looked at the lifelong consequences for rats of having had a highly attentive or highly inattentive mother. What counts as attentiveness? Groomin g and licking. Infants whose mothers groomed and licked who were maternally deprived the least produced kids who were milder versions of rats as infants, with elevated glucocorticoid levels.* human equivalent e a rat, it's not quite obvious what the * While this clearly emphasizes the importan ce of being a well-groomed child if you ar would be. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

53 Pa g e 53 of 212 What are the consequences of childhood stress for disease vulnerability during adulthood in humans? This has been difficult such studies are. A number of studies, mentioned studied only minimally, which is not surprising, given how earlier, show that loss of a parent to death during childhood increases the lifelong risk of depression. Another, ly trauma increases the risk of irr discussed in chapter 5, shows that ear itable bowel syndrome in adulthood, and similar animal studies show that early stre ss produces large intestines that contr act to abnormal extents in response to stress. Though the subject is still poorly studied, childhood stress may produce the building blocks for the sort of adult diseases we've been consider ing. For example, when you examine children who had been adopted more than a year before from Romanian orphanages, the longer the child spent in the orphanage, the higher the resting glucocorticoid id levels, and decreased size and activity levels.* Similarly, children who have been abused have elevated glucocortico in the most highly evolved part of the brain, the frontal cortex. , Romanian orphanages have become the st * For those not familiar with these hellholes udy subjects of choice for understanding t he consequences of massive sensory, intellectual, and emot ional deprivation in infants and children. skeletal growth and stress dwarfism )? Skeletal growth is great ferred to as skeletal growth How about the effects of stress on how tall you grow (often re when you are a ten-year-old lying in bed at night with a full belly. However, it's the usual scenario of it not making a ere is no time to derive any advantages from digesting your whole lot of sense when you're sprinting from a lion. If th meal at that point, there certainly isn't time to get any benefit from growth. To understand the process by which stress inhibits skeletal growth, it helps to begin with extreme cases. A child of, ped growing. There are none of the typical problems—the say, eight years is brought to a doctor because she has stop has no intestinal parasites that compete for nutrients. No kid is getting enough food, there is no apparent disease, she her problem; yet she doesn't grow. In ma one can identify an organic cause of ny such cases, there turns out to be something dreadfully stressful in her life—emotional neglect or psychological abuse. In such circumstances, the syndrome is called stress dwarfism, or psychosocial or psychogenic dwarfism.* A question now typically comes to mind among people who are below average height. If you are short, yet didn't have ful period in your childhood, are you a victim of mild any obvious chronic diseases as a kid and can recall a dread parents had a job necessitating freque nt moves, and every year or two stress dwarfism? Suppose one of your throughout childhood you were uprooted, forced to leave your friends, moved off to a strange school. Is this the sort something more severe? What about an c dwarfism? Definitely not. How about of situation associated with psychogeni ress dwarfism? Unlikely. acrimonious divorce? St re. These are the kids who are incessantly The syndrome is extremely ra harassed and psychologically terrorized by the wn the door, are discovered crazy stepfather. These are the nd the social workers break do kids who, when the police a to have been locked in a closet for 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

54 Pa g e 54 of 212 * Some clinical nomenclature: "m ly refer to infants aternal deprivation syndrome," "deprivation syndro me," and "nonorganic failure to thrive" usual "psychogenic dwarfism," and "psychosocial dwarfism" usually refer of the mother. "Stress dwarfism," and invariably to the loss to children aged ilure to thrive in e dichotomy; during the nineteen three years or older. However, some papers do not follow this ag th century, infants dying of fa orphanages were said to suffer from "marasmus," Greek for "wasting away." extended periods, fed a tray of food slipped under the door. These are the products of vast, grotesque psychopathology. And they appear in every endocrinology textbook, standing nude in front of a growth chart. Stunted mental development, bruised, little kids, years behind their expected height, years behind in with distorted, flinching angles that accompany all naked people postures, haunted, slack facial expressi ons, eyes masked by the obligatory rect in medical texts. And all with stories to take your breath away and make you wonder at the potential sickness of the human mind. few years later, after having second photo—the same child a Invariably, on the same page in the text is a surprising environment (or, as one pe diatric endocrinologist term been placed in a different ed it, having undergone a "parentectomy"). No bruises, maybe a te ntative smile. And a lot taller. So long as the stressor is removed before the ), there is the potential for child is far into puberty (when the ends of the long bones fu se together and growth ceases some degree of "catchup" growth (although shortness of stature and some degree of stunting of personality and intellect usually persist into adulthood). story. One possible dwarfism, instances pop up throughout hi case arose during the Despite the clinical rarity of stress thirteenth century as the result of an experiment by that noted endocrinolo gist, King Frederick II of Sicily. It seems that his court was engrossed in philosophic disputation over the natural language of humans. In an attempt to resolve the question, Frederick (who was apparently betting on Hebrew, Greek, or Latin) came up with a surprisingly sophisticated idea for an experiment. He commandeered a bunch of infants and ha d each one reared in a room of its the best quality. But they ts, and clean clothes, all of own. Every day someone would bring the child food, fresh blanke wouldn't stay and play with the infant, or hold it—too mu ch of a chance that the person would speak in the child's presence. The infants would be reared without human language, and everyone would get to see what was actually the natural language of humans. Of course, the kids did not spontaneously burst out of the door one day reciting poetry in Italian or singing opera. The survived. The lesson is obvious to us now—optimal growth and kids didn't burst out of the door at all. None of them development do not merely depend on being fed the right number of calories and being kept warm. Frederick "laboured in vain, for the children could not live without clappings of hands and gestures and gladness of countenance and blandishments," reported the contemporary historian Salimbene. A child suffering from stress dwarfism: changes in appearance during hospitalization (left to right). It seems quite plausible that these kids, all healthy and well fed, died of a nonorganic failure to thrive.* Another study that winds up in half the textbooks makes the same point, if more subtly. The subjects of the two different orphanages in Germany after World War II. Both orphanages were "experiment" were children reared in important controls in place— the kids in both had the same general diet, the run by the government; thus there were same frequency of doctors' visits, and so on. The main id entifiable difference in thei r care was the two women who ds like a parable. In one orphanage checked them, and their description soun ran the orphanages. The scientists even was Fraulein Grun, the warm, nurturing mother figure who ildren, comforted them, and spent all played with the ch day singing and laughing. In the other was Fraulein Schwarz, a woman who was clearly in the wrong profession. She discharged her professional obligations, but minimized her co ntact with the children; she frequently criticized and eers. The growth rates at the two orphanages berated them, typically among their assembled p 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

55 Pa g e 55 of 212 * Ol' King Fred was quite the budding scien ther digestion was tist. Then there was the time he got interest ed in digestion. Frederick wondered whe n brought from his prison, fed identical and sumptuous di you exercised. He had two me faster when you rested after eating or if nners, and sent one That phase of the experiment completed, he had both men return off to nap afterward, while the other went for a strenuous hunt. ed to his court, disemboweled in front of him, and their innards examined. The sleeper had digested his food better. study, growth rates in Orphanage A, Growth rates in the two German orphanage s. During the first 26 weeks of the under the administration of Fraulein Grun, were much greater than those in Orphanage B, with the stern Fraulein Schwarz. At 26 weeks (vertical line), Fraulein Grun left Orphanage A and was replaced by Fraulein Schwarz. The rate of growth in that orphanage promptly slowed; growth in Orphanage B, now minus the stern Fraulein Schwarz, accelerated and soon surpassed that of Orphanage A. A fascinating elaboration emerges from the fact that Schwarz was not completely heartless, but had a subset of children who were her favorites (Curve C), whom she had transferred with her. Fraulein Schwarz's kids grew in height and wei ght at a slower pace than the kids in the other were entirely different. orphanage. Then, in an elabor ation that couldn't have been more useful if it had been planned by a scientist, Fraulein Grun moved on to greener pastures and, for some bureaucra tic reason, Fraulein Schwarz was transferred to the other in her new one decreased. orphanage. Growth rates in her former orphanage promptly increased; those A final and truly disturbing example comes to mind. If y ou ever find yourself reading chapter after chapter about I don't recommend), you growth endocrinology (which will note an occasional odd re ference to Peter Pan—perhaps a a snide comment about Tinker Bell. I'd long quotation from the play, or noted the phenomenon and finally, in a chapter in one textbook, I found the explanation for it. The chapter reviewed the regulation of gr owth in children and the capacity for severe psychological stress to trigger tish Victorian family. A son, age thirteen, the beloved e that occurred in a Bri psychogenic dwarfism. It gave an exampl favorite of the mother, is killed in an accident. The mother, despairing and bereaved, takes to her bed in grief for years afterward, utterly ignoring her other, si x-year-old son. Horr ible scenes ensue. For exampl e, the boy, on one occasion, enters her darkened room; the mo s it is the dead son—"David, is that you? ther, in her delusional state, briefly believe Could that be you?"—before realizing: "Oh, it is only you." Growing up, being "only you." On the rare instances ger son, she repeatedly expresses the same obsessive thought: the only solace when the mother interacts with the youn she feels is that David died when he was still perfect, still a boy, never to be ruined by growing up and growing away from his mother. vant to the family dynamics), seizes ant father seemed to have been irrele The younger boy, ignored (the stern, dist upon this idea; by remaining a boy forever, by not growing up, he will at least have some chance of pleasing his -do family, he ceases mother, winning her love. Alth ough there is no evidence of disease or maln utrition in his well-to growing. As an adult, he is just barely five feet in height, and his marriage is unconsummated. at the boy became the author of th J. e much-beloved children's classic— And then the chapter informs us th Peter Pan. M. Barrie's writings are filled with children who didn't grow up, who were fortunate enough to die in childhood, who visit their mothers. came back as ghosts to THE MECHANISMS UNDERLYING STRESS DWARFISM 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

56 Pa g e 56 of 212 Stress dwarfism involves extremely low growth hormone levels in the circulation. The sensitivity of growth hormone ed a single child with stress dwarfism. own as clearly as in a paper that follow to psychological state has rarely been sh ssigned to a nurse who spent a great deal of time with him and to whom he When brought to the hospital, he was a became very attached. Row A in the tabl e below shows his physiolo gical profile upon entering the hospital: extremely low growth hormone levels and a low rate of growth. Row B shows his profile a few months later, while still in the hospital: growth hormone levels have (without his having received any synthetic hormones), and more than doubled the growth rate has more than tripled. The y of Growth to Emotional State A Demonstration of the Sensitivit Growth hormone Growth Food intake Condition 1663 0.5 5.9 A. Entry into hospital B. 100 days later 13.0 1.7 1514 1504 C. Favorite nurse on vacation 6.9 0.6 15.0 1521 D. Nurse returns 1.5 Source: From Saenger and colleagues, 1977. Growth hormone is measured in nanograms of the hormone per milliliter d as centimeters per 20 days. Food intake is expressed in of blood following insulin stimulation; growth is expresse calories consumed per day. stress dwarfism is not a problem of insufficient food—the boy was eating more at the time he entered the hospital than a few months later, when his growth resumed. rse went on a three-week vacation. De spite the same food intake, growth Row C profiles the period when the nu ter the nurse returned from vacation. nally, Row D shows the boy's profile af hormone levels and growth plummeted. Fi eature of growth, the rate at which this child was depositing This is extraordinary. To take a concrete, nuts and bolts f calcium in his long bones could be succe ssfully predicted by his proximity to a loved one. You can't ask for a clearer y cell in our bodies. heads influences ever demonstration that what is going on in our Why do growth hormone levels decline in these kids? Growth hormone is secreted by the pituitary gland, which in turn is regulated by the hypothalamus in the brain (see chapter 2) . The hypothalamus controls the release of growth hormone through the secretion of a stimulatory hormone and an inhibitory one, and it looks as if stress dwarfism involves too much release of the inhibitory hormone. Stre e sympathetic nervous system ss-induced overactivity of th may play some role in this. Furthermore, the body becomes less responsive to what little growth hormone is actually secreted. Therefore, even ad ministering synthetic growth hormone doesn't necessarily solve the growth problem. growth hormone release as Some stress dwarfism kids have elevated glucocorticoid levels, and the hormone blunts well as responsiveness of the body to growth hormone. Kids with stress dwarfism also have gastrointestinal problem s, in that they're impaired at absorbing nutrients from their intestines. This is probably because of the enhanced activity of their sympathetic nervous syst ems. As discussed in chapter 5, this intestinal walls, of the stomach and scular contractions will halt the release of various digestive enzymes, stop the mu and block nutrient absorption. This tells us something about which stress hormones shut down growth. But what is it about being reared under growth? Cynthia Kuhn and Saul Schanberg of Duke pathological conditions that causes a failure of skeletal University and, in separate studies, Myron Hofer of the New York State Psyc hiatric Institute, have examined that the smell of Mom that would normally stimulate growth? Is it question in infant rats separated from their mothers. Is it something in her milk? Do the rats get chilly without her? Is it the rat lullabies that she sings? You can imagine the various ways scientists test for these possibilities—playing recordings of Mom's vocalizations, pumping her odor into titutes for the real thing. the cage, seeing what subs 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

57 Pa g e 57 of 212 It turns out to be touch, and it has to be active touching. Separate a baby rat from its mother and its growth hormone levels plummet. Allow it contact with its mother while she hormone is still low. Mimic is anesthetized, and growth active licking by the mother by stroking the rat pup in the proper pattern, and growth normalizes. In a similar set of findings, other investigators have observed that handling neonatal rats causes them to grow faster and larger. classic study. Tiffany Field The same seems to apply in humans, as demonstrated in a of the University of Miami School of Medicine, along with Schanberg, Kuhn, and others, performed an incredibly simple experiment that was smal mortality rates in orphan ages and pediatric wards, as inspired both by the rat research and by the history of the di discussed earlier. Studying premature infants in neonatology wards, they noted that the premature kids, while conditions, were hardly ever touched. So Field and crew pampered and fretted over and maintained in near-sterile went in and started touching them: fifteen-minute periods, three times a day, stroking their bodies, moving their limbs. 50 percent faster, were more active an d alert, matured faster behaviorally, It worked wonders. The kids grew nearly and were released from the ho spital nearly a week earlier than the premature infants who weren't touched. Months touched. If this were done in every neonatology ward, later, they were still doing better than infants who hadn't been this would not only make for a lot more healthy infants, but would save approximately a billion dollars annually. It's gans, pacemakers—has the medical instrumentation—MR rare that the highest technology of I machines, artificial or potential for as much impact as this simple intervention. Pigtailed macaque mother and infant. an infant. We readily think of stressors as consisting of various unpleasant Touch is one of the central experiences of things that can be done to an organism. Sometimes a stressor can be the failure to provide something essential, and the rked developmental stressors that we can suffer. absence of touch is seemingly one of the most ma STRESS AND GROWTH HORMONE SECRETION IN HUMANS in humans from rodents, and the implications can be The pattern of growth hormone secretion during stress differs fainthearted. So feel free to go to the bathroom now and fascinating. But the subject is a tough one, not meant for the come back at the ne xt commercial break. mediately. If the stressor e circulation decline almost im When a rat is first stressed, growth hormone levels in th as we have seen, in humans major and prolonged stressors continues, growth hormone levels remain depressed. And cause a decrease in growth hormone levels as well. The weird thing is that during the period immediately following the onset of stress, growth hormone levels actually go up in humans and some other species. In these species, in other ually stimulates growth hormone secretion for a time. words, short-term stress act 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

58 Pa g e 58 of 212 Why? As was mentioned, growth hormone has two classes of effects. In the first, it stimulates somatomedins to stimulate bone growth and cell division. This is the growing part of the story. But in addition, growth hormone works is the energy for the growth. em into the circulation. This directly on fat cells, breaking down fat stores and flushing th for the new building, but arranges financing for the work In effect, growth hormone not only runs the construction site as well. Now that business about breaking down stored energy and flushing it into the circulation should sound familiar— that's precisely what glucocorticoids, epinephrine, norepinephrine, and glucagon are doing during that sprint from the lion. So those direct growth hormone actions are similar to the energy mobilization that occurs during stress, while the somatomedin-mediated growth hormone actions are not what you want to be doing. During stress, therefore, it is mone insofar as it helps to mobilize energy, but a bad move to secrete growth hormone adaptive to secrete growth hor insofar as it stimulates an expens oject like growth. ive, long-term pr as is the sensitivity of the body to that hormone. This is As noted, during stress, somatomedin secretion is inhibited, s, while blocking its more perfect—you secrete growth hormone during stress and still ge t its energy-mobilizing effect explicit growth-promoting effects. To extend the metaphor used earlier, growth hormone has just taken out cash from solve the body's immediate on; instead, the cash is used to the bank, aiming to fund the next six months of constructi emergency. Given this clever solution—sp are the growth hormone, block the somatomedins—why should growth hormone levels ther immediately, as in the rat, or after a while, as in humans)? It is probably because decline at all during stress (whe the system does not work pe rfectly—somatomedin action is not completely shut down during stress. Therefore, the energy-mobilizing effects of growth hormone might still be used for growth. Perhaps the timing of the decline of growth hormone levels in each speci es is a compromise between the trait triggered by the hormone that is good news during stress and the trait that is undesirable. What impresses me is how careful and calculating the body has to be during stress in order to coordinate hormonal balance the costs and benefits, knowi stop secreting the activities just right. It must perfectly ng exactly when to hormone. If the body miscalculates in one direction and growth hormone secretion is blocked too early, there is relatively less mobilization of energy for dealing with the stre ssor. If it miscalculates in the other direction and growth hormone secretion goes on too long, stress may actually enhance growth. One oft-quoted study suggests that the second type of error occurs during some stressors. hn Whiting of Harvard methodically studied the rites of In the early 1960s, Thomas Landauer of Dartmouth and Jo passages found in various non-Western societies around the world; they wanted to know whether the stressfulness of the ritual was related to how tall the kids wound up being as adults. Landauer and Whiting classified cultures according to whether and when they subject ed their children to physi cally stressful development rites. Stressful rites or ears; circumcision, inoculation, scarification, or cauterization; stretching or binding included piercing the nose, lips, of limbs, or shaping the head; exposure to hot baths, fire, or intense sunlight; exposure to cold baths, snow, or cold air; emetics, irritants, and enemas; rubbing with sand, or scraping with a shell or other sharp object. (And you thought having to play the piano at age ten for your grandmother's friends was a stressful rite of passage.) sion of the time, Landauer and Whiting only studied males. They examined Reflecting the anthropological tunnel vi efully controlled for a potential problem with the data—they collected eighty cultures around the world and car and without those stressful examples from cultures from the same gene pools, with rituals. For example, they e Yoruba (stressful rituals) and Ashanti (nonstressful), and similarly matched compared the West African tribes of th Native American tribes. With this appr tic contributions to stature (as well as oach, they attempted to control for gene nutrition, since related ethnic groups were likely to have similar diets) and to examine cultural differences instead. of ages six to fifteen went Given the effects of stress on growth, it was not surprising that among cultures where kids (relative to cultures without such rituals, the difference through stressful maturational rituals, growth was inhibited was about 1.5 inches). Surprisingly, going through such rituals at ages two to six had no effect on growth. And most surprising, in culture s in which those rituals took place with kids under two years of age, growth was stimulated—adults were about 2.5 inches taller than in cultures without stressful rituals. There are some possible confounds that could explain the results. One is fairly silly—maybe tall tribes like to put their young children through stressful rituals. One is more plausible—maybe putting very young children through these stressful rituals kills a certain percentage of them, and wh at doesn't kill you makes you stronger and taller. Landauer and Whiting noted that possibility and could not rule it out. In addition, even though they attempted to pair similar groups, there may have been differences other than just th e stressfulness of the rites of passage—perhaps in diet or child-rearing practices. Not surprisingly, no one has ever measured levels of growth hormone or somatomedins, in, say, Shilluk or Hausa kids while they are undergoing some grueling ritual, so there is no direct endocrine evidence 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

59 Pa g e 59 of 212 that such stressors actually stimulate growth hormone s ecretion in a way that incr eases growth. Despite these anthropologists as ve been interpreted by many biological problems, these cross-cultural studies ha evidence that some types of stressors in humans can actually stimulate growth, amid the broader literature showing the growth- suppressing effects of stress. ENOUGH ALREADY have bad and long-term consequences. prenatal or early childhood stress can So there's a whole bunch of ways that This can be anxiety provoking; it gets me into a storm of parental agitation just to write about this. Let's figure out what's worrisome and what's not. First, can fetal or childhood exposure to synthetic glucocorticoids have lifelong, adverse effects? Glucocorticoids anti-inflammatory immunosuppressive or in vast amounts, because of their (such as hydrocortisone) are prescribed effects. During pregnancy, they are ad ministered to women with certain endocr o are at risk for ine disorders or wh delivering preterm. Heavy administration of them during pregnancy has been reported to result in children with smaller head circumferences, emotional and behavioral pr oblems in childhood, and slowing of some developmental landmarks. Are these effects lifelong? No one knows. At this point, the experts have weighed in emphatically stating or postnatal life has no advers e effects, though there is that a single round of glucocorticoids during either fetal potential for problems with heavy use. But heavy doses of glucocorticoids are not ss going on, so the most prudent advice is administered unless there's a serious illne to minimize their use clinically but disease that prompted the treatment in the first place, is most probably worse. to recognize that the alternative, the e an adverse scar forever after, unto What about prenatal or postnatal stress? Does every little hiccup of stress leav ology may apply to extreme si multiple generations? Many times, some relationship in bi tuations—massive trauma, a y, even the normal ones. Unfortunatel whole winter's famine, and so on—but not to more everyday range of birth Metabolic syndrome. So these appear not to be phenomena weights predicts adult glucocorticoid levels and the risk of only of the extremes. een evidence that increasing am Next important question: How big are the effects? We've s ounts of fetal stress, over the normal range, predict incr easing risk of Metabolic synd rome long afterward. That statement may be true and describes one of two very different scenario s. For example, it could be that the lowest levels of fetal stress result in a 1 sk until an exposure to a percent risk of Metabolic syndrome, and each increase in st ress exposure increases the ri maximal fetal stress results in a 99 per uld result in a 1 percent risk, and each cent chance. Or the least fetal stress co l stress results in a 2 percent risk. In both increase in stress exposure in creases the risk until exposure to maximal feta of fetal stress to increase cases, the endpoint is sensitive to small incr ements in the amount of stress, but the power tail in later chapters, early stress and rst scenario. As we will see in more de disease risk is vastly greater in the fi trauma seem to have a tremendous powe r in increasing the risk of various psychiatric disorders many years later. ion that it constitutes cool biology of the "Gee whiz, isn't Some critics of the FOAD literature seem to be of the opin these adult diseases vary nature amazing" variety, but is not a major source of worry. However, the risks of some of manyfold as a function of birth weight—so these strike me as big effects. Next question: Regardless of how powerful these effects are, how they? Lose it once in a crazed, inevitable are sleepless moment at two in the morning and yell at your colicky infant and is that it, have you just guaranteed more clogging of her arteries in 2060? Not remotely. As discussed, stress dwarfism is reversible with a different environment. Studies have shown that the lifelong changes in glucocorticoid levels in prenatally stressed rats can be of preventative medicine is a demonstration that vast prevented with particular mothering styles postnatally. Much tions can be reversed—in fact, th at is a premise of this book. numbers of adverse health situa which Our Babies, Ourselves, The Cornell anthropologist Merideth Small has written a wonderfully un-neurotic book, across the planet. In a particular culture, how often is a child typically held by parents, looks at child-rearing practices by non-parents? Do babies sleep alone ever and, if so, starting at wh at age? What is the aver age length of time that a fore she is picked up and comforted? child cries in a particular culture be ates, come out at the extreme in these eties and, in particular, the United St In measure after measure, westernized soci cross-cultural measures, with our emphasis on individuality, independence, and self-reliance. This is our world of both ds, of day care and latchkey kids. There is little evidence parents working outside the home, of single-parent househol cal scars, in contrast to th that any of these childhood expe e results of horrific childhood riences leave indelible biologi trauma. But whatever style of child-rear ing is practiced, it will have its consequences. Small makes a profound point. You begin by reading her book assuming it is going to be an assortment box of prescriptions, that at the end, you'll obriand Sleeping Program, akiutl Baby Diet, the Tr emerge with a perfect combo for your kids, a mixture of the Kw ural" program. Societies and the Ituri Pygmy Infant Aerobics Pl an. But, Small emphasizes , there is no perfect, "nat to adults who behave in a way valued by that society. As Harry Chapin sang in raise their children so that they grow in "Cat's in the Cradle," that ode to baby boomer remorse, "My boy was just like me." 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

60 Pa g e 60 of 212 GROWTH AND GROWTH HORMONE IN ADULTS Personally I don't grow much anymore, except wider. According to the textbooks, another half-dozen Groundhog Days or so and I'm going to start shrinking. Yet I, like other adults, still secrete growth hormone into my circulation . What good is it in an adult? than when I was an adolescent) (although much less frequently the bodies of adults have to work harder and harder just to keep standing Alice in Wonderland, Like the Red Queen in te, the hormones of growth in the same place. Once the growth period of youth is fini shed and the edifice is comple mostly work at rebuilding and remodeling—shoring up the sagging foundation, plastering the cracks that appear here and there. etty boring and phlegmatic— probably view our bones as pr Much of this repair work takes place in bone. Most of us they just sit there, inert. In reality, they are dynamic outposts of activity. They are filled with blood vessels, with little fluid-filled canals, with all sorts of cell types that are actively growing and dividing. New bone is constantly being formed, in much the same way as in a teenager. Old bone is being broken down, disintegrated by ravenous enzymes (a process called d away. Growth hormone, resorption). New calcium is shuttled in from the bloods tream; old calcium is flushe somatomedins, parathyroid hormone, and vitamin D stand around in hard hats, supervising the project. Why all the tumult? Some of this bustle is because bo nes serve as the Federal Reserve for the body's calcium, constantly giving and collecting loans of calcium to and from other organs. And part is for the sake of bone itself, allowing it to gradually rebuild and change its shape in response to need. How else do cowboys' bow-legged legs get bowed from too much time on a horse? The process has to be kept well balanced. If the bones sequester too much of ; if the bones dump too much the body's calcium, much of the rest of the body shuts down of their calcium into the ing calcified e and prone to fracture, and can start form bloodstream, they become fragil that excess circulating calcium kidney stones. Predictably, the hormones of stress wreak havoc with the trafficking of calcium, biasing bone toward disintegration, rather than growth. The main culprits are glucocorticoids. They inhibit the growth of new bone by disrupting the . Furthermore, they reduce th division of the bone-precursor cells in the ends of bones e calcium supply to bone. Glucocorticoids block the uptake of di etary calcium in the inte stines (uptake normally st imulated by vitamin D), dney, and accelerate the increase the excretion of calcium by the ki resorption of bone. orticoids, this increases the risk that your bones will eventually give you If you secrete excessive amounts of glucoc problems. This is seen in people with Cushing's syndrome (in which glucocorticoids are secreted at immensely high levels because of a tumor), and in people being treated with high doses of glucoc orticoids to control some disease. In sis (softening and weakening at greater risk for osteoporo those cases, bone mass decreases markedly, and patients are of bone).* Any situation that greatly el particular problem evates glucocorticoid concentrations in the bloodstream is a for older people, in whom bone ld War II. The recent sustained in the PT109 disaster in Wor * JFK had a famously bad back, which his public ists always attributed to the injuries he due to severe osteoporosis, du e to the massive levels of sy nthetic glucocorticoids opening of his sealed medical records indicate that it was probably he took for his Addison's disease and colitis. resorption is already predominant (in cont rast to adolescents, in whom bone growth predominates, or young adults, in which the two processes are balanced). This is especially a problem in older women. Tremendous attention is now being paid to the need for calcium supplements to preven t osteoporosis in postmenopausal women. Estrogen potently r menopause, the bones suddenly begin to degenerate.* A inhibits bone resorption, and as estrogen levels drop afte hefty regimen of glucocorticoids on top of that is the last thing you need. These findings suggest that chronic st ress can increase the risk of osteoporo sis and cause skeletal atrophy Most clinicians would probably say that the glucocorticoi d effects on bone are "pha rmacological" rather than "physiological." This means that normal (physiological) levels of glucocorticoids in the bloodstream, even those in it takes pharmacological levels of the response to normal stressful events, ar e not enough to damage bone. Instead, hormone (far higher than the body can normally generate), due to a tumor or to ingestion of prescription chronic social stress glucocorticoids, to cause thes group has shown that e effects. However, work from Jay Kaplan's leads to loss of bone mass in female monkeys. A FINAL WORD ABOUT THE L-WORD s of all sorts of In looking at research on how stress and understimulation can disrupt growth and increase the risk ll fed, maintained at an adequate an infant human or animal can be we diseases, a theme pops up repeatedly: 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

61 Pa g e 61 of 212 temperature, peered at nervously, and ministered to by the best of neonatologists, yet still not thrive. Something is still missing. Perhaps we can even risk scientific credibility and detachment and mention the word here, because that love thing roughly akin to love is needed for rks between the lines of this chapter. Some most ephemeral of phenomena lu proper biological development, and its absence is among the most aching, di storting stressors that we can suffer. s importance in the mundane Scientists and physicians and other caregivers have ofte n been dim at recognizing it develop. For example, at th e beginning of the twentieth biological processes by which organs and tissues grow and rt on child-rearing century the leading expe disease, it remains ial whether estrogen protects from cardiovascular * To reiterate a point from chap ter 3, while right now it is wildly controvers clear that it protects from osteoporosis. rents of the adverse effects of the "vicious practice" of was a Dr. Luther Holt of Columbia University, who warned pa using a cradle, picking up the child when it cried, or handling it too often. All the experts believed that affection not only wasn't needed for development but was a squishy, messy thing that kept kids from becoming upright, wrong in a classic set of independent citizens. Yet young organisms were able to teach about how these savants were studies begun in the 1950s—studies that are, in my opinion, among the most haunting and troubling of all the pages of science. The work was carried out by the psychologist Harry Harlow of the University of Wisconsin, a renowned and nated by either Freudians or controversial scientist. Psychology at that time was domi a rather extreme school of thought called behaviorism, in which beha vior (of an animal or a human) was thought to operate according to rather simple rules: an organism does somethi ng more frequently because it has been re warded for it in the past; an organism that behavior. In been punished for has failed to be rewarded, or has even does something less frequently because it this view, just a few basic things like hunger, pain, or sex lie forcement. Look at the behaviors, view at the basis of rein op a predictive mathematics built around the idea of rewards organisms as machines responding to stimuli, and devel and punishments. Harlow helped to answer a seemingly obvious question in a non-obvious way. Why do infants become attached to as attachment was thought to arise . For behaviorists, this was obvious, their mothers? Because Mom supplies food solely from the positive reinforcement of food. For Freudians, it was also obvious—infants were thought to lack the "ego development" to form a relationship with any thing/ one other than Mom's breast. For physicians influenced by for mothers to visit hospitalized infants—anyone with a the likes of Holt, it was obvious and convenient—no need out preemies kept antiseptically isolated in incubators— bottle would supply attachment needs. No need to worry ab regular feeding suffices for human contact. No need for children in orphanages to be touched, held, noted as individuals. What's love got to do with healthy development? rhesus monkeys without mothers. Instead, he gave them a choice of two types Harlow smelled a rat. He raised infant of artificial "surrogate" mothers. One pseudo-mother had a monkey head constructed of wood and a wire-mesh tube of milk. This surrogate mother gave nutrition. The other resembling a torso. In the middle of the torso was a bottle o. But instead of containing a milk bottle, this one's torso was head and wire-mesh tors surrogate mother had a similar wrapped in 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

62 Pa g e 62 of 212 Infant monkey and cloth mo ther, in a Harlow study. nuggling up to the milk-mom within seconds. But not the terry cloth. The behaviorists and the Freudians would be s ecause Mom balances their don't love their mothers b baby monkeys—they chose the terry-cloth mothers. Kids sults suggested. They love th them back, or at least is nutritive intake, these re em because, usually, Mom loves someone soft to cling to. "Man cannot live by milk alone. Love is an emotion that does not need to be bottle- or spoon -fed," wrote Harlow. ntroversy arises from the nature of his experiments and Harlow and his work remain immensely controversial.* The co te social isolation, in whic variations on them (for example, raising monkeys in comple h they never see another living and they are often among the primary on es cited by those opposed to animal animal). These were brutal studies, reover, Harlow's scientific writing experimentation. Mo Love at Goon Park: Harry Harlow and the Science * An excellent biography about Harlow, by the Pulitzer Prize-winning author Deborah Blum, is of Affection (Perseus 2002). s—I remember as a student being moved to tears of e suffering of these animal displayed an appalling callousness to th rage by the savage indifference of his writing. been extremely useful (alt hough my feeling is that there should have been far But at the same time, these studies have ce of why we primates love individuals who treat us badly, fewer of them carried out). They have taught us the scien a child increases why being abused as e the love. They have taught us about why the mistreatment can at times increas the risk of your being an abusive adult. Other aspects of Harlow's work have taught us how repeated separations of infants from their mothers can predispose those in dividuals to depression when they are adults. The irony is that it required Harlow's pioneering work to de of that work. But wasn't it monstrate the unethical nature ally isolate us as infants, do we not suffer? Few in the obvious before? If you prick us, do we not bleed?; if you soci me to have been ght now wrongly assu know thought so. The main point of Harl ow's work wasn't teaching what we mi obvious then, namely that if you isolate an infant monkey, it is a massive stressor, and th at she saddens and suffers for if you do the same to a human infant, the same occurs. long after. It was to teach the utterly novel fact that 7 SEX AND REPRODUCTION 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

63 Pa g e 63 of 212 Kidneys and pancreas and h eart are important, but what we really want to know is why, when we are being stressed, our menstrual cycles become irregular, erections are more difficult to achieve, and we lose our interest in sex. As it turns out, there are an astonishing number of isms may go awry when we are ways in which reproductive mechan upset. MALES: TESTOSTERONE AND LOSS OF ERECTIONS It makes sense to start simple, so let's initially consider th e easier reproductive system, that of males. In the male, the stimulates the pituitary to release brain releases the hormone LHRH (lutei nizing hormone releasing hormone), which one).* LH, in turn, stimulates the testes to release LH (luteinizing hormone) and FSH (follicle-stimulating horm ed by follicle-stimulating hormone, FSH instead stimulates testosterone. Since men don't have follicles to be stimulat sperm production. This is the reproductive system of your basic off-the-rack male. LHRH concentrations decline, followed shortly thereafter With the onset of a stressor, the whole system is inhibited. and FSH, and then the testes clos line in circulating testosterone e for lunch. The result is a dec by declines in LH levels. The most vivid demonstrations of this "gonadotropin releasing hormone." * LHRH is also known as GnRH, or 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

64 Pa g e 64 of 212 A simplified version of male reproductive endocrinology. The hypothalamus releases LHRH into the private ary. LHRH triggers the release by the pituitary of LH and circulatory system that it shares with the anterior pituit FSH, which work at the testes to cause testosterone secretion and sperm production. occur during physical stress. If a male goes through surgery, within seconds of the first slice of a scalpel through his skin, the reproductive axis begins to shut down. Injury y—all of these drive down , illness, starvation, surger testosterone levels. Anthropologists have even shown that in human societies in which there is constant energetic ere are significantly lower test osterone levels than among stress (for example, those of rural Nepalese villagers), th sedentary Bostonian controls. primate and down go rank of a social st as disruptive. Lower the dominance But subtle psychological stressors are ju his testosterone levels. Put a person or a monkey through a stressful learning task and the same occurs. In a celebrated mous amount of physical study several decades ago, U.S. Officer Candidate School train ees who underwent an enor and psychological stress were subjected to the further indignity of having to pee into Dixie cups so that military hold, testosterone levels were down; maybe not to the psychiatrists could measure their hormone levels. Lo and be levels found in cherubic babies, but still it's worth keeping in mind the next time you see some leatherneck at a bar bragging about his circulating androgen concentrations. easons. The first occurs at a stressor? For a variety of r Why do testosterone concentrations plunge with the onset of two important classes of hormones, the endorphins and enkephalins (mostly the the brain. With the onset of stress, mus. As will be discussed in chapter 9, endorphins play former), act to block the release of LHRH from the hypothala 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

65 Pa g e 65 of 212 a role in blocking pain perception and ar e secreted in response to exercise (h elping to account for the famed "runner's high" or "endorphin high" that hits many hardy joggers around the 30-minute mark). If males secrete endorphins when d these compounds inhibit testosterone they are experiencing runner's high, an release, will exercise suppress male extreme amounts of exer onal soccer players and reproduction? Sometimes. Males who do cise, such as professi runners who cover more than 40 or 50 miles a week, have less LHRH, LH, and testosterone in their circulation, smaller testes, less functional sperm. They also have higher le vels of glucocorticoids in their bloodstreams, even in the absence of stress. (A similar decline in reproductive function is found in men who are addicted to opiate drugs.) To also seen in women athletes, an jump ahead to the female section, reproductive dysfunction is d this is at least partially due to endorphin release as well. Up to half of competitive runners have menstrual irregularities, and highly athletic For example, in one study of fourteen-year-olds, ap proximately 95 percent of girls reach puberty later than usual. control subjects had started menstruating, whereas only 20 percent of gymnasts and 40 percent of runners had. ' good. Obviously, if you don't exercise at all, it is not This brings up a broader issue important to our era of lookin good for you. Exercise improves your health. And a lot of ex ercise improves your health a lot. But that doesn't mean are insanely good for your body. At some point, too much begins to damage that insanely large amounts of exercise be as bad as too little. various physiological systems. Everything in physiology foll ows the rule that too much can There are optimal points of al lostatic balance. For example, while a moderate amount of exercise generally increases bone mass, thirty-year-old athletes who with decalcified bones, decreased bone run 40 to 50 miles a week can wind up and scoliosis (sideways curv ature of the spine)—their mass, increased risk of stress fractures skeletons look like those of seventy-year-olds. group of hunter-gatherers from the African grasslands and To put exercise in perspective, imagine this: sit with a explain to them that in our world we ha ve so much food and so much free time th at some of us run 26 miles in a day, are likely to say, "Are you crazy? That's stressful." Throughout hominid simply for the sheer pleasure of it. They very intent on eating someone or someone's very intent on history, if you're running 26 miles in a day, you're either eating you. secretion declines. In addition, prolactin, another pituitary Thus, we have a first step. With the onset of stress, LHRH hormone that is released during major stressors, decreases the sensitivity of the pituitary to LHRH. A double whammy—less of the hormone dribbling out of the brain, and the pituitary no longer responding as effectively to it. LH, just in case any of that hormone manages to reach Finally, glucocorticoids block the response of the testes to elevations of glucocorticoids in their hletes tend to have pretty dramatic them during the stressor (and serious at circulation, no doubt adding to the reproductive problems just discussed). A decline in testosterone secretion is only half the story of what goes wrong with male reproduction during stress. The work properly is so incredibly other half concerns the nervous syst em and erections. Getting an erection to complicated physiologically that if men ever actually had to understand it, none of us would be here. Fortunately, it runs automatically. In order for a male pr imate to have an erection, he has to divert a considerable amount of blood flow to his penis, engorging it.* rote that, "The penis flow to the penis. He also w ections arise from increased blood * Weirdly, Da Vinci was the first to demonstrate (how!?) that er [It] must be said to have a mind of its own." When combining his statement and scie ntific observation, it's does not obey the order of its master. . .. to his penis and brain simultane ously. only a few short steps to the fa med wisecrack and near truism th at a man can't have blood flow 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

66 Pa g e 66 of 212 Overexercise can have a variety of dele photographic terious effects. {Left) Max Ernst, Health Through Sport, collage with Above the Clouds Midnight Passes, enlargement of a photomontage mounted on wood, 1920; (right) fragments of photographs and pencil, 1920. vous system. In other words, This is accomplished by activating his parasympathetic ner the guy has to be calm, vegetative, relaxed. ybe you are breathing faster, ific time with someone. Ma What happens next, if you are male? You are having a terr your heart rate has increased. Gradually, parts of your body are taking on a sympathetic tone—remember the four F's of sympathetic function introduced in chapter 2. After awhile, most of your body is screaming sympathetic while, heroically, you are trying to hold on to parasympathetic tone in that one lone outpost as long as possible. Finally, when you can't take it anymore, the parasympathetic shuts tic comes roaring on, and you off at the penis, the sympathe graphy between these two systems; don't try this unsupervised.) This new ejaculate. (Incredibly complicated choreo understanding generates tricks that sexual therapists advise—if you are close to ejaculating and don't want to yet, take a deep breath. Expanding the chest muscles briefly triggers a parasympathetic volley that defers the shift from parasympathetic to sympathetic. What, then, changes during stress? One is that sufficient prior stress will damage and clog up your blood vessels— t what if you're stressed in that immediate situation? severe vascular disease can seriously impede blood flow. Bu calm or vegetative. First, it becomes difficult to establish Well, obviously, if you're nervous or anxious, you're not parasympathetic activity if you are nervous or anxious. You have trouble having an erection. Impotency. And if you already have the erection, you get in trouble as well. You' re rolling along, parasympathetic to your penis, having a wonderful time. Suddenly, you find yourself worrying about the strength of the dollar versus the euro and— ed. Premature ejaculation. shazaam—you switch from parasympathetic to sympathetic far faster than you want d premature ejaculatio It is extremely common for problems with impotency an n to arise during stressful times. Furthermore, this can be co mpounded by the fact that erectile dysfunction is a major stressor on its own, getting men fear itself. A number of studies xiety cycle of fearing have shown that more than half into this vicious performance an the visits to doctors by males complaining of reproductive dysfunction turn out to be due to "psychogenic" impotency rather than organic impotency (there's no disease there, just too much stress). How do you tell if it is organic or psychogenic impotency? This is actuall y diagnosed with surprising ease, b ecause of a quirky thing about human and enter REM (rapid eye movement) males. As soon as they go to sleep dream sleep, they get erections. I've consulted with Earth's penis experts, and no one is sure why this should occur, but that's how it works.* So a man comes in complaining that he hasn't been able to have an erection in six months. Is he just under stress? Does he have some neurological disease? Take a handy little penile cuff w ith an electronic pressure transducer attached to it. Have him put it on just before he goes to sleep. By the next morning you may have your answer—if this guy gets an + erection when he goes into REM sleep, hi s problem is likely to be psychogenic. good is that). "So aising the question, of course, of what o trigger sexual themes during dreams" (r * There's some great speculations, however: "T the body can practice at having erections, in preparation for the real thing." "Because." having to use one of these fancy electronic cuffs that seems l + I've been told about an advance on this technology. Instead of ikely to electrocute nstitutes a stressor on its own, here's what y you during the night, and thus co y) postage stamps. ou do. Take a string of (I don't specify how man the others, forming a postage stamp ring. The next morning, ch Wrap it around the guy's penis, moisten the last one, tape it to eck: if the stamps have been pulled loose on one side or torn, the guy had a REM-stage erection during the night—fabulous , a lab result for a couple of bucks. The out reimbursement for it, though. insurance people will hassle you ab l, the problems with erections are more disruptive than Thus, stress will knock out erections quite readily. In genera problems with testosterone secretion. Testosterone and sperm production have to shut down almost entirely to affect performance. A little testosterone and a couple of sperm wa ndering around and most males can muddle through. But no erection, and forget about it.* The erectile component is exquisitely sensitive to stress in an incredible array of species . Nonetheless, there are some ress the reproductive system in a male. Suppose you're some big bull moose circumstances where stress does not supp and it's mating season. You're spending all your time strutting your stuff and growing your antlers and snorting and having head-butting territorial disputes with the next guy and forgetting to eat right and not getting enough sleep and getting injured and worrying about the competition for some female moose's favors.+ Stressful. Wouldn't it be pretty maladaptive if the male-male competitive behaviors needed to get the opportunity to mate were so stressful that when the opportunity came, you were sexually dysfunctional? Not a good Darwinian move. Or suppose that in your species, sex is this wildly meta bolically demanding activity, involving hours, even days of copulation at the cost of resting or feeding (lions fall in ample). High energetic demands plus little this category, for ex eating or sleeping equals stress. It would be disadvantageous if the stress of mating caused erectile dysfunction. It turns out that in a lot of species, stressors associated with mating season co mpetition or with mating itself not only a bit. In some species where this applies, the seeming don't suppress the reproductive system, but can stimulate it 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

67 Pa g e 67 of 212 stressor doesn't cause secretion of stress hormones; in other cases, the stress hormones are secreted but the reproductive system becomes insensitive to them. l the rules concerning which, regardless of whether it is mating s And then there is one species eason or not, breaks al function. It is time we had a little talk about hyenas. the effects of stress on erectile sence of desire. This is illustrate * It is important to note that an inability to have an d by a story I once read erection is not synonymous with an ab about Marx in his old age— Grouc ho in this case. A visitor to his home was admiring his various awards and com-memoratives of h is career. Marx upting erections, ll for one good erection. Stress can most ce waved them away saying, I'd trade them a rtainly squelch desire, independent of disr through mechanisms that are poorly understood. + Actually, I have no idea if moose grow an tlers during mating season, or even if thos e things that Bullwinkle had on top of his head are technically called antlers or horns or what have you's, but you get the point—all this macho male display stuff. OUR FRIEND, THE HYENA The spotted hyena is a vastly unappreciated ecause over the years, in my work in , misrepresented beast. I know this b East Africa, I have shared my campsite with the hyena biologist Laurence Frank of the University of California at Berkeley. For lack of distracting television, radio, or telephone, he has devoted his time with me to singing the hyena's praises. They are wondrous animals who have gotten a bad rap from the press. Wild Kingdom vanna. Marlin Perkins of Mutual of Omaha's We all know the scenario. It's dawn on the sa is there filming lions eating something dead. We are delighted, craning to get a good view of the blood and guts. Suddenly, on untrustworthy hyenas looking to dart in and steal some the edge of our field of vision, we spot them— skulky filthy, of the food. Scavengers! We are invited to heap our contempt on them (a surprising bias, given how few of the canines). It wasn't until the Pentagon purchased a new carnivorous among us ever wr estle down our meals with our line of infrared night-viewing scopes and decided to unload its old ones on various zoologists that, suddenly, t (important, given that hyenas mostly sleep during the day). Turns out that researchers could watch hyenas at nigh t particularly effec d you know what happens? Lions, who are no tive hunters, because they are fabulous hunters. An they are big and slow and conspicuous, spend most of their time keying in on hyenas and ripping off their kills. No riphery are looking cranky, wi wonder when it's dawn on the savanna the hyenas on the pe th circles under their eyes. They stayed up all night hunting that thing, and who's having breakfast now? is really strange about them. Among Having established a thread of sympathy for these beasts, let me explain what , which is fairly rare among mammals . They are more muscular and more hyenas, females are socially dominant in their aggressive, and have more of a male sex horm one (a close relative of testosterone called androstenedione) ll the sex of a hyena by looking at its external genitals. bloodstreams than males. It's also almost impossible to te More than two thousand years ago, Aristotle, for reasons obscure to even the most l earned, dissected some dead hyenas, discussing them in his treatise VI, XXX. The conclusion among hyena savants at the Historia Animalium, aphrodites—animals that possess all the time was that these animals were herm machinery of both sexes. Hyenas are actually what gynecologists would call pseudohermaphrodites (they just look that way). The female has a fake scrotal sac made of Behold, the female hyena. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

68 Pa g e 68 of 212 compacted fat cells; she doesn't really have a penis but, in stead, an enlarged clitoris that can become erect. The same clitoris, I might add, with which she has sex and through which she gives birth. It's pretty wild. Laurence Frank, who zed, into camp. Excitement; we animal and haul it, anestheti is one of Earth's experts on hyena genitals, will dart some it, he kind of thinks he knows what sex this particular go to check it out, and maybe twenty minutes into examining one is. (Yes, the hyenas themselves know exactly who is which sex, most probably by smell.) Perhaps the most interesting thing about hy enas is that there is a fairly plausibl e theory as to why they evolved this way, a theory complicated enoug h for me mercifully to relegate it to the endnotes. For our purposes here, what is important is that hyenas have evolved not only genitals that look unique, but also unique ways to use these organs for where stress comes into play social communication. This is mpetitive situations as a si Among many social mammals, males have erections during co gn of dominance. If you are it around in his face to show what a r male, you get an erection and wave having a dominance display with anothe this all the time. However, among hyen as, an erection is a sign of social tough guy you are. Social primates do subordinance. When a male is menaced by a terrifying female, he gets an erection—"Look , I'm just some poor no- account male; don't hit me, I was just leaving." Low-ranking females do the same thing; if a low-ranking female is about to get trounced by a high-ranking one, she gets a conspicuous clitoral erection—"Look, I'm just like one of those males; don't attack me; you know you're dominant over me, why bother?" If you're a hyena, Among male hyenas, the autonomic wiring has got to be completely when you are stressed. you get an erection 't yet been demonstrated, but perhaps reversed in order to account for the fact that stress causes erections. This hasn Berkeley scientists working on this, squandering tax dollars that could otherwise be going to Halliburton and Bechtel, will do it. ing adversely affected by stress, a to the rule about erectile functions be Thus the hyena stands as the exception broader demonstration of the importance of looking at a zoological oddity as a means of better seeing the context of our own normative physiology, and a friendly word of warning before you date a hyena. FEMALES: LENGTHENED CYCLES AND AMENORRHEA ilar to that of the male. LHRH We now turn to female reproduction. Its basic outline is sim is released by the brain, which releases LH and FSH from the pituitary. The latter stimul ates the ovaries to release eggs; the former stimulates nstrual cycle, the "follicular" stage, levels of LHRH, LH, ovaries to synthesize estrogen. During the first half of the me FSH, and estrogen build up, head ing toward the climax of ovulation. This us hers in the second half of the cycle, the "luteal" phase. Progesterone, made in the corpus luteum of the ovary, now becomes the dominant hormone on the lls to mature so that an egg, if fertilized just after ovulation, scene, stimulating the uterine wa can implant there and fancy quality of fluctuating rhythmically over the lease of hormones has the develop into an embryo. Because the re menstrual cycle, the part of the hypothalamus that regul ates the release of these hormones is generally more females than in males. structurally complicated in the system. There is a small ncerns a surprising facet of The first way in which stress disrupts female reproduction co amount of male sex hormone in the bloodstream of females, even non-hyena females. In human beings, this doesn't come from the ovaries (as in the hyenas ), but from the adrenals. The amount of these "adrenal androgens" is only about 5 percent of that in males, but enough to cause trouble.* An * Point of information: the adrenal androgens ar e usually not testoster one, but androstenedione. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

69 Pa g e 69 of 212 A simplified version of female reproductive endocrinology . The hypothalamus releases LHRH into the private circulatory system that it shares with the anterior pituitary. LHRH triggers the release by the pituitary of LH and FSH, which in turn bring about ovulation and hormone release from the ovaries. them to estrogens. Problem these androgens by converting enzyme in the fat cells of females usually eliminates se the crops failed this year? Body weig solved. But what if you are starving becau ht drops, fat stores are depleted, and convert all the androgen to estrogen. suddenly there isn't enough fat around to Less estrogen, therefore, is produced. More important, androgen concentrations build up, which inhibits numerous steps in the reproductive system (it should be noted that this is but one of the mechanisms by which starvation inhibits reproduction). One of the hallmarks of anorexia nervosa is disruption of Reproduction is similarly inhibited if you starve voluntarily. reproduction in the (typically) young women who are starving themselves. There's more to the reproduction cessation than just the weight loss, since cyclin g doesn't necessarily resume in women wh en they regain the weight unless the initial psychological stressors have been sorted out. But the weight loss still plays a critical, initiating role. And loss of ms by which reproduction is impaired in females who are body fat leading to androgen buildup is one of the mechanis extremely active physically. As noted abov e, this has been best documented in young girls who are serious dancers or in women who exercise enorm runners, in whom puberty can be delayed for years, and ous amounts, in whom cycles can become irregular or cease entirely. Ov the human, an average pregnancy costs erall, this is a logical mechanism. In neither is something that should be approximately 50,000 calories, and nursi ng costs about a thousand calories a day; amount of fat tucked away. gone into without a reasonable 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

70 Pa g e 70 of 212 Stress also can inhibit reproduction in ways other than sh rinkage of fat cells. Many of the same mechanisms apply as lease (as discussed, this occurs in female athletes as in the male. Endorphins and enkephalins will inhibit LHRH re readily as in males); prolactin and glucocorticoids will bloc k pituitary sensitivity to LHRH; and glucocorticoids will LH. The net result is lowere also affect the ovaries, making them less responsive to d secretion of LH, FSH, and estrogen, making the likelihood of ovulating decrease. As a result, the follicular stage is extended, making the entire y machinery is not merely delayed, but shut down, a cycle longer and less regular. At an ex treme, the entire ovulator condition termed anovulatory amenorrhea. one levels are often inhibited, which disrupts maturation Stress can also cause other reproductive problems. Progester actin during stress adds to this effect, interfering with the activity of of the uterine walls. The release of prol progesterone. Thus, even if there is st ill enough hormonal action during the follicular period to cause ovulation, and the egg has become fertilized, it is now much less likely to implant normally. uences beyond the reproductive realm. For example, amid The loss of estrogen with sustained stress has some conseq the controversies discussed in chapter 3 about whether estrogen protects agains t cardiovascular disease, it is quite s, and stress-induced declines in estr clear that it protects against osteoporosi ogen levels have bad effects on bone strength. ng stress, prolactin is probably the most interesting. It is Of all the hormones that inhibit the reproductive system duri this is the hormone to have lots of in your bloodstream. extremely powerful and versatile; if you don't want to ovulate, It not only plays a major role in the suppression of repr oduction during stress and exercise, but it also is the main reason that breast feeding is such an effective form of contraception. Oh, you are shaking your head smugly at the ignorance of th is author with that Y chromo some; that's an old wives' fabulously. It probably prevents more aceptive. On the contrary, nursing works tale; nursing isn't an effective contr pregnancies than any other type of contracep tion. All you have to do is do it right. Breast feeding causes prolactin secretion. There is a reflex loop that goes straight from the nipples to the (in males as well as females), the hypothalamus signals the hypothalamus. If there is nipple stimulation for any reason . And as we now know, prolactin in sufficient quantities causes reproduction to cease. pituitary to secrete prolactin ing as a contraceptive is how it is done in Wester n societies. During the six months or so that The problem with nurs day, each for 30 to ther in the West allows perhaps half a dozen she breast-feeds, the average mo periods of nursing a 60 minutes. Each time she nurses, prolactin levels go up in the bloodstream within sec onds, and at the end of the feeding, prolactin settles back to pre-nursing levels fairly quickly. This most likely produces a scalloping sort of pattern in prolactin release. This is not how most women on earth nurse. A prime example emerged a few years ago in a study of hunter-gatherer Africa (the folks de Bushmen in the Kalahari Desert of southern picted in the movie The Gods Must Be Crazy). no one uses contraceptives, but the women have a child Bushman males and females have plenty of intercourse, and only about every four years. Initially, this seemed easy to explain. Western scientists looked at this pattern and said, "They're hunter-gatherers: life for them must be short, nasty, and brutish; they must all be starving." Malnutrition induces cessation of ovulation. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

71 Pa g e 71 of 212 A Kalahari Bushman mother with her child in a hip sling. However, when anthropologists looked more closely, they found that the Bushmen were anything but suffering. If you alist or an agriculturist. er over being a nomadic pastor are going to be nonwesternized, choose to be a hunter-gather The Bushmen hunt and gather only a few hours a day, and spen d much of the rest of thei r time sitting around chewing e four-year birth interval is ciety. Out goes the idea that th the fat. Scientists have called them the original affluent so due to malnutrition. Instead, the lengthy interval is probably due to their nursin g pattern. This was discovered by a pair of scientists, Melvin Konner and Carol Worthman.* When a hunter-gatherer woman gives birth, she * The work and thinking of Konner, who was on ce my advisor at college, runs throughout this book, as he is the person who has h ad the greatest intellectual influence on my life. begins to breast-feed her child for a minute or two appr oximately every fifteen minutes . Around the clock. For the does it?) The young child is carried in a next three years. (Suddenly th is doesn't seem like such a hot idea after all, ntly. At night, he sleeps near his mother and will nurse sling on the mother's hip so he can nurse easily and freque every so often without even waking her (as Konner and Worthman, no doubt with their infrared night-viewing their clipboards at two in the morn ing). Once the kid can walk, he'll come goggles and stopwatches, scribble away on running in from play every hour or so to nurse for a minute. When you breast-feed in this way, the endocrine story is very different. At the first nursing period, prolactin levels rise. And with the frequency and timing of the thousands of subsequent nursings, prolactin stays high for years. e suppressed, and you don't ovulate. Estrogen and progesterone levels ar This pattern has a fascinating implication. Consider the life history of a hunter-gatherer woman. She reaches puberty at about age thirteen or fourteen (a bit later than in our society). Soon she is pregna nt. She nurses for three years, weans her child, has a few menstrual cycles, becomes preg nant again, and repeats the pattern until she reaches , she has perhaps two dozen pe riods. Contrast that with menopause. Think about it: over the course of her life span time. Huge difference. The modern Western women, who typically experience hundreds of periods over their life hunter-gatherer pattern, the one that has occurred throughout most of human history, is what you see in nonhu-man primates. Perhaps some of the gynecolo gical diseases that plague modern we sternized women have something to do times when it may have evolved to be r piece of physiological machinery hundreds of with this activation of a majo used only twenty times; an example of this is probably endometriosis (having uterine lining thickening and sloughing 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

72 Pa g e 72 of 212 off in places in the pelvis and abdominal wall where it do g women with esn't belong), which is more common amon fewer pregnancies and who start at a later age.* \FEMALES: DISRUPTION OF LIBIDO le reproduction—ut erine walls, eggs, The preceding section describes how stre ss disrupts the nuts and bolts of fema ovarian hormones, and so on. But what about its effects upon sexual behavior? Just less often than se of the circumstances of ed in zoo animals who, becau * Remarkably, the same is now being report their captivity, reproduce far those in the wild. as stress does not do wonders for erections or for the desire of a male to do something with his erections, stress also d by any number of circumstances, as commonplace experience among women stresse disrupts female libido. This is a well as among laboratory animals undergoing stress. It is relatively easy to document a loss of sexual desire among women when they are stressed—just hand out a drive studied in a questionnaire on the subject and hope it is answered honestly. But how is sexual laboratory animal? ple, as she gazes into the next cage at h on the part of a female rat, for exam How can one possibly infer a libidinous itc incisors? The answer is surprisingly simple—how often would she be willing the male with the limpid eyes and cute to press a lever in order to gain access to that male? This is science's quantitative way of measuring rodent desire (or, to use the jargon of the trad e, "procep-tivity").* A simila r experimental design can be used to measure pro-ceptive behavior in primates. Proceptive and r eceptive behaviors fluctuate among female an imals as a function of factors like the point in the reproductive cycle (both of these measures of sexual behavior generally peak around ovulation), the recency of sex, the time of year, or va garies of the heart (who is the male in question). In general, stress suppresses both proceptive and receptive behaviors. This effect of stress is probably rooted in its suppression of the secretion of various sex hormones. Among rodents, removed, and the absence of estrogen both proceptive and receptive behaviors disappear when a female's ovaries are evidence, injection of ov after the ovariectomy is responsible; as estrogen reinstates these ariectomized females with ound ovulation explains why sexual behavior is almost sexual behaviors. Moreover, the peak in estrogen levels ar entirely restricted to that period. A similar pattern holds in atic as in rodents. A decline primates, but it is not as dram iectomy in a primate. For human s, estrogen plays a role in in sexual behavior, although to a lesser extent, follows ovar terpersonal factors are far more important. sexuality, but a still weaker one—social and in attractivity refers to how much the subject animal interests another animal. animal sex the way professionals do: * Quick primer on how to describe This can be operationally defined as how many times the other an imal is willing to press a lever, for example, to gain access t o the subject. can be defined by the occurr ence of the Receptivity describes how readily the subject responds to the entreaties of the other animal. Among rats, this e primates show a king it easier for the male to mount. Femal e female in which she arches her back, ma "lordosis" reflex, a receptive stance by th refers to how actively the subject pursues the variety of receptive reflexes that facilitate Proceptivity ing on the species. male mounting, depend other animal. Estrogen exerts these effects both in the brain and peripheral tissue. Genitals and other parts of the body contain itive to tactile stimulation by the hormone. Within the tors and are made more sens ample amounts of estrogen recep r in areas that play a role in sexual behavior; through on e of the more brain, estrogen receptors occu poorly understood mechanisms of neuroendocrinology when estrogen floods those parts of the brain, salacious thoughts follow. also play a role in precep Surprisingly, adrenal androgens tive and receptive behaviors; as evidence, sex drive goes down following removal of the adrenals and can be reinstated by administration of synthetic androgens. This appears to be more of a factor in primates a nd humans than in rodents. While the subject has not been studied in great detail, stress suppresses the levels of adrenal androgens in the bloodstream. And stress certainly there are some reports that suppresses estrogen secretion. As noted in the stressor of social subordinance in chapter 3, Jay Kaplan has shown that moving her ovaries. Given these findings, it is relatively a monkey can suppress estrogen levels as effectively as re easy to see how stress disrupts sexual behavior in a female. HIGH-TECH FERTILIZATION STRESS AND THE SUCCESS OF In terms of psychological distress, few medical maladies ma tch infertility—the strain pl aced on a relationship with a lity to concentrate at work, the estrangement from friends significant other, the disruption of daily activities and abi gh-tech advances has been a ting infertility with recent hi and family, and the rates of depression.* Thus, circumven wonderful medical advance. of assisted fertilization: artificial insemination; in vitro fertilization (IVF), in which There is now a brave new world sperm and egg meet in a petri dish, and ferti lized eggs are then implanted in the woman; preimplantation screening, , their DNA is analyzed, and sorder; after eggs are fertilized carried out when one of the couple has a serious genetic di only those eggs that do not carry the genetic disorder are 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

73 Pa g e 73 of 212 family relations * Two of the most common subject ndle the damage done to friendships and s discussed in infertility support groups: (1) how to ha ays because of all those nieces and nephews j s, can no longer join the family at holid when you can no longer attend baby shower ust learning to walk, can no longer see the old friend who is pregnant; and (2) what happens to a re n sex has been turned lationship with one's significant other whe pecially an unsuccessful one. into a medical procedure, es implanted. Donor eggs, donor sperm. Injection of an individual sperm into an egg, when the problem is an inability of the sperm to penetrate the egg's membrane on its own. y simple procedures, but others involve extraordinary, Some forms of infertility are solved with some relativel nology, however. The first is that it is an astonishingly innovative technology. There are two problems with that tech hermore, it's expensive as hell, and is often not paid for stressful experience for the individuals who go through it. Furt experimental techniques are being tried. How many young by insurance, especially when some of the fancier new couples can afford to spend ten to fifteen thousand dollars out of pocket each cycle they attempt to get pregnant? at many participants have to spend Next, most IVF clinics are located only near major medical centers, meaning th s and family. For some genetic screening techniques, only weeks in a motel room in some strange city, far from friend a handful of places in the world are available, thus adding a long waiting list to the other stress factors. mpared with the stress generated by th e actual process. Weeks of numerous, But those stress-induced factors pale co painful daily shots with synthetic hormones and hormone suppre ssors that can do some pretty dramatic things to mood constant emotional roller-coaster of whether the day's news and mental state. Daily blood draws, daily sonograms, the is good or bad: how many follicles, how big are they, what circulating hormone levels have been achieved? A surgical her you have to try the whole thing again. procedure and then the final wait to see whet The second problem is that it rarely works. It is very hard to figure out how often natural attempts at fertilization are for the high-tech rd to find out what the success rates actually succeed in humans. And it is ha procedures, as r brochures—"We don't like to publish our success rates, because we take on clinics often fudge the numbers in thei worse than those of other numbers must superficially seem only the most difficult, challenging cases, and thus our e easy ones"—and thus, they say, it is hard to gauge just how bad the odds are clinics that are wimps and take only th for a couple with an infertility problem going this route. Nevertheless, going through one of those grueling IVF cycles has a pretty low chance of succeeding. ess of IVF procedures, All that has preceded in this chapter would suggest that the fi rst problem, the stressfuln contributes to the second problem, th examined whether s have specifically e low success rate. A number of researcher women who are more stressed during IVF cycles are the on ccessful outcomes. And the es less likely to have su show that the more stressed women (as determined by answer is a resounding maybe. The majority of studies do self-report on a questionnaire) are ity to an experimental stressor, or cardiovascular reactiv glucocorticoid levels, indeed less likely to have successful IVFs For one thing, some of the studies were carried . Why, then, the ambiguity? n have already gotten plenty of feedback as to whether out many days or weeks into the long process, where wome things are going well; in those cases, an emerging unsuccessful outcome migh t cause the elevated stress-response, taken at the beginning of the process, in studies in which stress measures are rather than the other way around. Even the number of previous cycles must be controlled for. In other words, a stressed woman may indeed be less likely to ally poor candidate who has have a successful outcome, but both traits may be due to th e fact that she is an especi and is a wreck. already gone through eight unsuccessf ul prior attempts . If the correlation does tu In other words, more research is needed hopes that the outcome of rn out to be for real, one that will be something more constructive than clinicians saying, "And try not to be stressed, because studies have ogress in this area actually resulted in shown it cuts down the chances IVF will succeed." It would be kind of nice if pr mplexities in the first place, namely, the infertility. eliminating the stressor that initiated all these co MISCARRIAGE, PSYCHOGENIC ABOR TIONS, AND PRETERM LABOR The link between stress and spontaneous abortion in humans prompted Hippocrates to caution pregnant women to a thread that runs through some of our most florid and avoid unnecessary emotional disturbances.* Since then, it is romantic interpretations of the biology of pregnancy. There's Anne Boleyn attributing her miscarriage to the shock of seeing Jane Seymour sitting on King Henry's lap, or Rosamond Vincy losing her baby when frightened by a horse in In the 1990 movie Mid-dlemarch. era to its logical extreme, Pacific Heights (which took the Reagan-Bush encouraging us to root for the poor landlords being menaced by a predatory tenant), the homeowner, abortion and everyday clinical usage, ed throughout this section. In * are used interchangeably in medical texts and will be so us Miscarriage than abortion. close to being viable is more however, spontaneous termination of a pregnancy when the fetus is likely to be termed miscarriage played by Melanie Griffith, has a miscar riage in response to psychological ha rassment by the Machiavellian renter. ress of a high-demand/low-control job ndane realm of everyday life, the st And in the less literary and more mu increases the risk of miscarriage among women. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

74 Pa g e 74 of 212 Stress can cause miscarriages in other animals as well. This may occur, for example, wh en pregnant animals in the exam) or are stressed by being transported. be captured for some reason (a veterinary wild or in a corral have to animals in the wild have revealed one instance in which stress-induced Studies of social hierarchies among al species, not all males do equivalent amounts of reproducing. Sometimes the miscarriages often occur. In many soci all the mating; sometimes there are a em male") who does group contains only a single male (typically called a "har produce.* Suppose the harem male is killed or driven out number of males, but only one or a few dominant males re by an intruding male, or a new male migrates into the multi-male group and moves to the top of the dominance his own reproductive success, at the male goes about trying to increase hierarchy. Typically, the now-dominant species, males will systematically try to kill the infants expense of the prior male. What does the new guy do? In some observed in a number of species, including lions and some in the group (a pattern called competitive infanticide and ing male. Following the kil monkeys), thus reducing the re productive success of the preced ling, moreover, the female the convenient advantage of the newly nd ready for mating, to oon ovulating a ceases to nurse and, as a result, is s resident male. Grim stuff, and a pretty strong demonstration of something well recognized by most evolutionists these days; contrary to what Marlin Perkins taught us, animals ra rely behave "for the good of the species." Instead, they their own genetic legacy and that of thei r close relatives. Among some species—wild typically act for the good of any pregnant females to the point of horses and baboons, for example—the ma le will also systematically harass miscarriage, by the same logic. This pattern is seen in a particularly subtle way among r odents. A group of females resides with a single harem male. s who have recently become sidence, within days, female If he is driven out by an intruder male who takes up re egg. Remarkably, this termination of pregnancy does not require physical pregnant fail to implant the fertilized harassment on the part of the male. It is his new, strange odor that "gigolo males." equally aptly, as atologist who refers to single males, * Although there is one august (female) prim causes the failed pregnancies by triggering a disruptive rise oof of this, researchers can in prolactin levels. As pr Parkes effect) with merely the odor of a novel male. Why is it adaptive for trigger this phenomenon (called the Bruce- has arrived on the scene? If the female completes her females to terminate pregnancy just because a new male pregnancy, the kids will promptly be killed by this new guy. So, making the best of a bad situation, evolution has s that would be devoted to the futile pregnancy—terminate it sculpted this response to at least save the further calorie and ovulate a few days later.* Despite the drama of the Bruce-Parkes effect, stress-induced miscarriages are relatively rare among animals, particularly among humans. It is not uncommon to decide retrospectively that when something bad happens (such as a icant stress beforehand. To add to the confusion, there is a tendency to attribute miscarriage), there was signif carriages involve the actuality, most mis ents occurring a day or so preceding them. In miscarriages to stressful ev expelling of a dead fetus, which has typically died quite a wh ile before. If there was a stressful cause, it is likely to e miscarriage, not i have come days or even weeks before th mmediately preceding it. occur, however, there is a fairly plausible explana When a stress-induced miscarriage does tion of how it happens. The delivery of blood to the fetus is exquisitely sensitive to blood flow in the mother, and anything that decreases uterine blood flow will be disruptive to the fetal blood supply. More tracks that of the mother, and over, fetal heart rate closely e heart rate of the mother will cause a similar change a various psychological stimuli that stimulate or slow down th minute or so later in the fetus. This has been shown in a number of studies of both humans and primates. Trouble seems to occur during stress as a result of repeated powerful activat ion of the sympathetic nervous system, of different species show causing increased secretion of norepine phrine and epinephrin e. Studies of a large number that these two hormones will decrease cally, in some cases. Exposing animals blood flow through the uterus—dramati noise in the case of pregnant to something psychologically stressful (for example, a loud sheep, or the entrance of a strange person into the room in which a pregnant rhesus monkey is housed) will s. One is to go into * Not to be outdone, females have evolved many strategies of their own to salvag e reproductive success from these battling male of the offspring she is alr thinking he's the father s) to sucker the new guy into a fake heat (in primates, called pseudo-estru eady carrying. Given the appalling lack of knowledge about obst etrics among most male rodents and primates, it usually works. Touche. hypoxia) to the fetus. This is cause a similar reduction in blood flow, decreasing the delivery of oxygen (called of prenatal stress returns us to all th e issues of growth in chapter 6. The certainly not a good thing, and this sort odes to cause asphyxiation. general assumption in the field is that it takes a number of these hypoxic epis Thus, severe stress can increase the like lihood of miscarriage. Furt hermore, if one is at a late stage in pregnancy, stress can increase the risk of preterm birt orticoids. Certainly not a h, an effect that is prob ably due to elevated glucoc good thing, given what we saw in the last chapter about the metabolic imprinting consequences of low birth weight. HOW DETRIMENTAL TO FEMALE REPRODUCTION IS STRESS? 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

75 Pa g e 75 of 212 As we have seen, there is an extraordinary array of mech anisms by which reproduction can be disrupted in stressed females—fat depletion; secretion of endorphins, prolactin, and glucocorticoids acting on the brain, pituitary, and ovaries; lack of progesterone; excessive prolactin acting on the uterus. Moreover, possible blockage of implantation of the fertilized egg and changes in blood flow to the fetus generate numerous ways in which stress can make it less ese different mechanisms implicat likely that a pregnancy will be carried to term. With all th ed, it seems as if even the mildest of stressors would shut down the reproductive system completely. Surprisingly, however, this is not the case; collectively, these mechanisms are not al l that effective. One way of appreciatin g this is to examine the effects of chronic low-grade stress on reproduction. Consider traditiona s with a fair amount of l nonwestern-ized agriculturist background disease (say seasonal malari a), a high incidence of parasites, and some seasonal malnutrition thrown in— mber of children born to a farmers in Kenya, for example. Before family planning cam e into vogue, the average nu this with the Hutterites, nonmechanized Kenyan woman was about eight. Compare farmers who live a life similar to stressors of the Kenyan farm ers, use no contraceptives, experience none of the chronic that of the Amish. Hutterites e rate—an average of nine children per wo man. (It is difficult to make a close and have an almost identical reproductiv of these two populations. The Hutterites, fo quantitative comparison r example, delay marriage, decreasing their lly do not. Conversely, Kenyan agriculturists typically reproductive rate, whereas Kenyan agriculturists traditiona breast-feed for at least a year, decreasing their reproductive rate, in contrast to the Hutterites, who typically nurse far less. The main point, different lifestyles, the two repr oductive rates are nearly equal.) however, is that even with such How about reproduction during extreme stress? This has been studied in a literature that always poses problems for those discussing it: how to cite a scientific finding withou t crediting the monsters who di d the research? These are the studies of women in the Third Reich's concentration camps, conducted by Nazi doctors. (The convention has evolved never to cite the names of the doctors, and always to note their criminality.) In a study of the women in the Theresienstadt concentration camp, 54 percent of the reproductive-age women were found to have stopped labor, and unspeakable psycho logical terror are going to menstruating. This is hardly surprising; starvation, slave the women who stopped menstruating, the majority stopped disrupt reproduction. The point typically made is that, of within their first month in the camps—before starvation and labor had pushed fat levels down to the decisive point. Many researchers cite this as a demonstration of how disruptive even psychological stress can be to reproduction. e opposite. Despite starvati To me, the surprising fact is just th on, exhausting labor, and the daily terror that each day would be their last, only 54 percen t of those women ceased menstruating. Reproductive mechanisms were still mber may have been having anovulatory cycles). And I working in nearly half the women (although a certain nu would wager that despite the horrors of their situation, there were still many men who were reproductively intact. That reproductive physiology still operated in any individual to any extent, under those circumstances, strikes me as extraordinary. Reproduction represents a vast hierarchy of behavioral and physiological events that differ considerably in subtlety. Some steps are basic and massive—the eruption of an egg, the diverting of rivers of blood to a penis. Others are as delicate as the line of a poem that awaken s your heart or the whiff of a person's scent that awakens yo ur loins. Not all the steps are equally sensitive to stress. The basic machinery of reproduction can be astoundingly resistant to stress in one of the strongest of biological om the Holocaust shows. Reproduction is a subset of individuals, as evidence fr reflexes—just ask a salmon leaping upstr eam to spawn, or males of various sp ecies risking life and limb for access to females, or any adolescent with that ster oid-crazed look. But when it comes to the pirouettes and filigrees of sexuality, may not be of enormous consequence to a stress can wreak havoc with subtleties. That ddle of a drought. But it matters to us, with our culture of multiple orgasms starving refugee or a wildebeest in the mi s and oceans of libido. And while it is easy and minuscule refractory period to make fun of thos e obsessions of ours, GQs and Cosmos those nuances of sexuality, the and other indices of our indulged lives, matter to us. They provide us with some of our greatest, if also our most fragile and evanescent, joys. 8 IMMUNITY, STRESS, AND DISEASE The halls of academe are filling with a newly evolved 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

76 Pa g e 76 of 212 species of scientist—the psychoneuroimmunologist— who makes a living studying ary fact that the extraordin can affect how well your what goes on in your head immune system functions. Those two realms were once thought to be fairly separate—your immune system kills bacteria, makes antibodies, hunts for tumors; your brain makes you do the bunny hop, invents the wheel, has favorite TV shows. Yet the dogma of the separation of the immune and nervous systems has fallen by the em sends nerves into tissues that wayside. The autonomic nervous syst une system and eventually enter the form or store the cells of the imm tissue of the immune system turns out to be circulation. Furthermore, for) all the in sensitive to (that is, it has receptors teresting hormones ntrol of the brain. The result is released by the pituitary under the co that the brain has a vast potential for sticking its nose into the immune system's business. fluence on the immune system goes back The evidence for the brain's in dating to the first at least a century, demonstration that if you waved an artificial rose in front of someone who is highly allergic to roses (and who didn't t demonstration of the brain know it was a fake), they'd get an allergic response. He re's a charming and more recen influencing the immune system: take some professional actors and have them spend a day doing either a depressing negative scene, or an uplifting euphoric one. Those in the former state show decreased immune responsiveness, while those in the latter manifest an increase. (And where was Los Angeles, of course, at such a study carried out? In UCLA.) But the study that probably most solidified the link between the brain and the immune system used a paradigm called conditioned immunosuppression. provide, a la Pavlov's experiments, a es the immune system. Along with it, Give an animal a drug that suppress imal will associate with the "conditioned stimulus"— for example, an artificially flavored drink, something that the an suppressive drug. A few days later, present the conditioned stimulus by itself—and down goes immune function. In 1982 the report of an experiment using a variant of this paradigm, carried out by two pioneers in this field, Robert ity of Rochester, stunned scientists. Th Ader and Nicholas Cohen of the Univers e two researchers experimented with a s. Normally, the their immune system lop disease because of overactivity of strain of mice that spontaneously deve disease is controlled by treating the mice with an immunosuppressive drug. Ader and Cohen showed that by using onditioned stimulus for the actual drug—and sufficiently alter their conditioning techniques, they could substitute the c immunity in these animals to extend their life spans. ts that there is a strong link betw Studies such as these convinced scientis een the nervous system and the immune system. It should come as no surprise th at if the sight of an artificial rose or the taste of an artificially flavored drink I discuss what stress does to immunity too. In the first half of this chapter, can alter immune function, then stress can, and how this might be useful during a stressful emergency. In the second half, I'll examine whether sustained stress, by way of chronic suppression of immunity, can impair the ability of a body to fight off infectious disease. This is a Although evidence is fascinating question, which can be answer ed only with a great deal of caution and many caveats. increase the risk and severi emerging that stress-induced immunosuppression can indeed ty of some diseases, the connection is probably relatively weak and its importance often exaggerated. In order to evaluate the results of this confusing but impor tant field, we need to star t with a primer about how the immune system works. IMMUNE SYSTEM BASICS 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

77 Pa g e 77 of 212 The primary job of the immune system is to defend the body ag ainst infectious agents such as viruses, bacteria, fungi, tell the difference between ing, the immune system must and parasites. The process is dauntingly complex. For one th cells that are normal parts of the body ogic jargon, distinguishing between "self" and "non-self." Somehow, the and cells that are invaders—in immunol immune system can remember what ever y cell in your body looks like, and any ce lls that lack your distinctive cellular when your immune system does encounter a novel invader, eria) are attacked. Moreover, signature (for example, bact logic memory of what the infectious agent looks like, to better prepare for the next it can even form an immuno en you are vaccinated with a mild versio n of an infectious agent in order to invasion—a process that is exploited wh em for a real attack. prime your immune syst monocytes a complex array of circulating cells called lymphocytes Such immune defenses are brought about by and (which are collectively known as white blood cells; cyte is a term for cells). There are two classes of lymphocytes: T mature in the thymus (hence the T), while cells and B cells. Both originat e in the bone marrow, but T cells migrate to ere are several kinds of T cells (T cells principally produce antibodies, but th B cells mature in the bone marrow. B helper and T suppressor cells, cytotoxic killer cells, and so on). ious agents in very different ways. T cells bring about cell-mediated immunity (see the The T and B cells attack infect illustration on page 147). When an infectious agent invades the body, it is recognized by a type of monocyte called a macrophage, which presents the foreign particle to a T help er cell. A metaphorical alarm is now sounded, and T cells system ultimately results in the activation and proliferation begin to proliferate in response to the invasion. This alarm ack and destroy the infectious of cytotoxic killer cells, which, as their name implies, att agent. It is this, the T-cell component of the immune system, that is knocked out by the AIDS virus. diated immunity (see the illustration on page 148). Once the macrophage-T By contrast, B cells cause antibody-me helper cell collaboration has occurred, th e T helper cells then stim ulate B-cell prolif eration. The main task of the B some specific feature of at will recognize and bind to cells is to differentiate and generate antibodies, large proteins th is critical—the antibody formed the invading infectious agent (typically, a distinctiv e surface protein). This specificity has a fairly unique shape, which will conform perfectly to th e shape of the distinctive feature of the invader, like the fit between a lock and key. In binding to the specific feature, ectious agent and target it antibodies immobilize the inf for destruction. for example, need to coordinate some system. If different parts of the liver, There is an additional twist to the immune activity, they have 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

78 e 78 of 212 g Pa The cascade of cell-mediated immunity. (1) An infectious agent is encountered by a type of monocyte called a macrophage. (2) This stimulates the macrophage to present th e infectious agent to aT helper cell (a type of white ates T helper cell activity. (3) The T helper cell, as a blood cell) and to release interleukin-1 (IL-1), which stimul result, releases interleukin-2 (4) This eventually causes another type of (IL-2), which triggers T-cell proliferation. white blood cell, cytotoxic killer cells, to proliferate and destroy the infectious agent. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

79 Pa g e 79 of 212 The cascade of antibody-mediated immu nity. (1) An infectious agent is en countered by a macrophage. (2) This encounter stimulates it to present the infectious agent to a T helper cell and to release interleukin-1 (IL-1), which secretes B-cell growth factor, triggering differentiation and stimulates T helper cell activity. (3) The T helper cell then proliferation of another white blood cell, B cells. (4) The B cells make and release specific antibodies that bind to surface proteins on the infectious agent, targeting it for destruction by a large group of circulating proteins known as complement. the advantage of sit throughout the ci e immune system is distributed ting adjacent to each other. But th rculation. In stem, blood-borne chemical me ssengers that communicate order to sound immune alarms throughout this far-flung sy rst recognize an have evolved. For example, when between different cell types, called cytokines, macrophages fi infectious agent, they release a messenger called This triggers the T helper cell to release interleukin-2, interleukin-1. a dozen additional interleukins with which stimulates T-cell growth (to make life complicated, there are at least half more specialized roles). On the antibody front, T cells also secrete B-cell growth factor. Other classes of messengers, broad classes of lymphocytes. such as interferons, activate The process of the immune system sorting self and non-self usually works well (although truly insidious tropical parasites like those that cause schistosomiasis have evolved to evade your immune system by pirating the signature of your own cells). Your immune system happily spends its time sorting out self from non-self: red blood cells, part of us. Eyebrows, our side. Virus, no good, attack. Muscle cell, good guy... What if something goes wrong with the immune system's sorting? One obvious kind of error could be that the ws. Equally bad is the sort of error in which the immune immune system misses an infectious invader; clearly, bad ne invader that really isn't. In one version of this, some perfectly innocuous system decides something is a dangerous you triggers an alarm reacti compound in the world around at you normally ingest, like on. Maybe it is something th peanuts or shellfish, or something airborne and innocuou s, like pollen. But your imm une system has mistakenly decided that this is not only foreign but dangerous, and kicks into gear. And this is an allergy. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

80 Pa g e 80 of 212 In the second version of the immune system overreacting, a normal part of your own body is mistaken for an infectious agent and is attack e body, a variety of s a normal part of th ed. When the immune system erroneously attack sclerosis, for example, part horrendous "autoimmune" diseases may result. In multiple of your nervous system is attacked; in juvenile diabetes, it's the cells in the pancreas that normall y secrete insulin. As we'l l see shortly, stress has ects on autoimmune diseases. some rather confusing eff , we've been concentrating on something called acquired immunity. So far in this overview of the immune system Suppose you're exposed to some novel, dangerous pathogen, pathogen X, for the first time. Acquired immunity has ecifically, with antibodies and cell-mediated three features. First, you acquire the ability to target pathogen X sp is really works immunity that specifically recognize that pathogen. Th n on it. Second, it takes some time to build up that to your advantage—a bullet with pathogen X's name writte immunity when you are first exposed to pathogen X—this involves finding which antibody has the best fit and now be geared up to specifically go after pathogen X for a generating a zillion copies of it. Finally, while you will long time to come once that specific defense is on line, repeated exposu re to pathogen X will boost those targeted defenses even more. t we also contain a simpler, Such acquired immunity is a pretty fancy invention, and it is found only in vertebrates. Bu innate stant as insects, called immunity. In more ancient branch of the immune system, one sh ared with species as di this realm, you don't bother with acquiring the means to ta rget pathogen X specifically with antibodies that will be ead, the second any sort of path ogen hits your system, this different from those that would target, say, pathogen Y. Inst nonspecific immune response swings into action. where a pathogen gets its first foothold, like your to occur at the beachhead This generalized immune response tends ep, your saliva contains a cl ass of antibodies that skin, or moist mucosal tissue, like in your mouth or nose. As a first st targeting specific invaders. stead of acquiring a means of microbe that it encounters, in generically attack any sort of These antibodies are secreted and coat at the site of paint. In addition, your mucosal surfaces like an antiseptic immune response to slip out of the circulation to infiltrate infection, capillaries loosen up, allowing cells of the innate which then the immediate area of infect natural killer cells, and macrophages, neutrophils, ion. These cells include ing of the capillaries also allows fluid containing proteins that can fight the invasive attack the microbe. The loosen microbes to flow in from the circulation. And what happens as a result of that? The protei ns fight the microbe, but the This is your innate immune system leaping into action, causing edema. fluid also makes the area swell up, causing inflammation.* This gives us a broad overview of immune function. Time to see what stress does to immunity. Naturally, as it turns out, a lot more complicated thin gs than used to be suspected. ea of injury. Among those proteins, f ighting those * As just mentioned, the innate immune re sponse involves proteins inf iltrating into the ar microbes, is one we heard about in chap ter 3 called "C-reactive protein." You will recall how gunk like cholesterol forms ather osclerotic plaques predictor of only at places where your blood vessels are ood vessels is a good flammation at your bl injured. Thus, a measure of injury and in is the most reliable indicator of such inflammation. atherosclerotic risk. C-reactive protein, as we learned, Photomicrograph of a natural killer T cell attacking a tumor cell. HOW DOES STRESS INHIBIT IMMUNE FUNCTION? 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

81 Pa g e 81 of 212 It's been almost sixty years uppression, noting that since Selye discovered the first evidence of stress-induced immunos ecific unpleasantness. subjected to nonsp immune tissues like the thymus gland atrophied among rats Scientists have learned more about the subtleties of the immune system since then, and it turns out that a period of stress will disrupt a wide variety of immune functions. ation, and shorten the time their release into the circul Stress will suppress the formation of new lymphocytes and hibit the manufacturing of new antibodies in response to an preexisting lymphocytes stay in the circulation. It will in es through the release of relevant messengers. And it infectious agent, and disrupt communication among lymphocyt flammation. All sorts of stressors do this—physical, will inhibit the innate immune response, suppressing in psychological, in primates, rats, birds, even in fish. And, of course, in humans, too. occurs is via glucocorticoids. Glucocorticoids, for The best-documented way in which such immune suppression example, can cause shrinking of th fect that in olden days (circa 1960), before e thymus gland; this is such a reliable ef it was possible to measure directly the amount of glucocorticoids in the bloodstream, one indirect way of doing so was to see how much the thymus gland in an animal had shrunk. The smaller the thymus, the more glucocorticoids in the circulation. Glucocorticoids halt the formation of new lymphocytes in ecreted into the bloodstream. the thymus, and most of the thymic tissue is made up of these new cells, ready to be s Because glucocorticoids inhibit and interferons, they also make circulating the release of messengers like interleukins lymphocytes less responsive to an inf ectious alarm. Glucocorticoids, moreover, cause lymphocytes to be yanked out es. Most of these glucocorticoi d effects are against T cells, of the circulation and stuck back in storage in immune tissu mediated immunity is more disrupted than antibody-mediated immunity. And rather than B cells, meaning that cell- most impressively, glucocorticoids can actually kill lymphocytes . This taps into one of the hottest topics in medicine, which is the field of "programmed cell d suicide sometimes. For example, if a eath."* Cells are programmed to commit cell begins to become cancerous, there is a suicide pathway that gets activated to kill the cell before it starts dividing ccur. It turns out that ogrammed cell death to o out of control; a few types of cancers in volve the failure of the pr action in lymphocytes, throu gh a variety of mechanisms. glucocorticoids can trigger those suicide pathways into Sympathetic nervous system hormones, beta-endorphin, and CRH within the brain also play a role in suppressing anisms by which this happens are nowh ere near as well understood as with immunity during stress. The precise mech glucocorticoid-induced immune suppression, and these ot her hormones have traditionally been viewed as less r, a number of experiments have shown that stressors can important than the glucocorticoid part of the story. Howeve suppress immunity independently of glucocorticoid secretion, strongly implicating these other routes. WHY IS IMMUNITY SUPPRESSED DURING STRESS? ss hormones suppress immunity is a very hot topic these Figuring out exactly how glucocorticoids and the other stre days in cell and molecular biology, especially the part abou t killing lymphocytes. But amid all this excitement about cutting-edge science, it would be which is derived from Latin for so mething like "falling off" (as in the falling off of leaves in the * Another trendy term in this field is apoptosis, a subtype of it (I to whether apoptosis equals programmed cell death or is just fall, an example of programmed death). There are great debates as in the word (I do, a pronuncia tion that is considered to subscribe to the latter view), as well as, p amazingly, whether you pronounce the second have a rough-hewn man-in-the -street plebian air to it). you should want your immune system suppressed during stress. In chapter 1, I why reasonable to begin to wonder at the process of stress-induced immunosuppression has been explained in a offered an explanation for this; now th little more detail, it should be obvious that my early explanation makes no sense. I suggested that during stress it is logical for the body to shut down long-term building projects in order to divert energy for more immediate needs— this inhibition includes the immune system, which, while fabulous at spotting a tumor that will kill you in six months vital in the next few moments' emergency. That explanation or making antibodies that will help you in a week, is not would make sense only if stress froze the immune system right where it was—no more immune expenditures until the energy in e expenditure of emergency is finished. However, that is not what happens. Instead, stress causes the activ order to disassemble the preexisting immune system—ti destroyed. This cannot be ssues are shrunk, cells are paying, e immune system. So out goes explained by a mere halt to expenditures—you're energetically, to take apart th versus short-term theory. this extension of the long-term ntly stupid as disassembling our immune system during Why should evolution set us up to do something as appare This actually isn't as crazy of a respon stress? Maybe there isn't a good reason. se as you might think. Not everything in the body has to have an explanation in terms of evolutionary adaptiven ess. Maybe stress-induced se that is adaptive; it ju st came along for the ride. immunosuppression is simply a by-product of something el system releases the chemi cal messenger interleukin-1, This is probably not the case. During infections, the immune ted in chapter 2, CRH stimulates the which among other activities stimulates the hypothalamus to release CRH. As no pituitary to release ACTH, which then causes adrenal release of glucocorticoid s. These in turn suppress the immune rmones that will e body to secrete ho stances, the immune system will ask th system. In other words, under some circum 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

82 Pa g e 82 of 212 ultimately suppress the immune system. For whatever reason the immunosupp ression occurs, the immune system probably not just an accident.* sometimes encourages it. It is group that discovered the fact that interleukin-1 s * My tiny footnote in science: I was part of timulates CRH release. Or at least I thought I was. the It was in the mid-1980s. The idea made so me sense, and the lab I was in jumped on it under my prompting. We worked like maniacs , and at two e printout from one of the mac hines and realizing, o'clock one morning I had one of those moments of euphoria that sc ientists die for: looking at th ." We wrote up the findings, th ey were accepted by the prest igious journal "Aha, I was right, it does work that way—interleukin-1 released CRH everyone Science, Various ideas have floated around over the years to explain why you actively disassemble immunity during stress with fairly plausible until people learned a bit more about the willing cooperation of the immune system. Some seemed immunity and could rule them out. Others were quite nutty , and I happily advocated a few of these in the first edition rns this field on its head. of this book. But in the last decade, an answer ha s emerged, and it really tu SURPRISE It turns out that during the first few minutes (say, up to about thirty) after the onset of a stressor, you don't uniformly suppress immunity—you enhance many aspects of it (phase A on the accomp anying graph). This is shown with all realms of immunity, but in particular for innate immunity . This makes sense—it may be helpful to activate parts of your immune system that are going to make some swell anti bodies for you over the next few weeks, but it makes even more sense to immediately activate part s of the immune system that are going to help you out right now. More immune cells are rushed into the circula tion and, in the injured nervous system, more inflammatory cells infiltrate the mphocytes are better at releasing and responding to those immune messengers. site of injury. Moreover, circulating ly And more of those generic antibodies of the innate immune system are released into your saliva. This boosting of immunity doesn't occur only after some in fectious challenge. Physical stressors, psychological stressors, all appear to ivation. Even more surprisingly, those immunosuppressive villains, cause an early stage of immune act glucocorticoids, appear to play a major role in this (along with the sympathetic nervous system). So, with the onset of all sorts of stre ssors, your immune defenses are enhan ced. And now we are ready for our usual other side of the two-edged sword, when the stress goes on longer. By the one-hour mark, more sustained glucocorticoid and sy mpathetic activation Paper gets published, and right next to it was an study from a group in Switzerland, sent was very excited, I called my parents, and so on. identical in to the journal the same exact week. So I became a discoverer of this obscure fact. (To hark back to a theme of chapter 2, if you are a mature, tly on opposite pleasure in this so confident individual—which unfortunately I am only rarely—you take rt of thing: two labs, working independen sides of the globe, come up with the same novel observa tion. It must be true. Science lurches forward an inch.) Stress turns out to transiently stimulate the immune system. begins to have the opposite effect, namely, suppressing immunity. If the stressor ends around then, what have you started, back to baseline accomplished with that immunosuppression? Bringing imm une function back to where it (phase B). It is only with major stressors of longer duration, or with really major exposure to glucocorticoids, that the immune system does not just return to baseline, but plummets into a range that really does qualify as immunosuppressing (phase C). For most things that you can measure in the immune system, sustained major stressors drive the numbers down to 40 to 70 percent below baseline. The idea of temporarily perking up your immune system with the onset of a stressor makes a fair amount of sense of the convoluted theories as to why su (certainly at least as much as some ppressing it makes sense). As does the notion that what goes up must come down. And as does the frequent theme of this book, namely, that if you have a stressor that goes on for too long, an adaptive decline back to baseline can overshoot and you get into trouble. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

83 Pa g e 83 of 212 Why did it take people so long to figure the techniques for this out? Probably for two reasons. Fi rst, because many of e enough to pick up small, ly recently become sensitiv measuring what's happening in the immune system have on rapid differences, the thing needed to catch phase A, that fast immunostimulatory blip at the beginning of a stressor. ught they were studying the immune respon Thus, for decades, people tho se to stress, whereas they were actually this field study major, studying the recovery of the immune response to stress. As a second r eason, most scientists in prolonged stressors, or administer major amounts of glucocorticoids for prolonged periods. This re presents a reasonable bias in how experiments are done— start with a sledgehammer of an experimental manipulation. If nothing happens, pick a new field to study. If something does happen and it's been replicated enough times that you're confident about it, only then begin to think e early years, people were only studying the sorts of stressors or patterns of about more subtle elaborations. So in th glucocorticoid exposure that pushed into phase C, and only later got around to the subtler circumstances that would reveal phase B. This reorientation of the field represents a triumph for Allan Munck of Dartmouth University, one of the godfathers of the field, who predicted most of these new findings in the mid-1980s. He also predicted what turns out to be the answer to a question that pops up after a while. Why would you want to bring immune function back down to the pre- stress level (phase B in the diagram)? Why not just let it remain at the enhanced, improved level achieved in the first thirty minutes and get the benefits of an activated immune system all the ti me? Metaphorically, why not have your e thing, it costs too much. And, even more important, a military that defends you always on maximal alert? For on rigger alert is more likely to get carried away at some point and shoot one of system that's always on maximal, hair-t that are chronically with immune systems your own guys in a friendly fire accident. And that's what can happen activated—they begin to mistake part of you for being something invasive, and you've got yourself an autoimmune disease. that activated immune system Such reasoning led Munck to predict that if you fail to have phase B, if you don't coast risk for an autoimmune disease. This id ea has been verified in at least three back down to baseline, you're more at ticoid levels in the low basal range in rats and then stress them. This produces realms. First, artificially lock glucocor by epinephrine), but there isn't the rise in glucocorticoids to fully pull off animals that have phase A (mostly mediated phase B. The rats are now more at risk for autoimmune disease. Second, doctors have to occasionally remove one of the two adrenal glands (the source of glucocorticoids) from a patient, typi cally because of a tumor. Immediately for a period, until the remaining adrenal bulks up enough to afterward, circulating glucocorticoid levels are halved take on the job of two. During that period of low glucocorticoid levels, people are more likely than normal to flare up ll off phase B when with some autoimmune or in flammatory disease—there's not enough glucoc orticoids around to pu something stressful occurs. Finally, if you look at strains of rats or, weirdly, chickens, that spontaneously develop out to have something wrong with autoimmune diseases, they all turn A schematic representation of how a failure to inhibit immune function during stress can bias you toward autoimmune disease. the glucocorticoid system so that th ey have lower than normal levels of the hormone, or have immune and inflammatory cells that are less responsive than normal to glucocorticoids. Same for humans with autoimmune diseases like rheumatoid arthritis. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

84 Pa g e 84 of 212 Thus, early on in the stress-response, the immune system is being activated, rather than in hibited, and a big thing that ne activation doesn't spiral into autoimmunity. the stress-response does is make sure that immu So that has forced some revisionism in this field. But just to add to this, once stress has gone on long enough to begin taken to be aspects of immune suppression are actually to suppress immunity, some of what have classically been more subtle versions of immune enhancement. This is seen in two ways. Give someone massive amounts of glucocorticoids, or a huge stressor that has gone on for indiscriminately, just mowing them down. Have a subtle many hours, and the hormones will be killing lymphocytes rise in glucocorticoid levels for a short time (like what is going on at the start of phase B), and the hormones kill only coids, at that stage, are don't work as well. Glucocorti a particular subset of lymphocytes—older ones, ones that aren't ideal for the immediate emergency. So the immune response, getting rid of lymphocytes that sculpt helping to version of immune enhancement. that indirectly counts as a ople have known since the dawn of humans (or at least A second subtlety reflects reinterpretation of something pe during Selye's prime). As yank some remaining lymphocytes out of the circulation. noted, glucocorticoids not only kill lymphocytes, but also Firdhaus Dhabhar of Ohio State University asked, Where do those immune cells go when they are pulled out of the circulation? The assumption in the field had always been that they all go into immune storage ti ssues (like the thymus gland)—they're taken out of action, so that they aren't much use to you. But Dhabhar's work shows that they don't all and epinephrine are divertin get mothballed. Instead, glucocorticoids g many of those lymphocytes to the specific site of infection, such as the sk ing deactivated—they're being tr ansferred to the front lines. in. The immune cells aren't be And a consequence of this is that wounds heal faster. Thus, early on during exposure to a stressor, glucocorticoids and other stress-responsive hormones transiently activate the immune system, enhancing immune defenses, sharpening them, redistributing immune cells to the scenes of infectious battle. Because of the dangers of the systems overshooting into autoimmunity, more prolonged rse these effects, bringing the syst em back to baseline. And during the glucocorticoid exposure begins to reve pathological scenario of truly major, sustained stressors, immunity is suppressed below baseline. radoxes in this field. It co ncerns autoimmune diseases. These new findings help to explain one of the persistent pa autoimmunity: Two facts about int of considering a healthy the immune system (to the po 1. Insofar as autoimmune diseases involve overactivation of constituent of your body to actually be something invasive), the most time-honored treatment for such diseases is to put people "on steroids"—to give them massive amounts of glucocorticoids. The logic here is obvious: by ous system, or whatever is dramatically suppressing the im mune system it can no longer attack your pancreas or nerv immune system will to this approach, your misplaced zeal (and, as an obvious side effect the inappropriate target of its also not be very effective at defending you against real pathogens). Thus, administration of large amounts of these jor stressors decrease the ng. Moreover, prolonged ma stress hormones makes autoimmune diseases less damagi symptoms of autoimmune diseases in lab rats. worsen 2. At the same time, it appears that stress can ong the most reliable, if not autoimmune diseases. Stress is am ch diseases. This has often been repo rted anecdo-tally by patients, and is the most reliable, factor to worsen su typically roundly ignored by clinicians who know that stress hormones help reduce autoimmunity, not worsen it. But some objective studies also support this view for au toimmune diseases such as multiple sclerosis, rheumatoid cerative colitis, inflammatory bo arthritis, Grave's disease, ul e have been only a handful wel disease, and asthma. Ther eported retrospective data, rather than on ffer from the weakness of relying on patient-r of such reports, and they su prospective data. Nevertheless, their findings are relatively co nsistent—there is a subset of patients whose initial onset of an autoimmune disease and, to an even greater extent, their intermittent flare-ups of bad symptoms are yoked to stress. Moreover, there is, by now, a pretty hefty literature showing that stress can wors en autoimmunity in animal models of these diseases. aph below gives an answer So, do glucocorticoids and stress worsen or lessen the symp toms of autoimmunity? The gr e now seen two scenarios that increase the that wasn't clear in earlier years. We'v risk of autoimmune disease. First, it (that is, lots of phases A and B) increase the risk of autoimmunity—for some seems as if numerous transient stressors reason, repeated ups and downs ratchet autoimmunity. Second , while it seems the system upward, biasing it toward not to be great to have lots of instances of phase A followed by phase B, having phase A not followed by phase B ve an adequate phase B, that pushes the immune system increases the risk of autoimmunity as well. If you don't ha spiral upward into autoimmunity (back to diagram on page 157). 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

85 Pa g e 85 of 212 As we would now expect, if you instead have massive prolonged stressors, or are administered big hefty doses of glucocorticoids, you put the system in phase C—dramatic immune suppression, which decreases the symptoms of autoimmunity. Supporting this summary ss increases the risk of autoimmune disease. A schematic representation of how repeated stre is the finding that while acute stress puts rats more at ri sk for a model of multiple scle rosis, chronic stress suppresses the symptoms of that auto immune disease. The system apparently did not evolve for dealing with numerous repetitions of coordinating the various on-and-off switches, and ultimately something uncoordinated occurs, system becomes autoimmune. increasing the risk that the CHRONIC STRESS AND DISEASE RISK A repeated theme in this book is how some physiological response to your average, run-of-the-mill mammalian e. The ability of major stressors to suppress immunity below stressor, if too long or too frequent, gets you into troubl ory. How damaging is stress-induced immunosuppression when baseline certainly seems like a candidate for this categ suppress the immune system su fficiently, a thirty-year-old it actually occurs? As the AIDS virus has taught us, if you will fester with cancers and pneu monias that doctors used to see once in an elderly patient during a fifty-year career. But can chronic stress suppress the immune system to the point of making you more susceptible to diseases you wouldn't otherwise get? Once you have a disease, are you now less capable of fighting it off? Evidence pouring in from many quarters suggests that stress may indeed impair our immune systems and increase the much chronic stress makes you mains far from clear just how risk of illness. But despite these striking findings, it re uld normally be fought off by the immune system. In order to appreciate the more vulnerable to diseases that wo current disarray of the research, let us try to break down the findings into their component parts. Essentially, all these studies show a link between something that increases or decreases stress and some disease or ologists is based on the assumption that this link is mortality outcome. The approach of many psychoneuroimmun established through the following steps: 1. The individuals in question have been stressed, 2. causing them to turn on the stress-response (the secretion of glucocorticoids, epinephrine, and so on). 3. The duration and magnitude of the stress-response in these individuals is big enough to suppress immune function, infectious disease, and impa irs their ability to defend 4. which increases the odds of these individuals getting some themselves against that disease once they have it. Thus, suppose you see that a certain im mune-related disease is more common in circumst ances of stress. You now ssed individuals with that 4 occurred in those stre can you show that steps 1 to have to ask two critical questions. First, disease? Second, is there some altern ative route that explains starting w ith stress and getting to the disease? Let's begin by analyzing those four separate steps, in order to see how tough it is to demonstrate that all four have occurred. In studies of nonhuman animals, the general consensus is Step 1, "The individuals in question have been stressed." that with enough stress, you are going to get to steps 2 through 4. But a problem in extrapolating to humans is that the l than what we typically experience. Not only that, udies are usually more awfu experimental stressors used in animal st 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

86 Pa g e 86 of 212 but we differ tremendously among ourselves as to what we experience as truly st ressful—the whole realm of s of the last chapter of this book. Therefore, if you try to study the effects of individual differences that will be the focu these things actually seem stressors on people's immune systems, you must wrestle with the problem of whether bly satisfied in stress/immune- stressful to a given individual or not. What that winds up meaning is that step 1 is proba uld consider pretty awful— related disease studies that involve even the death of a loved one, ts that most everyone wo divorce, financially threatening unemployment. But if the external reality is one that a lot of people would not matically accept that you're at step 1. consider to be stressful, you can't auto are really exposed to the stressors to which step 1: it's often not clear whether humans There is another problem with they claim they're exposed. We tend to be notoriously bad reporters of what goes on in our lives. An imaginary them bad stomachaches for a few days. experiment: take one hundred lucky people and slip them a drug that will give Then send them to a doctor secretly participating in this experiment, who tells them that they have developed stomach tly?" Perhaps ninety of those ticularly stressful for you recen innocently, "Have things been par ulcers. The doctor asks subjects will come up with something or other putatively stressful to which they will now attribute the ulcer. In e very likely to decide there were stressful events going on. retrospective studies, people confronted with an illness ar When you rely heavily on retrospective studies with humans, you are likely to get a falsely strong link between stress e retrospective (a problem that and disease; and the trouble is, most studies in this field ar popped up in the chapter on only recently becoming more digestive disorders as well). The expensive and lengt hy prospective studies are common—pick a bunch of healthy people and follow them for decades to come, recordin g as an objective outsider ssors and whether they become sick. when they are being exposed to stre We move to the next step: from the stressor to the stress-response (step 1 to step 2). Again, if you give an organism a massive stressor, it will reliably have a strong stress-response. With more subtle stressors, we have more subtle stress- responses. 3. In experimental animal studies, large amounts of The same thing holds for the move from step 2 to step oor. The same occurs if a human has a tumor that causes glucocorticoids will cause the immune system to hit the fl 's syndrome), or if a person is taking huge doses of massive amounts of glucocorticoids to be secreted (Cushing synthetic glucocorticoids to control some other disease. But as we now know, the moderate rises in glucocorticoid levels seen in response to many more typical stressor s stimulate the immune system , rather than suppress it. ed levels of glucocorticoids should be protective. As we saw in the last Moreover, in a few types of cancers elevat vels of estrogens in females and testosterone in males, and chapter, very high levels of glucocorticoids will suppress le by these hormones (most notably "estrogen-sensitive" forms of breast cancer certain types of cancers are stimulated and "androgen-sensitive" prostate cancers). In these cases, lo ts of stress equals lots of glucocorticoids equals less estrogen or testosterone equals slower tumor growth. does a change in immune profile alter patterns of disease? The odd thing is Moving from step 3 to step 4, how much that immunologists are not sure about this. If your immune system is massively suppressed, you are more likely to get sick, no doubt about that. People taking high doses of glucocorticoids as medication, who are thus highly with Cushing's syndrome. Or ectious diseases, as are people lnerable to all sorts of inf immunocompromised, are vu AIDS. in their implications, however. Few immunologists would be The more subtle fluctuations in immunity are less clear ecrease in some measure of immune functio n, there is a tiny increase in disease likely to assert that "for every tiny d may be nonlinear. In other immune competence and disease relationship between risk." Their hesitancy is because the words, once you pass a certain threshold of immunosuppression, you are up the creek without a paddle; but before that, immune fluctuations may not really matter much. The immu ne system is so complex th at being able to measure a change in one little piece of it in response to stress may mean nothing about the system as a whole. Thus, the link between relatively minor immune fluctuation and patterns of disease in humans winds up being relatively weak. There is another reason why it may be difficult to generalize from findings in the laboratory to the real world. In the and 3 on disease outcome 4. It is inconvenient for most laboratory, you might be studying the effects of steps 1, 2, oids, or immunity and then wait for the rest of the rat's scientists to manipulate a rat's levels of stress, glucocortic nd expensive. Typically, instead, a control rat. That's slow a lifetime to see if it is more likely to become ill than is scientists study induced diseases. Manipulate step 1, 2, or 3 in a rat that has b in virus; then see een exposed to a certa what happens. When you do that, you get information about steps 1 through 3 that have to do with step 4 when dealing with severe, artificially induced disease challenges. But it should be obvio us that an approach like this misses e. Instead, we spend our lives berately exposes us to diseas the point that we don't get sick because some scientist deli passing through a world filled with scattered 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

87 Pa g e 87 of 212 carcinogenic substances, occasional epid emics, someone sneezing from across th e room. Relatively few experimental us diseases, rather than induced ones. animal studies have looked at spontaneo stress and diseases associated with These are a lot of caveats. Let's consider some areas where there are links between tent these links are a function of progressing from steps 1 immune dysfunction. This will let us evaluate to what ex ks stress and disease. In each case, we'll through 4, what we w oimmune Route," which lin ill call the "Psy-choneur rnative sequence, what we'll loosely call the "Lifestyle Route," which can link stress and consider if there is an alte sing the sequence of immune-related disease while bypas steps 1 to 4. TESTING THE STRESS-DISEASE LINK Social Support and Social Isolation What the data show: the fewer social relationships a person has, the shorter his or her life expectancy, and the worse us diseases. Relationships that are medically the impact of various infectio protective can take the form of marriage, , church membership, or other group affi contact with friends and extended family liations. This is a fairly consistent erent settings. Moreover, these general findings are based on some careful pattern that cuts across a lot of diff American and European in both sexes and in different races, in prospective studies and are seen populations living in both urban and rural areas. Most important, this effect is bi g. The impact of social rela tionships on life expectancy at of variables such as cigarette smoking, hypertension, obesity, and level of appears to be at least as large as th approximately two-and-a-half west social connections have physical activity. For the same illness, people with the fe times as much chance of dying as those variables as age, gender, with the most connect ions, after controlling for such and health status. Very exciting. And what might explain this relationship? Maybe it's through the Psychoneuroimmune Route of steps 1 e are more stressed for lack of social outlets and support to 4, which would run something like: socially isolated peopl (step 1); this leads to chronic activation of stress-responses (step 2); leading to immune suppression (step 3); and more infectious diseases (step 4). these steps. First, just because some one is socially isolated doesn't mean Let's see what support there is for each of they are stressed by yet another crowded Twister party. Social isolation as a it—there are lots of hermits who would be happy to pass on bill as socially isolated stressor is a subjective assessm ent. In many of these studies, however, the subjects who fit the negative emotion. So we can check off rate themselves as lonely, certainly a step 1. On to step 2—do these people have chronically overactive stress-responses? We have little evidence for or against that. How about step 3—is social isolation associated with damping down some aspect of immune function? There's a lot an antibody response to a vaccine in ally isolated individuals having less of of evidence for that: lonelier, more soci 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

88 Pa g e 88 of 212 one study; in another study of people with AIDS, having a faster decline in a key category of lymphocytes; in another, of women with breast cancer, having less natural killer cell activity. ee of immune suppression play Then on to step 4—can you actually show that that degr ed a role in the disease occurring? The facts are relatively weak. olation and step 3; others show isolation and step Some studies show social is 4, but few show both and also explicitly show that the magnitude of step 3 has something to do with the transition to step 4. ing relevant. What about the Still, there is relatively good evidence for this pathway be Lifestyle Route? What if the to remind them to take their daily medication? It is lack that special someone problem is that socially isolated people to comply with a medical regime. What if they're more likely to subsist on known that isolated people are less likely something nutritious? Or more likely to indulge in some foolish risk-taking behavior, like reheated fast food instead of y to convince them to stop ? Many lifestyle patterns c ould link social isolation smoking, because there's no one to tr if the causality is reversed— what if the bypassing this sequence of steps. Or what with more infectious disease, able social relationships? be able to maintain st linkage occurs because sickly people are less likely to Numerous studies have controlled for these lifestyle risk factors like smoking, diet, or medication compliance and have shown that the isolation/poor health outcome relatio nship is still there. Moreover, critically, you can show the with Big Macs, alcohol, a same in nonhuman primates, who don't confound their health nd smoking. Infect monkeys with SIV (the simian equivalent of HIV) and more socially isolated animals had higher glucocorticoid levels, fewer rtality rate—in other words, steps 1 to 4. antibodies against the virus, more virus in their system, and a greater mo ealth through the effects of stress on made that social isolation can impact h Overall, I'd say a pretty good case can be immunity. But the case isn't airtight. Bereavement al isolation, is, of course, the loss Bereavement, an extreme version of soci of a loved one. An extensive literature des with depression, it is distinct fr shows that while bereavement often coinci om it. A common belief is that the one the masterless pet—now pines aw ay to an early death. A left behind—the grieving spouse, the bereft parent, even the effect is not all that e the risk of dying, although number of studies suggest that bereavement does indeed increas strong. This is probably because the risk occurs only in a subset of grieve rs, amid those people who have an additional physiological or psychological risk factor coupled with the bereavement. In one careful prospective study, the parents ard. Loss of a child did not re followed for ten years afterw of all the Israeli soldiers who died in the Lebanese war we affect mortality rates in the population of grieving parents in general. However, significantly higher mortality rates occurred among parents who were already widowed or divor ressor is associated with ced. In other words, this st minimal social support. the added risk factor of increased mortality in the subset of parents with Thus, we are turfed back to the subj ect of social isolation. Again, the evidence for the Psyc honeuroimmune Route there are many potential Lifestyle Routes—g rieving people are un occurring is decent but, again, likely to be eating, sleeping, exercising in a healthy manner. Sometimes the confound is more subtle. People tend to marry people who are ethnically and genetically quite similar to themselves. In trinsic in this trend toward "homogamy" is a tendency of married couples to have higher-than-random chances of sharing environmental risk factors (as well as to component of the Lifestyle disproportionately share disease-related genes, making this Route not really related to sick around the same time. None those confounds, lifestyle). This makes it more likely that they will get theless, amid ality rates among bereaved levant to the increased mort the Psychoneuroimmune Route's steps 1 to 4 are probably re g social support. individuals lackin The Common Cold Everybody knows that being stressed increases your chances of getting a cold. Just think back to being run down, frazzled, and sleep-deprived and runny nose. Examine the r during final exams, and, sure enough, there's that cough ecords at univer sity health me thing—students succumbing to colds left and right around exam period. Many of us services and you'll see the sa a few days and, suddenly, there's that later—burn the candle at both ends for continue to see the same pattern decades scratchy throat. Psychoneuroimmune Route steps 1 to 4 seem quite plausible. Some of the studies involve some pretty hefty external events that most people would consider stressful, like financially disastrous unemployment (step 1). But few have ges in relevant immune measures have been documented, looked at the magnitude of the stress-response (step 2). Chan , those same individuals are shown to ich stress increases the risk of a cold however—for example, in studies in wh have less of the cold-fighting class of antibodies that are secreted in your saliva and nasal passageways (steps 3 and 4). 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

89 Pa g e 89 of 212 But we have to consider some possible Lifestyle Route confounds. Maybe the disruptive effects of stress on memory we are under stress due to our overcoats. Or maybe when (stay tuned for chapter 10) cause us to forget to button up g to consort with people who sneeze recklessly without covering their faces. social isolation, we are more willin Okay, maybe those aren't confounds you have to worry about too much. But stress changes lifestyle and different e viruses that cause colds. degrees of exposure to th lifestyles mean differing r in a celebrated series of studies. In one version, some cheerfully compliant That possibility has been controlled fo volunteers were housed under conditions where some major life style confounds were controlled for. They then filled noses with equal amounts of were then spritzed up their out questionnaires regarding how stressed they were. Subjects on cold. Note that everyone was exposed to the same amount of pathogen. rhinovirus, the bug that causes the comm And the results? (Fanfare.) More stress equaled about three times the likelihood of succumbing to a cold after being nature provided the greatest exposed to the virus. Prolonged stressors more than a mont h long that were social in risk.* Moreover, the same thing works in * These studies came out of the famed Commo n Cold Unit of the Medical Research Council in Salisbury, England, which recruited v olunteers for their frequent two-week experiments about va rious aspects of coming down with and rec overing from the common cold. Apparently q uite an ful Salisbury countryside, daily experience: all expenses covered plus a small salary, many r ecreational activities in the peace blowing of noses into virus. One in three collection tubs for the staff, qu the nose with either pl acebo or a cold-causing estionnaires to fill out, and being spritzed up chance, on average, of getting a cold while there. People would co mpete for slots as volunteers; couples have (continued) laboratory mice and nonhuman primates—spr itz them with rhino-virus, and it is the stressed, socially subordinate animals who get their species' equivalent of the sniffles. convincing that stress makes the common cold more common at least partially along the Collectively, it seems pretty Psychoneuro-immune Route. AIDS Given that AIDS is a disease of profound immunosuppressi on, and that major stressors suppress the immune system, can stress increase the likelihood that someone who is HIV positive develops AIDS? And once AIDS is established, can stress worsen its course? These questions have been aired since the AIDS epidemic began. Since the last edition of this book, the triple apy has turned AIDS from a fatal disease to an often manageable chronic one, making combination antiretroviral ther more relevant.* these questions even think that stress can alter the course of AIDS. Suppose you grow human There is some good indirect evidence to lymphocytes in a petri dish and expose th glucocorticoids as well, they become em to HIV. If you expose the cells to virus. Moreover, norepinephr ine can also make it easier for the virus to invade a more likely to be infected with the lymphocyte and, once inside, enhances replication of the virus. Support also comes from a study with nonhuman primates, discussed earlier, which suggest HIV. To reiterate, the monkeys were s that steps 1 to 4 might apply to infected with SIV, the simian version the monkeys who were more socially of HIV. The authors then showed that 2), fewer antibodies against the virus (step 3), and a higher isolated (step 1) had higher glucocorticoid levels (step mortality rate (step 4). How about humans? (continued) met there, married, returned for honeymoons; folks with connections would maneuver for return visits, making it an annual paid would be involved in studies sho vacation. (All was not idyllic snif fling heaven at the Cold Unit, however. An occasional group wing that, for cause of budget d around for hours in we damp does not cause colds, and would have to stan example, being chilled and t socks.) Unfortunately, be h titles like, "How I Blew limitations, the unit has been closed. This para dise lost has been chronicled in at l east one scholarly book, plus articles wit My Summer Vacation." tions. money, or whose country has enough money, to afford the medica * Assuming you are one of the lucky few with AIDS who has enough To begin, starting with the same amount of HIV in your system, a faster decline and a higher mortality rate occur, on average, among people who have any of the following: (a) a coping style built around denial; (b) minimal social loss of loved ones. These are not huge support; (c) a socially inhibited temper ament; (d) more stressors, particularly ir consistency in the findings on this. So that seems to qualify for step 1. effects but, nevertheless, there seems a fa Do these individuals also have overact ive stress-responses (step 2)? Glucocorticoid levels are not particularly sk people with the socially inhibited temperaments have predictive of the course of HIV. However, the more at-ri even better predictor of elevated activity of their sympathetic ner vous system, and the extent of that overactivity is an decline than is the personality itself. So that seems to get us to step 2. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

90 Pa g e 90 of 212 Does lots of stress, an inhibited temper ament, denial, or lack of social support not only predict higher mortality rates n (step 3)? That seems to be the case as well. (step 4) but a faster decline of immune functio ute? The medication regimes How about the Lifestyle Ro So AIDS seems to follow the Psychoneuroimmune Route. for dealing with HIV can be en e that people who are more stressed are less ormously complex, and it is quite plausibl risk factors have not been all likely to take their antiviral medication, or to take it correct ly. My sense is that lifestyle connection runs in the opposite direction—what if having a that well controlled for in these studies. How about if the r fewer social connections? That seems you more socially inhibited, makes fo faster decline with the disease makes portant control, the personality style has been shown to predict immune profiles many quite plausible but, as an im months later. In summary, psychoneuroimmune aspects could well contribute to a link between stress and worsening of aspects of to be done to examine how much stress in AIDS. But more research needs fluences whether people comply with their ll their treatment regimes work. treatment regimes, versus how we Latent Viruses After rhinoviruses and the AIDS virus, there is one last category of viruses—those that, after initially infecting you, can go latent. "Latency" means that the virus, once burrowing into some cells of yours, goes into hibernation for a DNA, but not yet replicating itself. At some later point, something triggers while, just lurking near your own cellular the dormant virus out of latency and it reactivates. After go ing through a couple of rounds of replication the by now larger number of h, after infecting some of example are herpes viruses whic viral particles burrow in and go latent again. The classic decades, before flaring up out of latency. your neurons, can go latent for years, even evolved. Infect some cells, replicate, bur This is a clever tactic that viruses have st the cells open in the process, make in the immune system and, ju the sort of mess of things that sets off all sorts of alarms st as those activated immune ow into another round of cells. While the im mune cells are cleani cells are about to pounce, burr ng up, the virus goes latent again. t reactivate at any old time. They wait until the immune viruses have done? They don' The next clever thing that system of the host organism is lousy, and then gun for some quick rounds of replication. And when are immune systems often at their lousiest? You got it. It's been endlessly documented that latent viruses like herpes flare up during times of physical or psychological stress in all sorts of species. It's the same thing with some other viruses that go latent, like Epstein-Barr virus and varicella-zoster (which causes chicken pox and shingles). n. How does a latent herpes vi So hats off to these highly evolved viruses. Now a key questio rus that, after all, is just d inside a bunch of your neurons, know that you are some unschooled little stretch of DNA sitting mothballe attempting to come out of latency and, if your immune immunosuppressed? One possibility is that herpes is always nd possibility is that herpes system is working fine, it snuffs out the attempt. A seco can somehow measure how the immune system is doing. easure how your immune system is doing. d in the last few years. Herpes doesn't m Amazingly, the answer has emerge its purposes, gives it the information it needs—it measures your glucocorticoid It measures something else that, for levels. Herpes DNA contains a stretch that is sensitive to el evated glucocorticoid signals, and when levels are up, that ricella-zoster contain this latency. Epstein-Barr and va DNA sensor activates the genes involved in coming out of glucocorticoid-sensitive stretch as well. And now for something even more fiendish ly clever. You know what else herpes can do once it infects your nervous release CRH which releases ACTH which raises glucocorticoid levels. system? It causes your hypothalamus to Unbelievable, huh? So you don't even need a stressor. Herpes infects you, artificially pushes you to step 2 with your elevated glucocorticoid levels, which gets you to step 3, and allows the virus to come out of latency. Moreover, defenses against activated herpes. This leads to elevated glucocorticoid levels impair your immune clever with our big brains and opposable thumbs. step 4—a cold sore flare-up. And we think we're so that stress can increase the uroimmunol-ogy, and can see We've now looked at several favorite topics in psychone likelihood, the severity, or both of some immune-related di ude for considering the most seases. All of this is a prel contentious subject in th is whole field. The punch line is one of the mo st important in this book, and runs counter to what is distressingly common folk wisdom. STRESS AND THE BIG C What does stress have to do with getting cancer? 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

91 Pa g e 91 of 212 The first piece of evidence suggesting stress may increase th e risk of a cancer diagnosis comes from animal studies. tion literature showing that st ng animal-experimenta There is, by now, a reasonably convinci ress affects the course of some types of cancer. For exampl e, the rate at which some tumors grow in mice can be affected merely by what sort re noisy and stressful, the faster the tumors grow. Other studies show that of cages the animals are housed in—the mo nted tumors at a from which they can eventually escape, if you expose rats to electric shocks they reject transpla escape, yet give the same total number of shocks, and the rats lose their normal rate. Take away the capacity to on a rotating platform (basically, a record player), and capacity to reject tumors. Stress mice by putting their cages there is a tight relationship between the number of rotations and the rate of tumor growth. Substitute glucocorticoids e are the results of very careful studies for the rotation stressor, an d tumor growth is accelerated as well. Thes performed by some of the best scientists in the field. y at least partially. These Does stress work through the Psychoneuroimmune Route in these animals? Seemingl And these glucocorticoids directly influence tumor biology stressors raise glucocorticoid levels in these studies. through both immune and non-immune realms. As a first mech ntains a specialized class anism, the immune system co t the spread of tumors. Stre of cells (most notably, natural killer cells) that preven ss suppresses the numbers of route is probably non-imm unologic. Once a tumor starts circulating natural killer cells in these studies. A second growing, it needs enormous amounts of energy, and one of the first things that tumors do is send a signal to the nearest allows for the delivery of blood and blood vessel to grow a bush of capillaries into the tumor. Such angio-genesis nutrients to the hungry tumor. Glucocorticoids, at the concentration generated during stress, aid angiogenesis. A final the bloodstream. Recall the ery. Tumor cells are very g route may involve glucose deliv ood at absorbing glucose from ergy storage has stopped in order to ns of circulating zebra sprinting away from the lion: en increase concentratio lab reported some years back , when circulating glucose glucose to be used by the muscles. But, as my own ring stress, at least one kind of experimental tumor can grab the glucose before concentrations are elevated in rats du the muscle does. Your storehouses of energy, intended for your muscles, are being emptied and inadvertently transferred to the ravenous tumor instead. animals, and some psy-ch So we have some stress-cancer links in oneuroimmune mechanisms to explain those effects. Does this apply to humans? Two big features of these animal studies dramatically limit their relevance to us. First, to the animal. So we're not tumor, where tumorous cells ar induced these were studies of e injected or transplanted in altering the course of cancers introduced by looking at stress causing cancer in these animals, we're looking at stress the incidence of spontaneous shown that stress increases artificial routes. No animal studies to my knowledge have tumors. Furthermore, most of these studies have relied on such cases, viruses tumors that are cause d by viruses. In take over the replication machinery of a cell and cause it to start dividing and growing out of control. In humans most sure to environmental carcinogens, rather cancers arise from genetic factors or expo than from viruses, and those have boratory animals. So a cauti al studies: stress can not been the subject of study with la onary note from the anim cancers of limited relevance to humans, and mber of tumors, but these are types of accelerate the growth of a nu introduced through completely artificial means. Thus, we turn our attention to humans. Our first, simplest question: Is a history of major stressors associated with an increased risk of having can cer somewhere down the line? ffered from the same proble m, namely, that they were A number of studies seemed to show this, but they all su cer diagnosis is more likely to rememb retrospective. Again, someone with a can er stressful events than someone with a bunion. How about if you do a retrospective study where you rely upon a history of verifiable stressors, like the death of a family member, loss of a job, or a divorce? A couple of studies have reported a link between such major stressors and the onset of colon cancer five to ten years later. A number of studies, ng stress histories of women at the had a "quasi-prospective" design, assessi especially of breast cancer patients, have time that they are having a biopsy for a breast lump, r diagnosis with those who comparing those who get a cance don't. Some of these studies have show n a stress-cancer link, and this should be solid—after all, there can't be a ve cancer. What's the problem here? Apparently, people can retrospective bias, if the women don't know yet if they ha cancer at a better than ch guess whether it will turn out to be ance rate, possibly reflectin g knowledge of a family history of the disease, or personal ex posure to risk factors. Thus, such qu asi-prospective studies are already quasi- the least reliable kind. retrospective, and of When you rely on the rare prospectiv good evidence for a stress-cancer link. For e studies, there turns out not to be example, as we will see in chapter 14 on depression, having a major depression is closely linked to both stress and excessive glucocorticoid secretion, and one famous study of two thousand men at a Western Electric plant showed later. But a careful reexamination that depression was associated with doubling the risk of cancer, even up to decades le to a subset of men who were depressed as hell on-cancer link was attributab of those data showed that the depressi because they were stuck worki ng with some major carcinogens. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

92 Pa g e 92 of 212 Subsequent prospective studies of other populations have show n either no depression/cancer link, or a tiny one that is led out the alternative Lifestyle Route, in that depressed over, these studies have not ru biologically meaningless. More risk of cancer. Similar findings emerge from the careful people smoke and drink more, two routes to increase the prospective studies of bereavement as a stressor—no link with subsequent cancer. ion and altered sleep patterns chapter 11 how sleep deprivat Thus, we shift to a different literature. We'll be seeing in ressors. In searching for a link between stress and in (such as with night shifts) are major st creased risk of cancer, it these studies) wo n who have spent long periods (decades in may not be surprising to find that wome rking night shifts However, the most plausible explanation here has nothing to do with stress. have an increased risk of breast cancer. Instead, a shifted day/night schedule dram atically decreases the level of a light-responsive hormone called melatonin, types of cancer, including breast cancer. increases the risk of a number of and depletion of this hormone greatly More suggestive links go by the wayside as well. As discussed earlier, individuals who get organ transplants are at risk for rejecting them, and one of the prevention strategies is to give them glucocorticoids in order to suppress the immune system past the point of being a small subset of such individu als, there is an increased inci able to reject the organ. In dence of a few types of skin cancer (of the less serious, non-melanoma kind). Moreover, as noted, if someone's immune system is massively increased incidence of a handful of suppressed because of AIDS, there is an types of cancers. So do these findings tighten the links between cancer and st ress? No. This is because: (a) stress never suppresses the immune system to system is suppressed that much, only a small subset of organ transplant or that extent; (b) even when the immune subset of cancers that no w become more common. AIDS patients get cancer; and (c) it is only a tiny particular support for the idea that stress increases the risk So besides those two reports about colon cancer, there is no s numerous studies of breast can of cancer (and, it should be noted, this conclusion include cer, the type of cancer most frequently assumed by people to be stress related). But is there a subset of individuals who have a particular (and poor) style of coping with stress that puts them more at risk for cancer? We already saw, in chapter 5, the notion of there being personality types that are more prone toward func tional gastrointestinal disord ers. Is there a. cancer-prone personality, and can it be interpreted in the context of coping poorly with stress? een done with breast cancer Some scientists think so. Much of the work in this area has b , in part because of the However, the same pattern has been reported for other cancers as well. The prevalence and seriousness of the disease. told, is one of repression—emotions held inside, particularly those of anger. This is a cancer-prone personality, we're spectful individual with a strong desire to please—conforming and compliant. Hold those picture of an introverted, re emotions inside and it increases rding to this view. t will come cancer, acco the likelihood that ou e, and we have seen the problems endemic to such Most of these studies have been retros pective or quasi-prospectiv studies. Nonetheless, the prospec tive studies have shown there to be some link, though a small one. Are we in the realm of Psychoneuroimmune Route steps 1 through 4? No one has shown that yet, in my opinion. As rsonality is associated wi we will see in chapter 15, a repressed pe th elevated glucocorticoid levels, so we're in the range of step 2. But, to my knowledge, no one has shown evidence for step 3—some sort of immune suppression— occurring, let alone it being of a magnitude relevant to cance r. In addition, none of the good prospective studies have or, in the case of breast cancer ruled out the Lifestyle Route (such as smoking, drinking, , more fat consumption). So the jury remains out on this one. ception of two studies concerning one type of cancer, no overall suggestion that So collectively, we have, with the ex stress increases the risk of cancer in humans. Stress and Cancer Relapse es stress increase the risk of it coming What if your cancer has been cured? Do back? The handful of studies on this subject don't suggest that there's a conn ection—a few say yes, an equal number, no. Stress and the Course of Cancer Now on to the most complex and controversial issue of all. Sure, stress may not have anything to do with whether you come down with cancer, but once you have cancer, will stress make a tumor grow faster, increasing your risks of dying from the disease? And can st ress reduction slow down tumor growth, extending survival times? As we saw above, stress will accelerate tumor growth in animals, but those ty pes of instigated tumors and their biology are of limited relevance to the way humans get cancer. So we have to look at studies of humans. And here the subject is a mess. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

93 Pa g e 93 of 212 We begin by looking at whether different coping styles pr compare patients edict different cancer outcomes. When you ive) with those who collapse , they are optimistic and assert who respond to their cancer with a "fighting spirit" (that is live longer, after contro lling for cancer severity. into depression, denial, and repression, the former Findings like these prompted studies in which clinicians atte stress and inculcate more of mpted to intervene, to reduce that fighting spirit in people, in order to influence the patient's cancer outcome. The landmark study of this type was carried out in the late 1970s by the psychiatrist David Spiegel of Stanford University. Women who had just gotten a a group that received st ndomly assigned to either andard medical care or a metastatic breast cancer diagnosis were ra group that, in addition, had intensive supportive group psychotherapy with other breast cancer patients. As Spiegel has to it anticipating that the group therapy intervention might emphasized in his accounts of this famous study, he went in but he certainly didn't ex pect that it would affect the biology of the cancer. decrease psychological distress in patients, an an average of eighteen Amid his skepticism, what he found was that the group ther apy intervention extended life sp months, a whopping great effect. s been a big problem since then—it's just not clear if a psychosocial This made front-page news. But there' intervention actually works. Since the Spiegel study , there have been roughly a dozen others, and they are evenly split as to whether ther e is any protective effect from group therapy. In wh at was probably the most thorough attempt at a replication of Spiegel's findings, a study published in 2001 in the prestigious New England Journal of Medicine, there was no effect on survival time. Why has this finding been so difficult to replicate? Spiegel and others give a plausible explanation, having much to do many decades ago, cancer." Not that rred over the years in the "culture of with the massive changes that have occu getting cancer had a weirdly shameful quality to it—doctors wouldn't want to tell their patients about the embarrassing and hopeless diagnosis; patients would hide having the disease. As one example, in a 1961 survey, a boggling 90 percent of American physicians said they did not typically reveal a cancer diagnosis to their patients; doctors have come to 3 percent. Moreover, over the years, within two decades, the number was down to consider the fighting the cancer, and see the course of medical treatment psychological well-being of their patients as essential to as a collaboration between themselves and the patient. As Spiegel says, when he began his work in the 1970s, the group to be willing to waste their time with something as biggest challenge was to get patients in the "experimental" irrelevant as group therapy. In contrast, by the 1990s vers ions of these studies, the bi ggest challenge was to convince the "control" subjects to forgo group therapy In this view, it has become difficult to show that introducing a stress- everyone, including control reducing psychosocial interv ention extends cancer survival over control subjects because support all over seeks psychosocial duce stress during cancer treatment, and subjects, now recognizes the need to re the place, even if it doesn't come with an offi ly group psychotherapy." cial stamp of "twice week cing. Thus we accept the premise that rrect, and I do find it to be convin Let's assume this explanation is co psychosocial interventions that re duce stress do extend cancer survival. Le t's grind through the steps of the such an effect. Are the why the group therapy has Psychoneuroimmune Route to see if we can understand psychosocial interventions perceived as being stress reducing by the patients (step 1)? There are striking individual exceptions, but the studies, overall, show this resoundingly to be the case. ssociated with a damping of the stress Are those psychosocial interventions a -response (step 2)? A few studies have shown that psychosocial interventions can lower glucocorticoid levels. Flip the question the other way—does having horter cancer survival? No. In the most an overactive stress-response predict s detailed study of this, following a subsequent population of Spiegel's metastatic breast cancer patients, having high glucocorticoid levels around the time of diagnosis didn't predict a shorter survival time.* So while psychosocial interventions ere's little evidence that elevated can reduce glucocorticoid levels, th do cancer patients with more glucocorticoid levels predict shorter cancer survival. But psychosocial support have better immune function (step 3)? Seemingly. Breast cancer patients who reported more stress had lower activities of those natural killer cells, while there's higher NK cell activity in women who report more social support or who received some sort of group therapy intervention. Were those immune changes relevant to the change in survival time levels of NK cell activity didn't predict survival times in these studies. (step 4)? Probably not, since someone's ychoneuroimmune Route. How about the So there's not much evidence for a Ps Lifestyle Route? There are lots of reasons to think lifestyle plays a key role in the link be tween stress and the course of cancer, but it's very hard to eat confounds in cancer therapy is that cer patients don't about a quarter of can show, for a subtle reason. One of the gr take their medications as often as pr escribed, or miss chemothera py appointments. Go figure, when these treatments make you feel so so awful. And what happens in a group therapy setting, when you're surrounded by people going through the same hell as you? "You can go the extra round of chemo, I know you can—yeah, I felt awful the whole time during mine, but you can do it, too," or "Have you eaten today? I know, I have no appetite either, but we're going to get something to eat right after this," or "Have you taken your meds today?" Compliance goes up. Any sort of will increase the success rates of treat ments. And because a cancer patient, intervention that increases compliance 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

94 Pa g e 94 of 212 reasonably, would often be very uncomfortable about admittin g that she's not completely complying with a treatment ocial therapy are kicking in e protective effects of psychos regime, it's hard to detect accurately whether any of th + through this route. * Instead, independent of the abso at the time had a glucocorticoid levels lacked a 24-hour rhythm lute levels of glucocorticoids, patients whose much this section is, perhaps, shorter survival time. Given how reading like a critical dissection worth noting that I was a of this field, I think it is ls predicted a bad ation in glucocorticoid leve of the daily rhythmic fluctu puzzled as to why the loss coauthor on this study. We're still utterly outcome. A possibility is that the loss of irrelevant, a red herring, an d the key thing is that th e daily rhythm of some the glucocorticoid rhythm is is something that is now being investigated. other hormone, like melatonin, has been lost. This + The whole issue of compliance is somethin g Spiegel raises in his writings. His renown ed study is endlessly misinterpreted as explicitly him enormously for resisting that bandwagon on which he'd be supporting a Psychoneuroimmune Route of protection, and I respect given a front- row seat. What we have here are some extremely interesting but murky waters. There appears to be virtually no link between a incidence of cancer, or a greater risk of history of a lot of stress and a greater relapse out of remission. There seems to be a link between a certain personality type and a somewh at greater cancer risk, but no studies have shown where stress physiology fits into that story, nor have lifestyle confounds been ruled out. Next, the findings are about evenly at reduce stress improve cancer divided as to whether psychosocial interventions th outcomes. Finally, when little support for a Psychoneu-roimmune intervention is effective, there's considering the cases where psychosocial easons to think that an alternative ro ute involving issues of lifestyle and Route to explain the efficacy, and good r compliance is important. . However, it is time to search, of course. Lots more What does one do with these findings? Right on cue—more re not gs in the meantime. discuss what one should do with these findin CANCER AND MIRACLES This leads to a tirade. Once we recogn ize that psychological factors, stress-reducing interventions, and so on can lusion that such factors can control influence something like cancer, it is often a hopeful, desperate leap to the conc cancer. When that proves to be false, th ere is a corrosive, poisonous flip side: if you falsely believe you had the power to prevent or cure cancer through positive thinking, you may then come to believe that it is your own fault if you are dying of the disease. The advocates of a rather damaging ov hology-health relationships are not always addled erstatement of these psyc voices from the lunatic fringe. They in clude influential health practitioners whose medical degrees appear to lend claims of Bernie S. Siegel, a Yale will focus my attention here on the credence to their extravagant claims. I University surgeon who has been wildly effective at disseminating hi s ideas to the public as the author of a bestseller. (New York: Harper & Row, 1986), Love, Medicine and Miracles The premise of Siegel's still-popular magnum opus, stem is through love, and that miraculous healing happens is that the most effective way of stimulating the immune sy to patients who are brave enough to love. Siegel purports to demonstrate this. As the book unfolds, you note that it is a strange world that ing on anesthetized patients, Siegel inhabits. When operat "I also do not hesitate to ask the [anesthetized] patient not to bleed if sserts (p. 49). In his world, circumstances call for it," he a ed countries in which individu deceased patients come back as birds (p. 222), there are unnam als consistently live for a le who have the right spirituality not only successfully fight century (p. 140), and best of all, peop cancer but can drive cars that consistently break down for other people (p. 137). even feel comforted by those among us who live the belief This is relatively benign gibberish, and history buffs may system of medieval peasants. Where th is when Siegel concentrates on the e problems become appallingly serious main point of his book. No matter how often he puts in disclaimers saying that he's not trying to make people feel guilty, the book's premise is that (a) cancer can be caused the person; (b) cancer (or any by psychosocial factors in other disease, as far as I can tell) is cu rable if the patient has sufficient courage, love, and spirit; (c) if the patient is not is not how cancer have just seen, this ounts of those admirable traits. As we cured, it is because of insufficient am works, and a physician simply should not go about telling seriously ill people otherwise. nd lack of spirituality. He His book is full of descript ions of people who get cancer because of their uprightness a "Naturally [my emphasis], Jan got breast speaks of one woman who was repressed in her feelings about her breasts: at Siegel is aware of the literature on cancer-prone personality, but this cancer" (p. 85)—this seems an indication th another patient: "She held all her feelings inside and e mostly careful studies. Of constitutes a caricature of thos to appear in response to developed leukemia" (p. 164). Or, in an extraordinary stat ement: "Cancer generally seems at this time, the impulse behind it becomes misdirected into loss ... I believe that, if a person avoids emotional growth malignant physical growth" (p. 123). 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

95 Pa g e 95 of 212 Naturally, those who do have enough courage, love, and spirit can defeat cancer. Sometimes it takes a little prodding from Siegel. He advises on page 108 that people with seri ous diseases consider the ways in which they may have ained to associate sickness with reward receiving cards and wanted their illness because we are tr ; Siegel cites our flowers on page 110. Sometimes Siegel a recalcitrant cancer patient. One woman has to be a bit more forceful with quested her to, being embarrassed about her poor drawing was apparently inhibited about drawing something Siegel re she didn't even have the cour xpected to get over cancer if age to do a picture" (p. 81). skills. "I asked [her] how she e if she eventually died. You know whose fault it was attitude problems and get with the program, miracles just start popping up But once the good patients overcome their everywhere you as long as he was at it, his his cancer, his arthritis, and, visualizing techniques cured look. One patient with the proper ll (p. 153). Of another, Siegel writes: "She chose the path of life, and as twenty-year problem with impotency as we she grew, her cancer shrank" (p. 113). Consider the following exchange (p. 175): I came in, and he said, "Her cancer's gone." "Phyllis," I said, "Tell them what happened." She said, "Oh, you know what happened." "I know that I know," I said, "But I'd like the others to know." Phyllis replied, "I decided to live to be a hundred and leave my troubles to God." I really could end the book here , because this peace of mind can heal anything. Thus, presumably, people who die from cancer never got around to deciding to live to be a hundred. According to Siegel, cancer is curable with the righ t combination of attributes, and those people without them may get cancer and fault of the victim. He tries to soft en his message now and then: "Cancer's die of it. An incurable disease is the complex causes aren't all in the mind," he says (p. 103), and on page 75 he tells us he's interested in a person gaining understanding of his or her role in a disease rather than in creating guilt. But when he gets past his anecdotes about individual patients and states his premise in its broadest terms, its toxicity is unmistakable: "The fundamental problem themselves" (p. 4); "I feel that all di sease is ultimately related to a lack of most patients face is an inability to love love" (p. 180). ose children trying to and for the parents of th r children with cancer Siegel has a special place in his book fo understand why it has occurred. After noting that developmental psychologists have learned that infants have considerably greater perceptual capacities than previously beli eved, Siegel says he "wouldn't be surprised if cancer in early childhood was linked to messages of parental conflict or disapproval perceived even in the womb" (p. 75). In other words, if your child gets cancer, consider the possibility that you caused it.* incurable diseases, only incurable pe ople" (p. 99). (Compare the statement And perhaps most directly: "There are no by the late stress researcher Herbert Weiner : "Diseases are mere abstractions; they can- * This was something that inflam ed me when first reading this book fifteen years ago as a puerile single guy; it does so to an indescribable extent ng the hell of a seriously ill child. now that I am a father of young children, and have peers sufferi " Superficially, Siegel's and Weiner's notions bear some not be understood without appreciating the person who is ill. resemblance to each other. The latter, howe ver, is a scientifically sound statemen t of the interactions between diseases and individual makeups of sick people; the former seems to me an unscientific distortion of those interactions.) s been a philosophical view of dis ease that is "lapsarian" in nature, Since at least the Middle Ages, there ha characterizing illness as the punishment meted out by God for sin (all deriving from humankind's lapse in the Garden of Eden). Its adherents obviously predated any knowledge about germs, infection, or the workings of the body. This view has mostly passed (although see the endnote for this page for an extraordinary example of this thinking that festered in the Reagan administration), but as you read through Siegel's book, you unconsciously wait for its reemergence, knowing that disease has to be more than just not having enough groovy New Age spirituality, that God is going to be yanked into Siegel's worl d of blame as well. Finally, it bubbles 179: "I suggest to the surface on page that patients think of illness not as God's will but as our deviation from God's will. To me it is the absence of spirituality that leads to difficulties." Cancer, thus, is what you get when you deviate from God's will. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

96 Pa g e 96 of 212 Oh, and one other thing about Siegel's views. He founded a cancer program ca lled Exceptional Cancer Patients, which my knowledge there have been only two ture of life, spirit, and disease. To incorporates his many ideas about the na published studies of his program and its effects on survival time. Both reported that the program has no significant effect on survival. And one last word from the good doctor (p. 185), washing his hands of the first study (the second and effective techniques, and had not yet been published when he wrote his book): "I pref er to deal with individuals let others take care of the statistics." Why is it worth going on at length about this subject, to pay so much attention to a more-than-fifteen-year-old book? Because of how influentia l Siegel's style of thinking has been. Here is ample: in one study, breast but one chilling ex thought had caused their cancer. Among the hundreds of participants, answers cancer patients were asked what they breast trauma. And what ent, hormones, diet, and came back such as genetics, environm was the most common attribution, by a wide margin? Stress. This, in a paper published in 2001, at the dawn of our new millennium. ss stress management theories. This topic is one that I will return to in the final chap ter of the book when I discu ecause of stress and how go wrong in the body b just how many things can Obviously, a theme of this book is to recognize this. However, important it is for everyone it would be utterly negligent to exaggerate the implications of this idea. Every child cannot grow up to be president; it turned out that merely by holding hands and singing folk songs we couldn't end all war, and hunger does not disappear just by visualizing a world without it. Everything bad in human health now is not caused by stress, nor is it in our power to cure ourselves of all our worst medical nightmares merely by reducing stress and thinking healthy thoughts full of courage and spirit and love. Would that it were so. And shame on those who would profit from selling this view. POSTSCRIPT: A GROTESQUE PI ECE 0F MEDICAL HISTORY The notion that the mind can distress can change resistance to certain influence the immune system, that emotional ul pull. Nevertheless, it mmunology exerts a powerf diseases, is fascinating; psychoneuroi sometimes amazes me just e even beginning to speciate into subspecialties. Some how many psychoneuroimmunologists are popping up. They ar study the issue only in humans, others in animals; some in large populations, others analyze epidemiological patterns study single cells. During breaks at scientific conferences, you can even get teams of psychoneuroimmunological pediatricians playing volleyball against the psychoneuroi mmunological gerontologists. I am old enough, I confess frankly, to remember a time when th ere was no such thing as a psychoneuroimmunologist. Now, like an aging w mammals proliferating. Cretaceous dinosaur, I watch these ne There was even a time when it was not common nd as a result, medical re searchers carried out some knowledge that stress caused immune tissues to shrink—a influential studies and misinterpreted their findings, which indirectly led to the deaths of thousands of people. By the nineteenth century, scientists and doctors were becoming concerned with a new pediatric disorder. On certain occasions parents would place their apparen tly perfectly healthy infant in bed, tu ck the blankets in securely, leave for "Crib death," or sudden infant death the morning to find the child dead. a peaceful night's sleep—and return in syndrome (SIDS), came to be itially had to explore the recognized during that time . When it happened, one in inated, and one was left with use, but that was usually elim unsettling possibility that there was foul play or parental ab their sleep for no discernible reason. the mystery of healthy infants dying in g SIDS. It seems to arise in infants who, during the third Today, scientists have made some progress in understandin r brains do not get enough oxygen, causing certain neurons in trimester of fetal life, have some sort of crisis where thei rol respiration to become esp ecially vulnerable. But in the the brain stem that cont nineteenth century, no one had a clue as to what was going on. Some pathologists began a logical course of research in the 1800s. They would carefully autopsy SIDS infants and btle, fatal mistake occurred: "normal compare them with the normal infant au topsy material. Here is where the su o gets autopsied? Who gets practiced on by ing hospitals? Whose bodies infant autopsy material." Wh interns in teach it has been poor people. medical students? Usually, wind up being dissected in gross anatomy by first-year when men with strong backs and a nocturnal bent could opt for a career as The nineteenth century was the time the medical schools for "resurrectionists"— grave robbers, body snatchers, who would sell corpses to anatomists at ed without coff odies of the poor, buri whelmingly, the b use in study and teaching. Over ins in shallow mass graves in potter's fields, were taken; the wealthy, by contrast, would be buried in triple coffins. As body-snatching anxiety spread, adaptations evolved for the weal thy. The "patent coffin" of 1818 was explicitly and expensively marketed to cemeteries of the gentry would offer a turn ere the well-guarded in the dead-house, wh be resurrectionist-proof, and body could genteelly putrefy past the point of interest to the dissectors, at which time it could be safely buried. This named after one William Burke, the aging resurrectionist who period, moreover, gave rise to the verb burking, pioneered the practice of luring beggar s in for a charitable meal and then st rangling them for a quick sale to the , were handed over to the dekick, after their execution anatomists. (Ironic-ending department: Burke and his si 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

97 Pa g e 97 of 212 anatomists. Their dissecti on included particular attention to their skulls, with an attempt to find phrenological causes of their heinous crimes.) some drawbacks. The poor tended to express a riotous All very helpful for the biomedical community, but with body snatcher complex (to coin a phrase). Frenzied crowds displeasure with the medico- lynched resurrectionists who were caught, attacked the homes of an atomists, burned hospitals. Concerned about the mayhem caused by unregulated preying on the bodies of the poor, governments moved decisively to supervise the preying. In the early nineteenth the anatomists, put the burkers and acted to supply adequate bodies to century, various European governments resurrectionists out of business, and keep the poor in line—all with one handy little law: anyone who died destitute in a poorhouse or a pauper's hospital would now be turned over to the dissectors. Doctors were thus trained in what the normal human body looked like by studying the bodies and tissues of the poor. eir poverty. In the "normal" autopsy Yet the bodies of poor people are change d by the stressful circumstances of th population of six-month-olds, the infants had typically died of chronic diarrheal disorders, malnutrition, tuberculosis. Prolonged, stressful diseases. Their thymus glands had shrunk. We now return to our pathologists, comparing the bodies of SIDS infants with those of "normal" dead infants. By definition, if children had been labeled as having died of SIDS, there was nothing else wrong with them. No prior stressors. No shrinking of the thymus gland. The researchers begin their studies and discover something striking: SIDS kids had thymuses much larger than those of "norma l "dead infants. This is where they got things backward. Not knowing that stress shrinks the thymus gland, they assumed that the thymuses in the "normal" autopsy population that SIDS is caused by were normal. They concluded that some children have an abnormally large thymus gland, and that large thymus pressing down on th e trachea and one night suffo cating the child. S oon this imaginary disorder had a fancy name, "status thymicolymphaticus." r SIDS provided a humane substitute for the usual explanation at the time, This supposed biological explanation fo al or incompetent, and some of the most progressive which was to assume that the parents were either crimin physicians of the time endorsed the "big thymus" story (including Rudolph Virchow, a hero of chapter 17). The SIDS, based on this nonsense. prevent trouble was, the physicians decided to make some recommendations for how to Get rid of that big thymus. Maybe do it surgically, which turned out to be a bit It seemed perfectly logical at the time. tes are that in the ensuing us through irradiation. Estima choice emerged: shrink the thym tricky. Soon, the treatment of decades it caused tens of thousands of which sits near the thymus. When I cases of cancers in the thyroid gland, er people whose parents, as late as th e 1950s, had their th roats irradiated for lecture on this subject, I regularly encount this reason. What recommendations does one offer from the history of status thymicolymphaticus? I could try for some big ones. That so long as all people are not born equal and certainly don't get to live equally, we should at least be dissected equally. How about something even more grandiose, such as that something should be done abou t infants getting small thymuses from economic inequality. we expend a great deal of scale. For example, while Okay, I'll aim for something on a more manageable scientific medical research—say, sequencing th e human genome—we still need smart effort doing extraordinary things in Because they are often people to study some of the moronically simple problems, like " how big is a normal thymus?" not so simple. Maybe another lesson is that confounds can come from unexpected quarters—bands of very smart public health researchers wres tle with that idea for a living. Perhaps the best moral is that when doing science (or perhaps when doing anything at all in a society as judgmental as our own), be very careful and very certain before e norm—because at that instant, you have ma pronouncing something to be th icult to ever again de it supremely diff look objectively at an exception to that supposed norm. 9 STRESS AND PAIN Catch- In Joseph Heller's classic novel about World War II, 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

98 Pa g e 98 of 212 22, the antihero, Yossarian, has an unlikely argument of God. Unlikely because with someone about the nature they are both atheists, which would presumably lead to However, it turns out that agreement about the subject. while Yossarian merely does not believe in the existence of a God and is rather angry about the whole concept, the God that she does not believe in is one who is good and warm and loving, and thus she is offended by the vehemence of his attacks. "How much reverence can you have fo ry to include such phenomena as r a Supreme Being who finds it necessa divine system of creation? What in the world was runnin g through that warped, evil, phlegm and tooth decay in His scatological mind of His when He robbed old people of the power to control their bowel movements? Why in the world did He ever create pain?" "Pain?" Lieutenant Scheisskopf's wife pounced upon the word victoriously. "Pain is a useful symptom. Pain is a warning to us of bodily dangers." ghed caustically. "Oh, He was really being charitable to "And who created the dangers?" Yossarian demanded. He lau us when He gave us pain! Why couldn't He have used a doorbe ll instead to notify us, or on e of his celestial choirs? Or ght in the middle of each kebox manufacturer worth a system of blue-and-red neon tubes ri person's forehead. Any ju his salt could have done that. Why couldn't He?" "People would certainly look silly walking around with red neon tubes in the middle of their foreheads." "They certainly look beautiful now writhing in agony or stupefied with morphine, don't they?" Unfortunately, we lack neon lights in the middle of our foreheads, and in the absence of such innocuous signs, we probably do need pain perception. Pain can hurt like hell, but sitting too close to the fire, it can inform us that we are or that we should never again eat the novel item that just gave us food poisoning. It effectively discourages us from trying to walk on an injured limb that is better left immob ilized until it heals. And in our westernized lives, it is often a o late. People who congenially lack the ability to feel pain (a good signal that we had better see a doctor before it is to when they step do are a mess; because they can't feel pain pain asymbolia) condition known as wn with too much force, their feet may ulcerate, their knee joints may disintegrate, and their long bones may crack; they burn themselves lose a toe without knowing it. unawares; in some cases, they even Pain is useful to the extent that it motivates us to modify our behaviors in order to reduce whatever insult is causing the pain, because invariably that insult is damaging our tissues. Pain is useless and debilitating, howe ver, when it is telling us that there is something dreadfully wrong that we can do nothing about. We must praise the fact that we have e same time we must deeply stomachs are empty. Yet at th evolved a physiological system that lets us know when our rue our evolving physiological syst em that can wrack a terminal cancer patient with unrelenting pain. Pain, until we get the lights on our foreheads, will remain a necessary but highly problematic part of our natural physiology. What is surprising is how malleable pain signals are—how readily the intensity of a pain signal is changed by the sensations, f eelings, and thoughts that coincide with the pain. One example of this modulation, the blunting of pain perception during some circumstances of stress, is the subject of this chapter. THE BASICS OF PAIN PERCEPTION eceptors located throughout our body. Some The sensation of pain originates in r are deep within the body, telling us about muscle aches, fluid-filled, swollen joints, or damage to organs. Or even something as 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

99 Pa g e 99 of 212 George Cruikshank, The Headache, hand-colored etching, 1819. mundane as a distended bladder. Others, in our skin, can tell us that we have been cut, burned, abraded, poked, or respond to the signal of local tissue compressed.* Often, these skin receptors damage. Cut yourself with a paring ze that then spill out their pr knife, and you will slice open various cells of microscopic si overbial guts; and, typically, within this cellular soup now flooding out of the area of injury is a variety of chemical messengers that trigger pain are there to scarf receptors into action. The tissue injury al immune system, which so triggers an influx of cells of the up and dispose of those sliced -up cells. The swelling ar ound the injury site because of this infiltration is what we call flammatory cells release chemicals that inflammation, and those in make pain receptors more sensitive. only about pain (for exam ple, the ones responding Some pain receptors carry information to cuts); others carry information about both pain and everyday sensations. How are the two differentiated? ain receptors for something called A compound found in * Great factoids: the pain receptors that respond to heat cont capsaicin. What is capsaicin? s to the key same neurons? One that respond of receptor is found in those red chilies. That's why spicy food tastes hot. And what other type component of horseradish, wasabi, and mustard. By intensity. For example, by way of va rious tactile receptors on my back, I am greatly pleased to have my back scratched and rubbed by my wife. Howeve r, as evidence that there are limits to all good things, I would not at all enjoy it if she vigorously scratched my back with coarse sandpaper. Similarly, we may be pleased to have our thermal ter. Sometimes pain consists of everyday sensations writ receptors stimulated by warm sunlight but not by boiling wa large. rticular receptor act ivated, all these receptors send nerve Regardless of the particular type of pain and the pa cord. This can activate a where spinal neurons rapidly send commands to your spinal reflex, projections to the spinal muscles (and thus, for example, you jerk your finger away from the flame). Information about the painful stimulus is also sent up to the brain (a lot more on this later). SENSORY MODULATION OF PAIN PERCEPTION A striking aspect of the pain system is how readily it can be modulated by other factors. The strength of a pain signal, for example, can depend on what other sensory information is tunneled to the spine at the same time. This, it turns out, is why it feels great to have a massage when you have sore muscles. Chronic, throbbing pain can be inhibited by certain types of sharp, brief sensory stimulation. The physiology behind this is one of the most elegant bits of wiring I know of in the nervous system, a circuit sorted out some decades ago by the physiologists Patrick Wall and Ronald Me lzack. It turns out that the nervous projections—the fibers carrying pain information from your periphery to the spinal cord—are not all of one kind. between fibers that carry information Instead, they come in different classes. Probably the most relevant dichotomy is about acute, sharp, sudden pain and those that carry information about slow, diffuse, constant, throbbing pain. Both project to spinal cord neurons and activate them, but in different ways (see part A of the figure on page 190). 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

100 Pa g e 100 of 212 Two types of neurons found in the spinal cord are being affected by painful information (see part B of the illustration). The first (X) is the same neuron diagrammed before, which relays pain information to the brain. The second neuron When Y is stimulated, it inhibits the activity of X. interneuron. (Y) is a local one called an sharp, painful stimulus is felt, the information is sent on the fast fiber. This stimulates As things are wired up, when a both neurons X and Y As a result, X sends a painful signal up th e spinal cord, and an The Wall-Melzack model of how pain information is passed to the brain, and how it can be modulated by the brain. (A) A neuron (X) in the spinal cord sends a signal to the brain that something painful has happened, once it is stimulated by a pain fiber. Such pain fibers can carry information about sudden pain or slow, diffuse pain. (B) A more realistic version of how the system actually works, showing why sudden and slow pain information is differentiated. In uron X, causing a pain signal to be relayed to the brain. the case of sudden pain, the sudden pain fiber stimulates ne The sudden pain fiber also stimulates an interneuron (Y) that inhibits neuron X, after a brief delay. Thus, neuron X sends a pain signal to the brain for only a short time. In contrast, the slow pain fiber stimulates neuron X and inhibits interneuron Y. Thus, Y does not inhibit X, and X continues to send a pain signal to the brain, producing a slow, diffuse pain. (C) Both stimulatory and inhibitory fibers come from the brain and send information to neuron X, modulating its sensitivity to incoming pain information. Thus, the brain can sensitize neuron X to a painful signal, or blunt its sensitivity. , such as after stepping on a es a brief, sharp burst of pain instant later, Y kicks in and shuts X off. Thus the brain sens tack. By contrast, when a dull, throbbing pain is felt, the information is sent on the slow fiber. It communicates with both fast fiber. Once again the X neuron is stimulated and lets neurons X and Y, but differently from the way it does on the the brain know that something painful has occurred. This time, however, the slow fiber inhibits the Y neuron from firing. Y remains silent, X keeps firing, and your brain senses a prolonged, throbbing pain, the type you'd feel for ologist David Yeomans has framed the functions of the fast hours or days after you've burned yourself. The pain physi and slow fibers in a way that fits perfectly with this book: what the fast fibers are about is getting you to move as quickly as possible (from the source of the piercing pain). What the slow fibers are about is getting you to hunker down, immobile, so you can heal. The two classes of fibers can interact, and we often intentionally force them to. Suppose that you have some sort of painful blister. How can you stop the throbbing? Briefly continuous, throbbing pain—sore muscles, an insect bite, a stimulate the fast fiber. This adds to th e pain for an instant, but by stimulating the Y interneuron, you shut the system down for a while. And that is precisely what we often do in all of those circ umstances. Experiencing a good vigorous mauling massage inhibits the dull throbbing pain of sore muscles for a while. An insect bite throbs and itches ves. In all these cases, the the pain. Or we'll pinch oursel unbearably, and we often scratch hard right around it to dull slow chronic pain pathway is shut down for up to a few minutes. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

101 Pa g e 101 of 212 This model has had important clinical implications. For one thing, it has allowed scientists to design treatments for people with severe chronic pain syndromes (for example, a patient who has had a nerve root crushed in his back). By implanting a little electrode into the fast pain pathway and attaching it to a stimulator on the person's hip, they enable off the chronic pain; works wonders in many cases. the patient to buzz that pathway now and then to turn PAIN THAT GOES ON LONGER THAN NORMAL If someone pokes you over and over, you if you get an injury that eel pain each time. Similarly, will continue to f ere are likely to be days of pain as well. But sometimes, something goes wrong with causes days of inflammation, th between those pain recep- pain pathways somewhere s stimulus has stopped or the injury has healed, or you feel tors and your spine, and you feel pain long after the noxiou which is feeling pain allo-dynia, pain in response to stimuli that shouldn't be painful at all. Now you've got problems— in response to a normal stimulus. themselves. Recall how when there is Some versions of allodynia can arise do wn at the level of the pain receptors that make those local pain receptors rate into the area and release chemicals tissue injury, inflammatory cells infilt ammatory cells are pret ty indiscriminate as to where they dump imulated. Now those infl more excitable, more easily st these chemicals, and some of them can leach over in the directio n of receptors outside th e area of injury, thereby making them more excitable. And sudden ly the perfectly healthy ti ssue surrounding the injure d area starts to hurt as well. ngs are severed near the pain thway are injured. If nerve endi ccur when neurons in the pain pa Allodynia can also o receptors, those inflammatory cel ls release growth promoting factors that pr ompt the nerves to regenerate. Sometimes the regeneration is bollixed up so that the nerve endings rewire into a tangle called a neuroma, which tends to be hyperexcitable, sending pain signals from perfectly healthy tissue. And if the nerve projections carrying pain this can lead to a cascade of infl information are severed near the spine, ammatory events that results in a hyperexcitable spinal cord. A mere touch now feels excruciating. as seen in severe cases of both The Wall-Melzack pathway model on page 190 explains another instance of allodynia, r 4, elevated levels of glucose in th e bloodstream can increase the risk of types of diabetes. As we saw in chapte atherosclerotic plaques, clogging up blood vessels. As a result, insufficient energy gets through those vessels, potentially damaging nerves that depend on that energy. In general it is the fast fibers, which take more energy to ged. Thus, the person loses the ability to shut down the operate than the lower-maintenance slow fibers, that are dama else becomes a constant throbbing one would be a transient pain for anyone Y interneuron in that pathway, and what for a diabetic. NO BRAIN, NO PAIN inal cord as far as the sp red all over the body, and have gotten receiving We started with pain receptors scatte projections from them. From there, a lot of thos e spinal neurons that are activated by pain send where things become really interesting. projections up into the brain. This is in the middle of some appalling battle, people being Consider three scenarios involving pain. First, a soldier is ing, but serious enough to warrant evacuation. Second, slaughtered all around. He is injured—not life-threaten consider someone with advanced liver cancer, administered an ex perimental drug. Within a few days, her gut hurts like hell, a sign of the drug killing the tumor cells. Or third, someone is abrading their rear end raw while enthusiastically having sex on a rough carpet. What do they all have in common? Their pain's not going to seem all that painful—the war's over for me; the drug's working; what carpet? The brain's interpretation of pain can be extremely subjective. A study conducted in the 1980s provides a striking example of this subjectivity. A scien tist examined a decade's worth of records at a suburban hospital, noting how many painkillers were requested by patients who had just had gallbladder surgery. It turned out that patients who had vi ews of trees from their windows requested significantly less pain medication than those who looked out on blank walls. Other studies of chronic pain patients show that so dramatically changes the quantity manipulating psychological variables such as the sense of control over events al ll be elaborated upon in th of painkillers that they request (this important finding wi e final chapter of the book). less pain-ometer, simply m easuring units of ouchness. This is because the brain is not a mind Certainly some parts of the brain allow you to make some objective assessments ("Whoa, this water is WAY too hot for the baby's bath"). And there are factors that can modulate how much those pain-ometer areas regi ster pain—for example, oxytocin, the hormone released in connection with birth and maternal behavior in mammals, will blunt pain responsiveness in these pathways. But most of what the brain's responses to pain are about is generating emotional responses and giving 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

102 Pa g e 102 of 212 contextual interpretations about the pain. This is how being shot in the thigh, gasping in pain, can also leave you gasping in euphoric triumph—I've survived this war, I'm going home. Three important things about the emotional ways the brain interprets and responds to pain: the objective amount of pain First, the emotional/interpretative level can be dissociated from signal that is coursing up to the brain from the spine. In other words, how much pain you feel, and how ing scenarios. , and tush-abrad 's implicit in the war, cancer unpleasant that pain feels, can be two separate things. That An elegant study shows it more explicitly. In it, volunteers dipped their hands into hot water before and after being given a hypnotic suggestion that they feel no pain. During both hand dips, brain imaging was carried out to show which parts of the brain were becoming active. The sensation-processing part of the cortex (kind of a pain-ometer in eat-sensitive pain milar number of h extents in both cases, reflecting the si this case) was activated to identical receptors being triggered to roughly the equivalent extent in both cases. But the more emotional parts of the brain pnosis case. The pain was the same in both cases; the response to it was not. activated only in the pre-hy As a second point, those more emotive parts of the brain not only can alter how you respond to pain information to pain information. responds alter how the spinal cord coming up the spinal cord; t hose areas of the brain can And the third point: this is where stress comes in big time. STRESS-INDUCED ANALGESIA Chapter 1 recounted anecdotal cases of people who, highly aroused during battle, did not notice a severe injury. This is certainly a useful thing for a soldier, or a zebra, who still needs to function despite those circumstances. One of the first to document this phenomenon of stress-induced analgesia was an anesthesiologist, Henry Beecher, who examined injured soldiers as a battlef them with civili an populations. He ront medic in World War II and compared found that for injuries of similar severity, approximately 80 percent of civilians requested morphine, while only a third of the soldiers did. ced analgesia in the midst of battle. For us, it is more likely to happen during some Few of us experience stress-indu sporting event where, if we are sufficiently excited and invo can easily ignore an injury. lved in what we are doing, we On a more everyday level, stress-indu ced analgesia is experienced by the dr oves who exercise. In variably the first stretch is agony, as you search for every possible excuse to stop before you suffer the coronary that you now fear. You even start feeling oddly ation, the pain melts away. Then suddenly, about half an hour into this self-flagell euphoric. The whole venture seems like th e most pleasant self-improvement con ceivable, and you plan to work out like this daily until your hundredth birthday (with all vows, of course, forgotten the next day when you start the painful process all over again).* Traditionally many hard-nosed laboratory scientists, when encountering something like stress-induced analgesia, would relegate it to the "psychosomatic" realm, dismissi ng it as some fuzzy aspect of "mind over matter." The analgesia, however, is a real biological phenomenon. ssertion is that stress-induced analgesia occurs in other animals as well, not just in One bit of evidence for that a humans emotionally invested in the succes s softball team. This can be shown in s of their nation's army or their office' animals with the "hot-plate test." Put a rat on a hot plate; then turn it on. Carefully time how long it takes for the rat to feel the first smidgen of discomfort, when it picks up its f oot for the first time (at which point the rat is removed from a rat that has been stressed—forced to swim in a tank of water, exposed to the hot plate). Now do the same thing to stress-induced analgesia. er. It will take longer for this rat to notice the smell of a cat, whatev the heat of the plate: The best evidence that such anal gesia is a real phenomenon is the neurochemi stry that has been discovered to underlie it. The tale begins in the 1970s, with the subject that interested every ambitious, cutting-edge neurochemist of the time. It concerned the various opiate drugs that were being used recreationally in vast numbers: heroin, morphine, opium, all of which have similar chemical structures. In the early 1970s, three groups of neurochemists almost opiate receptors in th that these opiate drugs bound to specific simultaneously demonstrated e brain. And these receptors tended to be located in the parts of the brain th ception. This turned out to solve the at process pain per descending pathways that blunt the sensitivity of the X problem of how opiate drugs block pain—they activate those neuron shown in the illustration on page 190. ing puzzling hits you. Wh y should the brain make receptors for a class of Terrific—but two beats later, someth in; there must be some chemical—a neurotransmitter? compounds synthesized in poppy plants? The realization rushes a hormone?—made in the body that is 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

103 Pa g e 103 of 212 ind that they've * A recent study that I find fascinating: Ta sport, and you'll f ke a bunch of jocks, of both genders, let th em compete at their keep their hand in a bucket of ice water lt (as measured by, say, their ability to developed stress-induced analgesia as a resu for a longer period after the women, the key variable is the exercise, in e on an exercise bike. In the athletics than before). For that the analgesia will also be produced by tim ced by a competitive video game. that the analgesia is also indu riable is the competition, in contrast, for the men, the key va structurally similar to opiates. Some kind of endogenous morphine must occur naturally in the brain. Neurochemists went wild at this point looking for endogenous morphine. Soon they found exactly what they were looking for: endogenous compounds with chemical structures reminiscent of the opiate drugs. They turned out to come in three different classes— (a contraction endorphins enkephalins, dynorphins, and the most famous of them all, The opiate receptors were discovered to bind these endogenous opio id compounds, just for "endogenous morphines"). as predicted. Furthermore, the opioids were synthesized and released in parts of the brain that regulated pain refers that relay pain signals in the spine less excitable. perception, and they would make some of the neurons (Opiate to analgesics not normally made by the body, such as heroin or morphine. refers to those made by the body Opioid itself. Because the field began with the study of the opi ates—since no one had discovered the opioids as yet—the is to bind the opioids.) receptors found th en were called opiate receptors. But clearly, their real job Chapter 7 introduced the finding that the endorphins and enkephalins also regulate sex hormone release. An additional intriguing finding concerning opioid action emerged: rel ease of these compounds expl ained how acupuncture worked. Until the 1970s, many Western scientists had heard about the phenomenon, but most had written it off, dumping it inese herbalists sticking needles into people, Haitian into a bucket of anthropological oddities—inscrutable Ch with their secret-recipe chicken soup. mothers curing any and all diseases shamans killing with voodoo curses, Jewish Then, right around the time of the explosion in opiate research, Nixon ventured to China, and documentation started coming out from there about the reality of acupuncture. Furthermore, scientists noted that Chinese veterinarians used e painkilling character istic of acupuncture als, thereby refuting the argument that th acupuncture to do surgery on anim cultural conditioning (no cow on earth will go along with unanesthetized was one big placebo effect ascribable to ral mores of the society in wh ich it dwells). Then, as the surgery just because it has a heavy investment in the cultu corker, a prominent Western jour nalist (James Reston of the New York Times) got appendicitis in China, underwent surgery, and was administered acupuncture for pain relief. He survived just fine. Hey, this stuff must be legit—it even works on white guys. ease of large quantities of endogenous opioids, for reasons no one really understands. Acupuncture stimulates the rel The best demonstration of this is what is called a subtraction experiment: block the activity of endogenous opioids by using a drug that blocks the opiate blocked, acupuncture no longer receptor (most commonly a dr ug called naloxo ne). When such a receptor is perception of pain. effectively dulls the vant to explaining placebos as well. A Endogenous opioids turn out to be rele placebo effect occurs when a person's because they believe that a medical ssment of their health improves, merely health improves, or the person's asse out on them, regardless of whether it actually has. This is where patients in a study either procedure has been carried get the new medicine being tested or, without knowing it, merely a sugar pill, and sugar pill folks get somewhat a few better. Placebo effects remain New England Journal of Medicine publicized paper in the controversial. A highly placebo treatments across the board in a ll realms of medicine. The authors years back surveyed the efficacy of examined the results of 1 ng a placebo treatment had no 14 different studies, and conc luded that, overall, receivi me no end, because the au thors included all sorts of significant effects. The study irritated realms where it seemed lieving you've received an crazy to expect a placebo effect to o ccur. For example, the st udy informed us that be effective medical treatment when you act ects for epilepsy, elevated cholesterol ually have not has no beneficial eff zheimer's disease, anemia, or schizophrenia. levels, infertility, a bacterial infection, Al d, amid the triumphant chest-thumpi ng by all sorts of dead-white-male Thus, the placebo effect got trashed an elements of the medical establishment, what was lost in that paper was a cl ear indication that placebo effects are highly effective against pain. the brain. As an example of This makes a great deal of sense, given what we have now s een about pain processing in of painkillers is more effective if the patien t sees the infusion occu such a placebo effect, IV infusion rring than if it is done on the sly—knowing that a pain-reducing procedure is be effectiveness. I saw a great ing carried out adds to its example of this a few years back when my then two-year-old daughter came down with an ear infection. She was miserable beyond consolation, clearly in tons of pain. Off to the pediatrician and, amid much wailing and said the doc, disappearing protestations of pain, she had her ears ex amined. Yup, she's got a h uge infection, both ears, to get an injection of antibiotics. We turn to find our daughter looking serene. "My ears feel much better now that the doctor fixed them," she announ ced. Placeboed by having some instrument stuck in her ears. Not surprisingly, it turns out that they work by releasing endogenous opioids. As but one example of the evidence for loxone, and placebos no longer work. that, block opiate receptors with na 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

104 Pa g e 104 of 212 All of this is a prelude to the discovery that stress releases opioids as well. Th is finding was first reported in 1977 by scoveries described in chapter 2, he demonstrated that Roger Guillemin. Fresh from winning the Nobel Prize for the di stress triggers the release of one type of endorphin, beta-endorphin, from the pituitary gland. The rest is history. We all know about the famed runner's high that kicks in after about half an hour and creates that rphin pours out of the ria, just because the pain has gone away. Du glowing, irrational eupho ring exercise, beta-endo pituitary gland, finally building up to levels in the bloodstream around the 30-minute mark that will cause analgesia. n and spine. They activate ll, mostly within the brai alins, are mobilized as we The other opiates, especially the enkeph e X neurons in the spinal cord , and they work directly at the descending pathway originating in the brain to shut off th the spinal cord to accomp lish the same thing. Moreover, they also work at the pain r eceptors in the skin and organs, blunting their sensitivity. All sorts of other stressors produce similar effects. Surgery, low blood sugar, exposure to cold, examinations, spinal ta ps, childbirth—all do it.* Certain stressors also cause analgesia through "nonopioid- mediated" pathways. No one is quite sure how those work, nor whether there is a systematic pattern as to which stressors are opioid-mediated. So stress blocks pain perception, enabling you to sprint away from the lion despite your mauling, or at least to put up ing the stressful meeting with the boss. This explains with the muscle ache of smiling obsequiously non-stop dur worse everything. Unless it happens to be the sort of stressful situation that makes pain instead of better. WHY IS MUZAK IN THE DENTIST'S OFFICE PAINFUL? you're the sort of person All that stress-induced analgesia stuff ma y be swell for that disemb oweled zebra, but what if where just seeing the nurse taking the cap off the hypodermic needle for the blood draw makes your arm throb? What hyperalgesia. we've got now is stress-induced The phenomenon is well documented, if studied less than stress-induced analgesia. What is known about it makes perfect sense, in that * It should be obvious to anyone who has gone through childbirth or at least observed it at close quarters—as I have twice sinc e the previous edition's version of this chapter was wr those contractions really get going. itten—that those opiates do squat once Vic Boff, New York Polar Bear Club member known as "Mr. Iceberg," sitting in the snow after a swim during the blizzard of 1978. nothing to do with pain receptors stress-induced hyperalgesia does not act ually involve more pain pe rception, and has or the spinal cord. Instead, ivity to pain, interpreting the same sensation as more it involves more emotional react unpleasant. So stress-induced hyperalgesia is just in your h ress-induced analgesia, just ead. On the other hand, so is st 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

105 Pa g e 105 of 212 a different part of your head. The pain-ometer parts of your brain respond to pain normally in people with stress- the brain that are induced hyperalgesia. It's rreactive, the parts of e brain that are hype the more emotional parts of th the core of our anxieties and fears. This can be shown with brain-imaging studies, showing what parts of pain circuitry in the brain become overly active during such hyperalgesia. Moreover, anti-anxiety drugs like Valium and Librium block stress-induced hyperalgesia. People who score high on tests for neuroticism and anxiety are most prone toward hyperalgesia during stress. have been bred for high anxiety. Amazingly, so are rat strains that makes science look kind of lame. Just So we're at one of those crossroads that like, "Stress can increase appetite. And e got, "Stress can blunt pain perception. But sometimes it does the opposite." How to it can decrease it, too," we'v the literature is that the analgesia arises more in combine these opposing effects of stress? My sense from circumstances of massive, physical injury. Half your body is burned and your ankle's sprained, and you're trying to induced analgesia is going to dominate. Discover some carry a loved one out of some inferno—that's when stress- weirdo growth on your shoulder that hurts a bit, decide in a panic that you've got fatal melanoma, be informed by an ree-day weekend. That unsympathetic answering machin e that your doctor has just left for a th 's when the stress- ree nights, thanks to how painful you've now decided the induced hyperalgesia will dominate, as you lie awake for th spot feels. So carefully in fact that in eeds to be treaded on carefully. This brings up a subject that n the last edition of the book, I bravely made a point of not mentioning a word about it. Fibromyalgia. This is the mysterious syndrome of people having markedly reduced pain tolerance and multiple tender spots throughout the body, often paralyzing extents of pain, and no one can find anything wrong—no pinched nerve, no arthritis, no inflammation. Mainstream medicine has ne (that is, "Get out of my office and go spent decades consigning fibrom yalgia to the realm of psychosomatic medici y to strike people with anxious or neurotic personalities. see a shrink"). It doesn't help that fibromyalgia is more likel e be the case. For starters, sufferers dical conclusion. But this may not quit There's nothing wrong, is the typical me have abnormally high levels of activity in parts of the brain that mediate the emotional/contextual assessments of pain, the same areas activated in stress-induced inal fluid contains elevated levels hyperalgesia. Moreover, their cerebral sp . And, as noted in chapter 2, of a neurotransmitter that mediates pain (called Substance P) unexpectedly, glucocorticoid these are highly stressed peopl e with some sort of defect levels are below normal in people with fibromyalgia. Maybe ing stress-induced analgesia, they get in glucocorticoid secretion, and because of that deficiency, instead of gett can tell. But there is increas ing evidence that there is hyperalgesia.* I don't know. No one knows, as far as I something biologically real going on in these cases. There, I've broken the ice on this subject; stay tuned for the next edition. involved in stress-induced analgesia. ation, glucocorticoids are not particularly * However, just to complicate that specul PAIN AND CHRONIC STRESS Time now for our usual question. What happens with pain perception when there is chronic stress? With stress- t what about stress- maybe even worsens. Bu seems to be, the pain just keeps going, induced hyperalgesia, the answer , lion-mauling scenario, it is adaptive. To follow the structure laid out in previous induced analgesia? In the acute ioid release make us sick news? How does an excess of op chapters, this represents the good news. So what's the bad in the face of the chronic ps ychological stressors that we specialize in? Do ke you an endogenous es chronic stress ma opioid addict? Does it cause so much of the stuff to be released that you can't detect useful pain anymore? What's the downside in the face of chronic stress? ed in this book. When hysiological systems examin ffers from all the other p Here the answer is puzzling because it di Hans Selye first began to note that chronic stress causes illn ess, he thought that illness occurs because an organism runs out of the stress-response, that the various hormones a nd neurotransmitters are depleted, and the organism is left undefended to the pummelings of the stressor. As we've seen in previous chapters, the mode rn answer is that the stress e itself eventually becomes because the stress-respons -response doesn't become depleted; instead, one gets sick damaging. analgesia does not go on fo Opioids turn out to be the exception to the rule. Stress-induced rever, and the best evidence ascribes this to depletion of opioids. You are not permanently out of business, but it takes a while for supply to catch up with demand. Thus, to my knowledge, there is no stress-related disease th at results from too much opi oid release during sustained stressors. From the standpoint of this book and our propensity toward chronic psychological stressors, that is good news—one less stress-related disease to worry about. From the standpoint of pain perception and the world of real physical stressors, the eventual depletion of the opioids m eans that the soothing effects of stress-induced analgesia are ng through terminal cancer, the soldier badly injured in just a short-term fix. And for the elderly woman agonizi to shreds but still alive, the consequence is obvious. The pain will soon return. combat, the zebra ripped 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

106 Pa g e 106 of 212 10 STRESS AND MEMORY and by now, I've forgotten a lot of them but, I tell you, I'm old now, very old. I've seen a lot of things in my time maybe twenty-five. It was a s-terday. I was twenty-four, that was one day that I'll remember forever like it was ye cold spring morning. Raw, gray. Gray sky, gray slush, gray people. I was looking for a job again and not having much luck, my stomach complaining about the bad rooming house coffee that was last night's dinner and today's breakfast. I was feeling pretty hungry, and I suspect I was starting to look pretty hungry too, like some half-starved animal that uldn't make much of an impression in an interview. And neither could the picks through a garbage can, and that co that last one I hadn't hocked. shabby jacket I was wearing, I was plodding along, lost in my thoughts, when some guy comes sprinting around the corner, yelling with he was shouting in my face. He was excitement, hands up in the air. Before I could even get a good look at him, babbling, yelling about something being "classic," something called "classic." I couldn't understand what he was talking about, and then he sprinted off. What the hell, crazy guy, I thought. But round the next corner, I see more people running aro und, yelling. Two of them, a man and woman, come running up to me and, by now, I tell you, I knew that something was up. They grabbed me by the arms, shouting "We won! We won!! We're getting it back!" They were pretty excited but at least maki ng more sense than the first guy, and I finally figured out what they were saying. I couldn't believe it. I tried to speak, but I got all choked up, so I hugged eet, where a big crowd was forming—people them as if they were my brother and si ster. The three of us ran into the str coming out of the office buildings, people stopping their cars, jumping out. Everyone screaming and crying and laughing, people shouting, "We won! We won!" Somebody told me a pregnant woman had gone right into labor, another that some old man had fainted right away. I saw a bunch of Navy guys, and one of them stepped right up and kissed this woman, a total stranger, leaning her way back—someone snapped a picture of them kissing, and I heard it became famous afterward. The weird thing is how long ago this was—the couple who first told me are probably long gone, but I can still see were dressed, the smell of the guy's afters have, the feel of the breeze that was blowing their faces, remember how they the confetti that people were tossing out the windows above. Still vivid. The mind's a funny thing. Well anyway, as I he day they brought back the original Coke. was saying, that's a day I'll always remember—t 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

107 Pa g e 107 of 212 A day to remember! We've all had similar experiences. Your first kiss. Your wedding ceremony. The moment when the war ended. And when those two guys mugged you. The time the car spun the same for the bad moments as well. The fifteen seconds out of control and just missed the oncoming truck. Where you were when the earthquake hit, when Kennedy was shot, your mind, when it's incon slightest thing about incidents on 9/11. All etched forever in ceivable that you can recall the ions, including stressful exciting, momentous occas fe-changing event. Arousing, in the twenty-four hours before that li ones, get filed away readily. Stress can enhance memory. At the same time, we've all had the opposite experience. You' re in the middle of the fi nal exam, nervous and frazzled, and you simply can't remember a fact that would come effortlessly at any other time. You're in some intimidating of course, at the critical moment, you can't remember the name of the person you have to social circumstance, and, introduce. The first time I was "brought home" to meet my future wife's family, I was nervous as hell; during a nner, I managed to blow the lead of the team consisting of my future mother frantically competitive word game after di -in-law and me by my utter inability at one critical juncture to remember the word And some of these casserole. eater traumas— the combat vet who went through some instances of failed memory revolve around infinitely gr unspeakable battle catastrophe, the surv the details are lost in an amnesiac ivor of childhood sexual abuse—for whom fog. Stress can disrupt memory. stress enhances some function under one circumstance and By now, this dichotomy should seem quite familiar. If e savanna versus decades of grinding course, think 30-second sprints across th disrupts it under another, think time worry. Short-term stressors of mild to moderate severity enhance cognition, while major or prolonged stressors are disruptive. In order to appr eciate how stress affects memory, we need to know something ab out how memories are formed (consolidated), how they are retrieved, how they can fail. A PRIMER OK HOW MEMORY WORKS different flavors. One par ticularly import To begin, memory is not monolithic, but instead comes in ant dichotomy distinguishes short-term versus long-term memories. With the former, you look up a phone number, sprint across the room convinced you're about to forget it, punch in the number. And then it's gone forever. Short-term memory is your brain's equivalent of juggling some balls in the air for 30 seconds. In contrast, long-term memory refers to remembering what you had for dinner last night, the name of the U.S. president, how many grandchildren you have, alized subset of long-term where you went to college. Neur opsychologists are coming to recognize that there is a speci 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

108 Pa g e 108 of 212 memory. Remote memories are ones stretching back to your childhood—the name of your village, your native language, the smell of your grandmother's baking. They appear to be stored in some sort of archival way in your brain ntia that devastates most long-term ries. Often, in patients with a deme separate from more recent long-term memo memory, the more remote facets can remain intact. implicit memory and Another important distinction in memory is that between declarative) (also known as explicit procedural (which includes an important subtype called mory concerns facts and memory) memory. Explicit me events, along with your conscious awareness of knowing them: I am a mammal, today is Monday, my dentist has cedural memories are about sk thick eyebrows. Things like that. In contrast, implicit pro ills and habits, about knowing how to do things, even without having to think consciously about them: shifting the gears on a car, riding a bicycle, rms of storage. For example, you are sferred between explicit and implicit fo doing the fox-trot. Memories can be tran music. Each time that stretch approaches, you must learning a new, difficult passage from a piece of piano consciously, explicitly remember what to do—tuck your elbow in, bring your thumb way underneath after that trill. And one day, while playing, you realize you just barreled through that section flawlessly, without having to think about it: you did it with implicit, rather than explicit, memory . For the first time, it's as if your hands remember better than your brain does. Memory can be dramatically di srupted if you force something that's implicit into explicit channels. Here's an example that will finally make reading this book worth your while—how to make neurobiology work to your competitive advantage at sports. You're playing tennis against someone who is beating the pants off of you. Wait until your are a fabulous tennis player. adversary has pulled off some amazing backhand, then offer a warm smile and say, "You did you do that? When you do a backhand like that, do How I mean it; you're terrific. Look at that shot you just made. you hold your thumb this way or that, and what about your other fingers? And how about your butt, do you scrunch up the left side of it and put your weight on your right toes, or the other way around?" Do it right, and the next time that shot is called for, your opponent/victim will make the mistake of thinking about it explicitly, and the stroke won't be anywhere near as effective. As Yogi Berra once said, ht of stairs in an explicit manner, something you " Imagine descending a flig "You can't think and hit at the same time. haven't done since you were two years old—okay, bend my left knee and roll the weight of my toes forward while shifting my right hip up slightly—and down you go down the stairs. memory, there are different areas of th e brain involved in memory storage and Just as there are different types of ain. Another is a region tucked just , the vast and convoluted surface of the br retrieval. One critical site is the cortex e cortex, called the hippocampus. (That's Latin for "sea horse," which the hippocampus vaguely underneath part of th resembles if you've been stuck inside studying neuroanatomy for too long instead of going to the seashore. It actually looks more like a jelly roll, but who knows the Latin term for that?) Both of these are regions vital to memory—for If you want a totally Alzheimer's disease. and cortex that are preferentially damaged in example, it is the hippocampus simplistic computer metaphor, think where memories are stored, and your of the cortex as your hard drive, the means by which you place and access memories in the cortex. hippocampus as the keyboard, There are additional brain re gions relevant to a different kind of memo ry. These are structures that regulate body ry? They appear to be relevant to as the cerebellum, have to do with memo movements. What do these sites, such t even consciously thinking flexive, motor actions withou implicit procedural memory, the type you need to perform re about them, where, so to speak, your body remembers how to do something before you do. The distinction between explicit and implicit memory, and the neuroanatomical bases of that distinction, was first one of the truly fascinating, really appreciated because of gy, perhaps the most famous tragic figures in neurolo neurological patient of all time. This man, known in the literature only by his initials, is missing most of his t in the 1950s, "H.M." had a severe form of epilepsy that was centered in his hippocampus. As an adolescen hippocampus and was resistant to drug tr eatments available at that time. In a desperate move, a famous neurosurgeon removed a large part of H.M.'s hippocampus, along with mu ch of the surrounding tissue. The seizures mostly abated, and in the aftermath, H.M. was left with a virtually complete inability to turn new short-term memories into long-term ones—mentally utterly frozen in ly become apparent that despite this time.* Zillions of studies of H.M. have been carried out since, and it has slow gs. Give him some mechanical puzzle to master day after profound amnesia, H.M. can still learn how to do some thin steadfastly denying each time that he has day, and he learns to put it together at the same speed as anyone else, while ever seen it before. Hippocampus and ex brain is intact, as is his ability to plicit memory are shot; the rest of the acquire a procedural memory. This shifts us to the next magnification of examining how the brain handles memories and how stress influences the process—what's going on at the level of clusters of neurons within the cortex and hippocampus? A long-standing , turn out to have a belief among many who studied th e cortex was that each individual cortical ne uron would, in effect single task, a single fact that it knew. This was prompted by some staggeringly important work done in the 1960s by r outposts of the cortex, an retrospect, one of the simple David Hubel and Torstein Wiesel of Harvard on what was, in 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

109 Pa g e 109 of 212 neuron responded to area that processed visual info al cortex in which each rmation. They found a first part of the visu one thing and one thing only, namely a single dot of light on the retina. Neurons that responded to a sequence of what was this neuron adjacent dots of light would fu nnel their projections to one neuron in the next layer. And thus, of these neurons would project to the ne xt level in a way that each neuron in responding to? A straight line. A series that cortical level would respond to a particular moving line of light. This led people to believe that there would be a to a particular collection of lines, and a fifth and sixth layer, all the way up fourth level, where each neuron responded until, at the umpteenth layer, there would be a neuron that responded to one thing and one thing only, namely your that recognized her face at a slightly grandmother's face at a particular angl e (and next to it would be a neuron different angle, and then the next one ...). People went looking for what were actually called "grandmother" neurons— neurons way up in the layers of the cortex that "knew" one thing and one thing only, namely a complexly integrated bit of sensory stimulatio n. With time, it became apparent that there could be very fe w such neurons in the cortex, because you simply don't have enough neurons to go ar ound to allow each one to be so narrow-minded and overspecialized. and there all * Brush with fame department: I met H.M. once—he won't remember me of course (ba-dum dum), and it was astonishing. You could st introducing himself. day with him repeatedly neuron that "knows" about Impressionist paintings. A highly hypothetical neural network involving a Rather than memory and information being stored in single neurons, they are stored in the patterns of excitation of vast arrays of neurons—in trendy jargon, in neuronal "networks." How does one of these work? Consider the wildly simplified neural network shown in the diagram above. s, which is to say that each The first layer of neurons (neuro ns 1, 2, and 3) are classical Hubel and Wiesel type neuron one "knows" one fact for a living. Neuron 1 knows how to recognize Gauguin paintings, 2 recognizes van Gogh, and 3 knows Monet. (Thus, these hypothetical neurons are more "grandmotherly"—specializing in one task—than any real ural networks are about.) Those three neurons project—send neurons in the brain, but help illustrate well what ne network, comprising neurons A to E. Note the projection pattern: 1 talks to information to— the second layer in this A, B, and C; 2 talks to B, C, and D; 3 talks to C, D, and E. ion only from neuron 1 about Gauguin paintings. Another What "knowledge" does neuron A have? It gets informat grandmotherly neuron. Similarly, E gets information only from neuron 3 and knows only about Monet. But what about neuron C; what does it know about? It knows about Impressionism, the features that these three painters had in common. It's the neuron that, metaphorically, says, "I can't tell you the painter, certainly not the painting, but it's one of thos e Impressionists." It has knowledge that does not come from into it. Neurons B and D are gence of information feeding any single informational input, but emerges from the conver have fewer examples to work also Impressionism neuron s, but they're just not as good at it as neuron C, because they with. Most neurons in your cortex process memory like neurons B through D, not like A or E. networks whenever we are trying to pul l out a memory that We take advantage of such convergent is almost, almost there. Continuing our art history theme, suppose you're trying to remember the name of a painter, that guy, what's his name. He was that short guy with a beard (activating your "short guy" neural network, and your "bearded guy" network). He painted all those Parisian dancers; it wasn't Degas (two more networks pulled in). My high school art appreciation teacher loved that remember his ... wow, remember that time guy; if I can remember her name, I bet I can 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

110 Pa g e 110 of 212 I was at the museum and there was that rea lly cute person I tried to talk to in fr ont of one of his paintings ... oh, what acks being too loose. With enough of those nets being was the stupid pun about that guy's name, about the train tr on of all of them: Toulouse-Lautrec, the activated, you finally stumble in to the one fact that is at the intersecti equivalent of a neuron C. That's a rough approximation of how a neural network operates, and neuroscientists have come to think of both learning and storing of memories as involving the "strengthening" of some branches rather than others of a network. How does such strengthening occur? For that, we switch to a final level of magnification, to consider the tiny gaps of two neurons, gaps called synapses. between the thready branches When a neuron has heard some fabulous gossip is triggers the release of chemical of electrical excitation sweeps over it, th and wants to pass it on, when a wave across the synapse and excite the next messengers—neurotransmitters—that float neuron. There are dozens, probably hundreds, of different kinds of neurotransmitters, and synapses in the hippocampus and cortex disproportionately tter there is, something called make use of what is probably the most excitatory neurotransmi glutamate. cal to memory. The first is two properties that are criti Besides being superexcitatory, "glutamatergic" synapses have es this mean? In a run-of-the -mill synapse, a little bit of that these synapses are nonlinear in their function. What do neurotransmitter comes out of the first neuron and causes the second neuron to get a little excited; if a smidgen more neurotransmitter is released, there is a smidgen more excitation, and so on. In glutamatergic synaps es, some glutamate is released and nothing happens. A larger amount is releas ed, nothing happens. It isn't until a certain threshold of suddenly, all hell breaks loose in the glutamate concentration is passed that, second neuron and there is a massive wave of excitation. This is what learning something is about. A professor drones on incomprehensibly in a lecture, a fails to sink in. Finally, the hundredth time it fact goes in one ear and out th e other. It is repeated again—and, again, it is repeated, a lightbulb goes on, "Aha!" and you get it. On a simplistic level, when you finally get it, that nonlinear ate excitation has ju st been reached. threshold of glutam The second feature is even more important. Under the right conditions, when a synapse has just had a sufficient number of superexcita-tory glutamate-driven "aha's," so mething happens. The synapse becomes persistently more gnal to get the aha. That syna excitable, so that next time it takes less of an excitatory si pse just learned something; it was "potentiated," or strengthened. The most amazing thing is that this strengthening of the synapse can persist for a long time. A huge number of neuroscientists flail away at figuring out how this process of "long-term potentiation" works. There's increasing evidence that the formation of new memories might also sometimes arise from the formation of new connections between neurons (in addition to the potenti ating of pre-existing ones) or , even more radically, the ial idea is discussed below. For the moment, this is all formation of new neurons themselves. This latter, controvers ies and sports statistics and you need to know about how your brain remembers anniversar the color of someone's eyes and how to waltz. We can now see what stress does to the process. IMPROVING YOUR MEMORY DURING STRESS makes sense, in that this rm stressors enhance memory. This The first point, of course, is that mild to moderate short-te tion"—alert and focused. This effect has been shown in is the sort of optimal stress that we would call "stimula particularly elegant study in this realm was carried out by Larry Cahill and laboratory animals and in humans. One James McGaugh at the University of Califo story to a group of control subjects: rnia at Irvine. Read a fairly unexciting ore and that one, cross the st reet and enter the hospital a boy and his mother walk through their town, pass this st where the boy's father works, are shown the a story that differs in X-ray room ... and so on. Meanwhile, the experimental subjects are read that the central core of mother walk through their town, pass this store and that it contains some emotionally laden material: a boy and his the boy is hit by a car! He's rushed to the ho one, cross the street where ... spital and taken to the X-ray room... Tested weeks later, the experimental subjects remember their story better than do the controls, but only the middle, exciting part. This fits with the picture of "flashbulb memory," in which people vividly remember some highly aroused scene, the accuracy isn't enhanced (although mory for the emotional components is such as a crime they witnessed. Me mory for the neutral details is not. necessarily all that good), whereas me This study also indicated how this effect on memory works. Hear the stressful story and a stress-response is initiated. As we by now well know, this includes the sympathetic nervous system kicking into gear, pouring epinephrine and norepinephrine into the bloodstream. Sympathetic stimulation appears to be critical, because when Cahill and McGaugh gave subjects a drug to block that sympathetic activation (the beta-blocker propranolol, the same drug used to lower blood pressure), the experimental group did not remember the middle portion of their story any better than the controls remembered theirs. Importan tly, it's not simply the case that pr opranolol disrupts memory formation. subjects did as well as the her words, the experimental Instead, it disrupts stress-enhanced memory formation (in ot 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

111 Pa g e 111 of 212 controls on the boring parts of the story, but simply didn't have the boost in memory for the emotional middle section). ocampus into a more alert, activated off by indirectly arousing the hipp The sympathetic nervous system pulls this area of the brain that is state, facilitating memory consolidation. This involves an going to become central to understanding anxiety when we get to chapter 15, namely the amygdala. The sympathetic nervous system has a second route for enhancing cognition. Tons of energy are needed for all that explosive, nonlinear, long-term potentiating, that turning on of light-bulbs in your hippocampus with glutamate. The sympathetic nervous system helps those energy needs to be met by eam and increasing the force with which mobilizing glucose into the bloodstr blood is being pumped up into the brain. These changes are quite adaptive. When a st ressor is occuring it is a good time to be at your best in memory retrieval ("How did I get out of this mess last time?") and memory fo rmation ("If I survive this, I'd better remember just what I did wrong so I don't get into a mess like this again."). So stress acutely causes in creased delivery of glucose to the br ain, making more energy available to neurons, and therefore better memory formation and retrieval. Thus, the sympathetic arousal membering the faces of the s the expensive process of re during stress indirectly fuel crowd chanting ecstatically about Classic Co ke. In addition, a mild elevation in glucocorticoid levels (the type you would see during a moderate, short-term stressor) helps memory as well. This occurs in the hippocampus, where those moderately elevated glucocorticoid levels facilitate long-term potentiati on. Finally, there are some obscure ive. Your taste buds, your sensory receptors more sensit mechanisms by which moderate, short-term stress makes your olfactory receptors, the cochlear ted under moderate stress and cells in your ears all requir e less stimulation to get exci pass on the information to your brain. In that special circumstance, you can pick up the sound of a can of soda being opened hundreds of yards away. ANXIETY: SOME FORESHADOWING moderate and transient stress can enhance th What we've just seen is how e sort of explicit memories that are the purview of the hippocampus. It turns ou t that stress can enhance another type of memory. This is one relevant to art from the hippocampus and its dull concern with factoids. This alternative type of emotional memories, a world ap brain area mentioned before, the amygdala. The response memory, and its facilitation by stress, revolves around that of the amygdala during stress is going to be critical to understanding anxiety and post-traumatic stress disorder in chapter 15. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

112 Pa g e 112 of 212 AND WHEN STRESS GOES ON FOR TOO LONG With our "sprinting across the savanna" versus "worrying about a mortgage" dichotomy loaded and ready, we can now look at how the formation and retrieval of memories goes awry when stressors become too big or too prolonged. People in the learning and memory business refer to this as an "inverse-U" relationship. As you go from no stress to a moderate, transient amount of stress—the realm of stimulation— memory improves. As you then transition into severe stress, memory declines. The decline has been shown in numerous studies with lab rats, and with an array of stressors—restraint, shock, has been shown when high levels of glucocorticoids are administered to rats exposure to the odor of a cat. The same instead. But this may not tell us anything interesting. Lots of stress or of glucocorticoids may just be making for a gener-ically messed-up brain. Maybe the rats would now be lo usy at tests of muscle coordination, or responsiveness to sensory information, or what have you. But careful control studies have shown that other aspects of brain function, e it's not so much that learning and me such as implicit memory, are fine. Mayb mory are impaired, as much as the rat agitated by it, that it does n't make much headway solving being so busy paying attention to that cat smell, or so thin that realm of explicit memory problems, the retrieval of prior memories whatever puzzle is in front of it. And wi seems more vulnerable to stress than th e formation of new ones. Similar findings have been reported with non-human primates. Hard-charging businessman Billy Sloan is about to lear n that continued stress does inhibit one's memory. What about humans? Much the same. In a disorder called Cush-ing's syndrome, people develop one of a number of types of tumors that result in secretion of tons of glucocorticoids. Understand what goes wrong next in a "Cushingoid" patient and you understand half of this book—high blood pressure, diabetes, immune suppression, reproductive n for decades that they get memory problems, specifically explicit memory problems, the works. And it's been know problems, known as Cushingoid dementia. As we saw in chapter 8, synthetic glucocorticoids are often administered to people to control autoimmune or inflammatory disorders. With prolonged treatment, you see explicit memory ther than to the glucocorticoids that were given for the problems as well. But maybe this is due to the disease, ra disease. Pamela Keenan of Wayne St ate University has studied individuals with these inflammatory diseases, comparing those treated with steroidal antiinflammatory compounds (that is, glucocorticoids) and those getting nonsteroidals; memory problems were a function of getting the glucocorticoids, not of the disease. of high doses of synthetic glucocorticoids impairs explicit memory in healthy As the clearest evidence, just a few days volunteers. As one problem in interpretin g these studies, these synthetic hormones work a bit differen tly from the real stuff, and the levels administered produce higher circulating glucocorticoid levels than the body normally produces, even during stress. Importantly, ucocorticoid that naturally occurs in humans, disrupts memory stress itself, or infusion of stress levels of the type of gl l, the retrieval of prior information, plicit memory is fine, and it's the recal as well. As with the nonhuman studies, im that is more vulnerable than the consolidation of new memories. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

113 Pa g e 113 of 212 There are also findings (although fewer in number) showing that stress disrupts something called "executive function." This is a little different from memory. Rather than this being the cognitive realm of storing and retrieving th the facts— whether you organize th facts, this concerns what you do wi em strategically, how they guide your part of the brain called the judgments and decision making. This is the province of a ex. We'll be prefrontal cort en we consider what stress ma y have to do with decision returning to this in considerable detail in chapter 16 wh making and impulse control. THE DAMAGING EFFECTS OF STRESS IN THE HIPPOCAMPUS How does prolonged stress disrupt hippocampal-dependent memory? A hierarchy of effects have been shown in laboratory animals: First, hippocampal neurons no longer work as well. Stress can disrupt long-term potentiation in the hippocampus even l glands have been removed) in the absence of glucocorticoids (as in a rat whose adrena , and extreme arousal of the in this area has focused on eless, most of the research sympathetic nervous system seems responsible for this. Noneth the glucocorticoids. Once glucocorticoid levels go from the range seen for mild or moderate stressors to the range typical of big-time stress, the hormone no longer enha nces long-term potentiation, that process by which the connection between two neurons "remembers" by becoming more excitable. Instead, glucocorticoids now disrupt the long-term depression, process. Furthermore, similarly high glucoc orticoid levels enhance something called which might be a mechanism underlying the process of forgetting, the flip side of hippocampal aha-ing. How can it be that increasing glucocorticoid levels a little bit (during moderate stressors) does one thing (enhances the ing glucocorticoid levels a lot does the opposite? In potentiation of communication between neurons), while increas the mid-1980s, Ron de Kloet of the University of Utr overed the very elegant echt in the Netherlands disc r glucocorticoids. hippocampus has large amounts of two different t answer. It turns out that the ypes of receptors fo a "high-affinity" Critically, the hormone is about ten time s better at binding to one of the recep tors (thus termed s is that if glucocorticoid levels only rise a little bit, most of the hormone receptor) than the other. What that mean ed by that high-affinity effect in the hippocampus will be mediat receptor. In contrast, it is not until you are dealing gically, it turns out that with a major stressor that the hormone activates a lot of the "low -affinity" receptor. And, lo activation of the high-affinity receptor en n, while activation of th e low-affinity one does hances long-term potentiatio the opposite. This is the basis of the "inverse-U" property mentioned above. In the previous section, I noted that the central role in the types of emotional memories involved in brain region called the amygdala plays a anxiety. But the ressors and sends a large, ghly activated during major st amygdala is relevant here as well. The amygdala gets hi influential neuronal projection to the hippocampus. Activation of this pathway seems to be a prerequisite for stress to sever its connection to the hippocampus, and stress no disrupt hip-pocampal function. Destroy a rat's amygdala, or longer impairs the kind of memory that the hippocampus mediates, even amid the usual high glucocorticoid levels. also demonstrates that some activities This explains a finding that harks back to the subject of stress "signatures," and allostasis without being psychologically can represent a challenge to physical y neurons; on the right, neurons with their projections Neurons of the hippocampus of a rat. On the left, health atrophied by sustained stress. a male rat— without activating the amygdala and without aversive. For example, sex raises glucocorticoid levels in disrupting hippocampal function. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

114 Pa g e 114 of 212 Second, neural networks get disconnected. If you look back at the diagram on the "Impressionism neuron" (see page 208), you'll see that there are symbols indicating how one neuron talks to another, "projects" to it. As mentioned a few paragraphs after that, those projections are quite literal—long multibranched cables coming out of neurons that form are obviously other neurons. These cables (known as and synapses with the multibranched cables of axons dendrites) . Bruce McEwen has shown that, in a rat, after as little at the heart of neuronal communication and neuronal networks as a few weeks of stress or of exposure to excessive glucocorticoids, those cables begin to shrivel, to atrophy and brain. When that happens, synaptic connections get pulled retract a bit. Moreover, the sa me can occur in the primate Fortunately, it appears that at the end of the stressful apart and the complexity of your neural networks declines. period, the neurons can dust themselves off and regrow those connections. ocesses probably explains a characteris This transient atrophy of neuronal pr tic feature of memory problems during ppocampus after a massive stroke or late terminal stage chronic stress. Destroy vast acres of neurons in the hi Alzheimer's disease, and memory is profoundly impaired. Memories can be completely lost, and never again will r spouses. "Weaken" a neural network these people remember, for example, so mething as vital as the names of thei during a period of chronic stress by retracting some of ose neuronal trees, and the the complex branches in th still there. You simply have to tap in memories of Toulouse-Lautrec's name are to more and more associative cues to pull it out, because any given network is less effective at doing its job. Me mories are not lost, just harder to access. Third, the birth of new neurons is inhibited. If you learned your introductory neurobiology any time in the last thousand years, one fact that would be hammered in repeatedly is that the ad ult brain doesn't make new neurons. In e study of "adult neurogenesis" is now, the last decade, it has become clear that this is utterly wrong.* As a result, th topic in neuroscience. arguably, the hottest Two features about such neurogenesis are highly relevant to this chapter. First, the hippocampus is one of only two sites in the brain * Actually, the evidence for new neurons in the adult brain wa handful of heretics who were s first reported in the 1960s by a eld has finally ca of science. The fi generally ignored or hounded out ught up with them. nd, the rate of neurogenesis can be regulated. Learning, an enriched where these new neurons originate.* Seco environment, exercise, or expo sure to estrogen all increase the rate of neurogenesis, while the strongest inhibitors orticoids—as little as a few hours of either in a rat. identified to date are, you guessed it, stress and glucoc Two key questions arise. First, when the stress stops, does neurogenesis recover and, if so, how fast? No one knows ogenesis? Intrinsic in this question is the larger question yet. Second, what does it matter that stress inhibits adult neur of what adult neurogenesis is good for. This is incredibly has adversaries practically controversial, an issue that wrestling each other on the podiu m during scientific conferences. At one extr eme are studies that suggest that under the right conditions, there are tons of neurogenesis in the adult hippocampus, that these new neurons form connections s of learning. At the other with other neurons, and that these new connections, in f act, are needed for certain type extreme, every one of these findings is questioned. So the jury's out on this one. within seconds of the onset of stress, glucose delivery Fourth, hippocampal neurons become endangered. As noted, eases. What if the stressor continues? By ab out thirty minutes into a continuous stressor, throughout the brain incr glucose delivery is no longer enhanced, and has returned to normal levels. If the stress or goes on even longer, the delivery of glucose to the brain is even inhibited, particularly in the hippocampus. Delivery is inhibited about 25 due to glucocorticoids.+ percent, and the effect is * The other region supplies new neurons to the olfactory system; for some strange reason, neurons that process odors constantly die off and have to hey are fully on line huge burst in the production of those new ol be replaced. It turns out that there is a factory neurons early during pregnancy. T and the scientists who discovered this speculate just around the time of birth, r the task of imprinting d that these new olfactory neurons are tagged fo n those new forever on the smell of your offspring (a critical event for mothers of most mammals). And what happens early in pregnancy, whe olfactory neurons are showing up, but not quite making sense yet? ancy, the food with the famed nausea of pregn I bet this has something to do aversions and olfactory sensitivities. This has nothing too cool not to mention. to do with stress, but it is + l outposts in your An obvious question: over and over I've emphasized how important it is during stress to cut down energy delivery to unessentia are spoon-fed energy your hippocampus to that list of places that scle. In the previous section, we added body, diverting it instead to exercising mu that would be a clever area to continue with the onset of a stressor. It seems like ld glucose delivery to stoke, as the stressor goes on. Why shou eventually be inhibited there? Probably because, as time goes it memory outposts by, you are running more on automatic, relying more on the implic to disarm the te rrorist or, at le ast, the coordinated in the brain to do things that involve reflexive movement—t he martial arts display you put on swinging of the Softball bat at the company (continued) Decreasing glucose uptake to this extent in a healthy, happy neuron is no big deal. It just makes the neuron a little queasy and lightheaded. But what if the neuron isn't healthy and happy, and is instead in the middle of a neurological crisis? It's now more likely to die than usual. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

115 Pa g e 115 of 212 Glucocorticoids will compromise the ability of hippocampal neuron s to survive an array of insults. Take a rat, give it a levels at the time of the seizure, the more hippocampal major epileptic seizure, and the higher the glucocorticoid y to the brain is cut off, or for a ac arrest, where oxygen and glucose deliver neurons will die. Same thing for cardi stroke, in which a single blood vessel in the brain shuts down. Same for concussive head trauma, or drugs that generate oxygen radicals. Disturbingly, same thing for the closest there is to a rat neuron's equivalent of being to fragments of an Alzhei damaged by Alzheimer's disease (exposing the neuron beta- mer's-related toxin called Same for a rat hippocampus's equivalent of having AIDS-related dementia (induced by exposing the neuron amyloid). gpl20).* to a damaging constituent of the AIDS virus called My lab and others have shown that the relatively mild energy problem caused by that inhibition of glucose storage by glucocorticoids or stress makes it harder for a neuron to contain the eleventy things that go wrong during one of these es for a neuron: cut off the glucose to neurological insults. All of these neurolog ical diseases are ultimately energy cris a neuron (hypoglycemia), or cut off both the glucose and oxygen (hypoxia-ischemia), or make a neuron work like mad (a seizure) and energy stores drop precipitously. Damaging tidal waves of neurotransmitters and ions flood into the wrong places, oxygen radicals are generated. If you throw in glucocorticoids on top of that, the neuron is even less ks to that stroke or seizure, today's the worst day of that neuron's life, and it able to afford to clean up the mess. Than goes into the crisis with 25 percent less energy in the bank than usual. Finally, there is now evidence that truly prolonged exposure to stress or glucocorticoids can actually kill hippocampal neurons. The e decreased glucose delivery to highfalutin brain regions like t (continued) picnic that you've been nervous about. And thus, th he hippocampus and cortex may be a means to divert energy to those more reflexive brain regions. s noted—seizure, head * Chapter 3 described how stress can indirectly give rise to a st roke or cardiac arrest. But for the other neurological problem trauma, AIDS-related dementia, an disease—there is no evidence th at stress or glucocorticoids cause these maladies. d most important, Alzheimer's they worsen preexisting cases. Instead, the possibility is that to pharmacological ea pigs are exposed 60s. Two researchers showed that if guin first hints of this came in the late 19 levels of glucocorticoids (that is, higher levels than the body ever normally generates on its own), the brain is damaged. Oddly, damage was mainly limited to the hippo campus. This was right around the time that Bruce McEwen eally appreciated yet ocorticoids and no one r ppocampus is loaded with receptors for gluc was first reporting that the hi how much the hippocampus was the center in the brain for glucocorticoid actions. Beginning in the early 1980s, various researchers, including myself, showed that this "glucocorticoid neurotoxicity" ing in the rat. Collectively, the studies effect, but was relevant to normal brain ag was not just a pharmacological showed that lots of glucocorticoid expo or lots of stress itself would accelerate sure (in the range seen during stress) shing glucocorticoid levels (by removing the adrenals the degeneration of the aging hippocampus. Conversely, dimini of the rat) would delay hippocampal aging. And as one might expect by now, the extent of glucocorticoid exposure over the rat's lifetime not only determined how much hippocampal degeneration there would be in old age, but how much memory loss as well. Where do glucocorticoids and stress get off killing your brain cel ls? Sure, stress hormones can make you sick in lots of ways, but isn't neurotoxicity going a bit beyond the bounds of good taste? A dozen years into studying the phenomenon, we're not yet sure. WHAT ABOUT DAMAGE TO THE HUMAN HIPPOCAMPUS? We know from earlier in this chapter that an excess of stress and/or glucocorticoids can disrupt functioning of the e hippocampus that we've been hippocampus. Is there any evidence that this can include th e sort of overt damage to th discussing? That is, can it disconnect neural networks by the atrophying of processes, inhibit the birth of new neurons, worsen the neuron death caused by other neurological insults, or overtly kill neurons? To date, six sets of findings in humans should raise some worries: 1. Cushing's syndrome. As discussed above, Cushing's involves any of a number of types of tumors that produce a vast, damaging excess of glucocorticoids, where the consequences include impairment of hippocampal-dependent memory. Monica Starkman at the University of Michigan has used brain imaging techniques on d the sizes of various subsections. She reports that there is Cushing's patients to look at the overall size of the brain, an a selective decrease in the volume of s. Moreover, the more severe the the hippocampus in these individual the memory problems. glucocorticoid excess, th e greater the loss of hippo campal volume and the greater 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

116 Pa g e 116 of 212 2. Post-traumatic stress disorder (PTSD). As will be disc ussed in more detail in chapter 15, this anxiety disorder can arise from a variety of types of traumatic stressors. Work pioneered by Douglas Bremner of Emory University, replicated by others, shows that people with PTSD from repeated trauma (as opposed to a single trauma)—soldiers as children—have smaller exposed to severe and repeated carnage in combat, in dividuals repeatedly abused t one of those studies, the hippocampi. Again, the volume loss appears to be only in th e hippocampus, and in at leas , the more extreme the volume loss. more severe the history of trauma 3. Major depression. As will be detailed in chapter 14, major depression is utterly intertwined with prolonged stress, and this connection includes elevated glucocorticoid levels in about half the people with major depression. Yvette Sheline of Washington University and others have shown that prolonged major depression is, once again, associated with a smaller hippocampus. The more prolonged the history of depression, the more volume loss. Furthermore, it is ed glucocorticoid levels where you see sociated with elevat in patients with the subtype of depression that is most as the smaller hippocampus. consider a single but intriguing study ex amining airline flight attendants with 4. Repeated jet lag. Chapter 11 will allowed to recover from The shorter the average time long careers of shifting time zones on intercontinental flights. e more memory problems. r the hippocampus and th each large bout of jet lag over a career, the smalle 5. Normative aging. Work by Sonia Lupien of McGill University, and replicated by others, has examined healthy elderly people. Check out what their resting glucocorticoid levels are, the size of their hippocampus, and the quality of their hippocampal-dependent memory Then come back some years later and retest them. As will be discussed in chapter 12, on aging, there is somewhat of a rise in resting glucocorticoid levels with age in humans, although there is a lot of variability in this. What is seen is that those whos e glucocorticoid levels have been rising over the years since the study began are the ones who have had the most severe loss of hippocampal volume and the greatest decline in memory. 6. Interactions between glucocorticoids and neurological insults. A handful of studies report that for the same severity at the time they come into of a stroke, the higher the glucocorticoid levels in a person an emergency room, the more ultimate neurological impairment. So these studies collectively demonstrat e that glucocorticoids damage the human hippocampus. Well, let's hold on a second. There are some pr oblems and complications: lower First, there have been some studies suggesting that PTSD involves than normal levels of glucocorticoids. Thus the hormones is damaging the hippocampus. However, it looks as if in those it can't be the case that an excess of PTSD patients with the low levels, there is excessive sensitivity to the glucocorticoids. So the hormones are still plausible culprits. l volume in PTSD is caused by the trauma itself, or by the As a next issue, it isn't clear whether the loss of hippocampa excellent study upending both of those ideas. at uncertainty, there has been at least one post-traumatic period; amid th kes you more likely to It suggested instead that havi the PTSD and, in fact, ma ng a small hippocampus comes before develop PTSD when exposed to trauma. ent a relationship that is merely correlative. In other Finally, it should be remembered that the aging studies pres ls with age lead to hippocam pal atrophy. But there are at words, yes, it could be that increasing glucocorticoid leve least as good reasons to think that it is the other way around, that progressive hippocampal atrophy leads to the rising because the hippocampus also helps to ained more fully in chapter 12, this is glucocorticoid levels (as will be expl inhibit glucocorticoid release, such that an atrophied hippocampus isn't very good at that task). In other words, no one is quite sure yet what is going on. One of the biggest problems is a lack of studies of brains like people have died. Phenomenally obsessive research could be carried out that would tell us whether the after these llions of hippocampa l neurons or because neurons have hippocampus is smaller because there are fewer of the mi fewer and shorter cables connectiong them to other neurons. Or both. If it turned out that there were fewer neurons, you might even be able to tell whether it is because more of them have died than usual, or because fewer of them were born. Or, again, both. Actually, even without the postmortem studies, there are a few hints about the sources of the volume loss. Intriguingly, when the tumor that gave rise to the Cushing's syndrome is removed and glucocorticoid levels revert to s slowly comes back normal, the hippocampu les connecting neurons to shrivel up, it is not a to normal size. As noted before, when glucocorticoids cause the cab permanent process—stop the glucocorticoid excess and the processes can slowly regrow. Thus, the best guess is that the volume loss in Cushing's is based on the retraction of pr ocesses. In contrast, the volume losses in PTSD and major ts in the former case decades after the depression appear to be something appro aching permanent, in that the loss persis medication. So in trauma, and, in the latter, years to d ecades after the depression has been gotte n under control with 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

117 Pa g e 117 of 212 those cases, the volume loss in the hippocampus probably can't be due to shriveling processes of neurons, given that the shriveling can reverse. Beyond that, no one knows at this point why the hippocampus winds up being smaller in these disorders and y, "More research is needed," situations. It is the knee-jerk reflex of all scientists to sa but more research really is nk it is fair to say that there is decen evidence that stress needed in this case. For the moment, I thi t but not definitive and/or prolonged exposure to glucocorticoids can cause structural, as well as functional, changes in the hippocampus, u probably wouldn't want to have happen to your hippocampus, and that these changes that these are changes that yo can be long-lasting. What are some of the disturbing implications of these findings? The first concerns the use by neurologists of synthetic methasone, or prednisone) after someone has had a stroke. versions of glucocorticoids (such as hydrocortisone, dexa are classic antiinflammatory As we know from our introduction to glands and hormones in chapter 2, glucocorticoids reduce the edema, the damaging brain swel compounds and are used to ling that often occurs after a stroke. Glucocorticoids do wonders to block the edema that occurs after something like a brain tumor, but it turns out that a. Worse, there's increasing evidence th at those famously antiinflammatory they don't do much for post-stroke edem compounds can actually be pro-inflammatory, worsening inflammation in the injured brain. Yet tons of neurologists still prescribe the stuff, despite decad es-old warnings by the best people in the field and findings that the neurological outcome. So these recen glucocorticoids tend to worsen the t findings add a voi ce to that caution— that involve a precarious hippocampus. clinical use of glucocorticoids tends to be bad news for neurological diseases (As a caveat, however, it turn s out that huge doses of glucocorticoids can occasionally help reduce damage after a spinal cord injury, for reasons having nothing to do with stress or with much of this book.) Related to this is the concern that physicians may use synt hetic glucocorticoids to treat problems outside the nervous system and, in the A scenario that particularly distur bs me concerns the ability of these process, might endanger the hippocampus. levance to AIDS-related dementia. (Remember?—the gpl20 hormones to worsen gpl20 damage to neurons and its re protein is found in the AIDS virus and appears to play a central role in damaging neurons and causing the dementia.) If, many experiments down the line, it turns out that glucocorticoids can worsen the cognitive consequences of HIV infection, this will be worrisome. That isn't just becau se people with AIDS are under st ress. It's also because people ely high doses of synthetic glucocorticoids to combat other aspects of the with AIDS are often treated with extrem disease. This same logic extends to the use of glucocorticoids in other realms of clinical medicine. About 16 million r glucocorticoids. Much of the use is benign—a little prescriptions are written annually in the United States fo hydrocortisone cream for some poison ivy, a hydrocortisone maybe even use of steroid injection for a swollen knee, inhalants for asthma (which is probably not a worrisome route for glucocorticoids to get into the brain). But there are still hundreds of thousands of people taking high-dose glucocorticoids to suppress the inappropriate immune sclerosis, or rheumatoid arthritis). As discussed earlier, responses in autoimmune diseases (such as lupus, multiple prolonged glucocorticoid exposure in these individuals is associated with problems with hippocampal-dependent memory. So should you avoid taking glucocorticoids for your autoimmune disease in order to avoid the possibility of wn the line? Almost certa n devastating diseases accelerated hippocampal aging somewhere do inly not—these are ofte fective treatments. Potentia lly, the memory problems are a particularly grim and glucocorticoids are often highly ef and unavoidable side effect. An even more disturbing implication of these findings is that if glucocorticoids turn out to endanger the human lt), you're still in trouble, even if your neurologist hippocampus (making it harder for neurons to survive an insu doesn't administer synthetic glucocorticoids to you. This is because your body secretes boat loads of the stuff during many neurological crises—humans coming into ERs after neurological insults have immensely high levels of glucocorticoids in their bloodstreams. And what we know from rats is that the massive outpouring of glucocorticoids at that time adds to the damage—remove the adrenals of a ra t right after a stroke or seiz ure, or use a drug that will transiently shut down adrenal secretion of glucocorticoids, and less hippocampal damage will result. In other words, what we think of as typical amounts of brain damage after a stroke or seizure is damage being worsened by the craziness of our bodies having stress-responses at the time. Consider how bizarre and maladaptive this is. Lion chases you; you secrete glucocorticoids in order to divert energy to your thigh muscles—great move. Go on a blind date, secrete glucocorticoids in order to divert energy to your thigh muscles—probably irrelevant. Have a gran d mal seizure, secrete glucocorticoids in order to divert energy to your thigh muscles—and make the brain damage worse. This is as stark a demonstration as you can ask for that a stress- response is not always what you want your body to be having. How did such maladaptive responses evolve? The most likely explanation is that the body simply has not evolved the tendency not to secrete glucocorticoids during a neurological crisis. Stress-induced glucocorticoid secretion works 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

118 Pa g e 118 of 212 roughly the same in all the mammals, birds, and fish ... and it has only been in the last half-century or so that westernized versions of just one of those species had mu something like a stroke. There ch of a chance of surviving neurological injury more the body's response to massive simply has not been much evolutionary pressure yet to make logical. We are now fifty, sixty years into thinking about ulcers, blood pressure, and aspects of our sex lives as being sensitive ize the ways in which stress can also disrupt to stress. Most of us recogn how we learn and remember. This chapter s system might extend even to damaging our neurons, and raises the possibility that the effects of stress in the nervou the next chapter continues this theme, ing of our brains. The ss might well accelerate the ag in considering how stre noted neuroscientist Woody Allen once said, "My brain is my second-favorite organ." My guess is that most of us would rank our brains even higher up on a list. 11 STRESS AND A GOOD NIGHT'S SLEEP Then there was the day when my son was about two weeks old. He was our first born, and we had been plenty nervous about how demanding parenting was going to be. It had been a great day—he'd slept well through the night, waking up a few times to nurse, and took some long naps during the day that allowed us to do the same. We'd settled into a schedule. My wife did the nursing, and I at she had become obsessed fetched the tureens of cranberry juice th with since giving birth. Our son filled his diapers on cue, and his every gesture was confirming how wondrous he was. Things were calm. In the evening, as he slept and we settled into our old routines, like doing dishes (the first time in days), I indulged myself in some editorializing about the human condition. "You know, this newborn business is really quite roll with the punches." I went manageable if you just stay on top of things. You need to work as a team, be organized, on fatuously like this for a while. That night, our son woke up to nurse right after we fell asleep. He was fussy, wouldn't go back to sleep unless I patted stop by waking up. This went on fo r an insane hour and then he needed him repeatedly, protested each time I tried to to nurse again. Then, after patting him some more, he responded by blowing out his diaper, making a mess of his m off. Finally, he then slept contentedly without murder when I washed hi onesie and me. Then he screamed bloody again, another blowout soiling of his fresh onesie, followed patting, for about twenty minutes, before needing to nurse by our discovery that we had no clean ones, having neglected to do the laundry. is, we're going to die, I'm Rather than doing something useful, I orated in a half-psych otic state, "We can't do th serious, people DIE from lack of sleep, it's not possible to do this, it's physiologically proven, we're all going to DIE." I swung my arms with emphasis, knocking over and loudly breaking a glass of cranberry juice. This woke up our, by ng all three of us to burst into tears. He eventually settled down and slept like a baby then, happily sleeping son, causi for the rest of the night, while I tossed anxiously, waiting for him to wake up again. apter. Not getting enough sleep is a stressor; being stressed Contained in this are the two central features of this ch makes it harder to sleep. Yup, we've got a dread vicious cycle on our hands. THE BASICS OF SLEEP All things considered, sleeping is pretty creepy. For a third of your life, you're just not there, floating in this suspended ain is more active than when you're awake, making your state, everything slowed down. Except, at points, your br the day and solving problems for you. Except when it's eyelids all twitchy, and it's consolidating memories from dreaming, when it's making no sense. And then you sometimes walk or talk in your sleep. Or drool. And then there's itoral erections that occur in termittently during the night.* those mysterious penile or cl . Instead, there are Weird. What's going on here? To star t, sleep is not a monolithic process, a uniform phenomenon and 2) sleep, where you are different types of sleep—shallow (also known as stages 1 easily awakened. Deep sleep Rapid Eye Movement (REM) sleep, where the puppy's paws (also known as stages 3 and 4, or "slow wave sleep"). a structure, an different stages, but eams happen. There are not only these flutter and our eyes dart around and dr 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

119 Pa g e 119 of 212 architecture to them. Yo u start off shallow, gradually sleep your way down to slow wave sleep, followed by REM, and then repeat the then back up again, their brain at a time, in order to keep on of species that sleep with only half of e eye and half the brain * And this isn't even going into the subject open to look out for predators. Mallards, fo r example, that are stuck on the edge of their group at night keep their outward fa cing eye, and the half it, preferentially awake. As more sleeping and some birds can f ly. oddities, dolphins can swim while of the brain that responds to y ninety minutes (and as we'll see in chapter 14, something goes wrong w ith the architecture of whole cycle about ever sleep during a major depression). Not surprisingly, the brain works differently in different stages of sleep. This can be studied by having people sleep in of different brain regions. Take some volunteers, sleep- a brain scanner, while you measure the levels of activity em in one of these imaging machines, poke them awake a deprive them for some godawful length of time, stick th little more while you get a measure of their brains' activity when they're awake, and then, snug as a bug in a scanner, let them go to sleep with the scanner running. The picture during slow wave sleep makes lots of sense. Part s of the brain associated with arousal activity slow down. Ditto for brain regions involved in controlling muscle movement. Interestingly, regions involved in the consolidation and retrieval of memories don't have much of a decrease in metabolism. However, the pathways that bring information to and from those regions shut down dramatically , isolating them. The parts of the brain that first respond to sensory information have somewhat of a metabolic sh changes are in downstream utdown, but the more dramatic brain areas that integrate, a ssociate those bytes of sensory information, and give them meaning. What you've got is a brain. This makes sense, as deep slow wa ve sleep is when energy restoration occurs. metabolically quiescent, sleeping nt of sleep deprivation is not a great This is shown by the fact that the exte is a good predictor of how much slow wave sleep there'll predictor of the total amount you will ultimately sleep, but it be—a very active brain or a sleep-deprived brain tends to co nsume a lot of a particular fo rm of energy; the breakdown ward slow wave sleep. e signal that biases to product of that depleted form of energy is th A very different picture emerges durin g REM sleep. Overall, there's an incr ease in activity. Some brain regions e brain that regulate muscle movement, than when you're awake. Parts of th become even more metabol-ically active increase their metabolic rate. In a part of the brain called brain stem regions that control breathing and heart rate—all the limbic system, which is involved in emotion, there is for areas involved in memory an increase as well. The same and sensory processing, especially t hose involved in vision and hearing. regions. The part of the co rtex that processes the first Something particularly subtle goes on in the visual processing there is a big jump in the crease in metabolism, whereas bits of visual information does not show much of an in ate simple visual informatio n.* How can this be, when, on top of it, your eyes are downstream regions that integr closed? This is dreaming. That tells us something about how dream imagery arises. But something else that happens in the brain tells us the last chapter, called the something about the the brain, briefly mentioned in of dreams. There's a part of content ecently evolved part of the human brain, is disp frontal cortex. It's the most r roportionately huge in primates, and is the the nearest thing we have to a superego. Starting from toilet last part of our brain to fully mature. The frontal cortex is thing—for example, thinking in a logical, sequential manner, training, it helps you to do the harder, rather than easier 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

120 Pa g e 120 of 212 rather than bouncing all over the place c because you feel like it, ognitively. It keeps you from murdering someone just stops you from telling someone exactly what you think of their hideous outfit and instead finds something complimentary. The frontal cortex does all this disciplining of you by inhibiting that frothy, emotional limbic system.+ If you damage the frontal cortex, someone gets "frontally disinhibited"—doing and saying the things we may think about but would never act upon. During REM sleep, metabolism in the frontal cortex goes way down, disinhibiting the limbic system to come up with is the Hubel and Weisel part of the visual co d lines. mple stuff like dots an rtex that responds to si * Harking back to chapter 10, this + part of the brain to fully mature, typi cally not going comple tely online until you a Amazingly, the frontal cortex is the last re well into your twenties. Doesn't that begin to explain a lot of the imprudent things you did back when? (detail), 1999. Alfredo Castaneda, Our Dream e—illogical, nonsequential, hyperemotional. You breathe the most outlandish ideas. That's why dreams are dreamlik underwater, fly in the air, communicate telepathically; you announce your love to strangers, invent languages, rule kingdoms, star in Busby Berkeley musicals. without it. Even fruit flies do. The most s of sleep. But what is sleep for? You die So those are the nuts and bolt obvious answer is to have a stretch where your brain is going at half speed, in order to build up supplies of energy. al amounts of energy to pull off all that calculus and symphony writing that you do— Your brain consumes phenomen the brain constitutes something like 3 percent of your body weight but needs nearly a quarter of the energy. So stores tend to decline during the day and some solid slow wave sleep is needed to restock those stores (mostly of a molecule energy store in liver and muscle).* called glycogen, which is also an tty lousy at storing energy, given the magnitude of its energy demands. This comes ba * Despite this, your brain is actually pre ck to haunt your neurons big-time during a number of neurological disasters involving a shortage of energy. Others speculate that sleep is for decreas ing brain temperature, letting it cool off from all that daytime brainstorming, or for detoxifying the brain. Weirdly, another major reason to sleep is to dream. If you skip a night's sleep, when you finally get to sleep the next night, you have more REM sleep than normal, suggesting that you've built up a real deficit queasy just to contemplate de prive people or animals of of dreaming. Some extremely difficult studies that make me uivalent amount of an they do for the eq REM sleep preferentially, and th e study subjects go to pieces much faster th deprivation of other types of sleep. Thus, this begs the question of what dreaming is for. To work out unresolved issues about your mother? To provide a living for surrealists and dadaists? So you can have a sex dream about some unlikely person in your waking life and e. The marked increase in then act all weird around that person the next morning by the water cooler? Well, mayb metabolic activity during REM sleep, and in some of the most inhibited areas of the brain during waking, have 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

121 Pa g e 121 of 212 suggested to some a sort of "use it or lose it" scenario in which dreaming gi ves some aerobic exercise to otherwise musical brain circuit). glected Busby Berkeley underutilized brain pathways (that is, the oft-ne s a role in cognition. For example, sleep can facilita What has become clear is that sleep play te problem solving. This is the realm of "sleeping on a problem," and then suddenly discovering a solution the next morning while you're cleaning crud out of the corners of your eyes. The neurobiologist Robert Stickgold of Harvard has emphasized that this type of problem solving is the kind where a morass of unhelpful facts are broken through to get to feelings. As he d then "sleep on it" to remember it. You do it for some complex, ambiguous says, you don't forget a phone number an problem. in the formation of new memories, the consolidation of Both slow wave and REM sleep also seem to play roles ou while awake over the course n that became less accessible to y e previous day, even informatio information from th ce supporting this is the fact that if you teach an animal some task and disrupt its sleep of the day. One type of eviden that night, the new information isn't consolidated. While this has been shown in many different ways, the chapter, stress can disrupt me interpretation remains controversial. As we saw in the last mory consolidation. As we're l. Maybe sleep deprivation disrupts memory consolidation about to see in great detail, sleep deprivation is stressfu merely because of the stress, lidation. But the pattern of normally helps memory conso which wouldn't prove that sleep memory disruption caused by sleep deprivation is different from that caused by stress. Another type of evidence is co rrelative. Being exposed to lots of new info rmation during the day is associated with more REM sleep that night. Moreover, the amount of certain subtypes of sleep at night predicts how well new information is recalled the next day. Fo r example, lots of REM sleep during the night predicts better consolidation of nsolidation of a motor task, emotional information from the day before, while lots of st age 2 sleep predicts better co ow wave sleep predicts better retention of perceptual information. Others and a combination of lots of REM and sl have taken this further, reporting that it's not just the amount of some subtype of sleep that predicts some subtype of learning, but whether it occurs early or late in the night. Another style of evidence fo r the "sleep helps you consolidate memories" story was first obtained by Bruce McNaughton of the University of Arizona. As we saw in s a central role in explicit chapter 10, the hippocampus ha the activity of single hippocampal neuron learning. McNaughton recorded s in rats, identifying ones that became particularly busy while the rat was lear ning some new explicit information. That night, during slow wave sleep, it of would be those same neurons that would be particularly busy. Taking that one step further, he showed that patterns are then repeated when th e animal is sleeping. Brain- activation of hippocampal neurons that occur during learning imaging studies with humans have shown something similar. There's even evidence that wh en consolidation is going on during REM, genes are act ivated that help form new connections between neurons. During slow wave sleep, is the time when the brain pocampus. It's as if sleep metabolism remains surprisingly high in areas like the hip practices those new memory patterns ov er and over, cementing them into place. ing cognition, at least one type of learning is facilitated Weirdly, amid this general picture of sleep deprivation disrupt by sleep deprivation, as shown in some recent work by a graduate student of mine, Ilana Hairston. Suppose you have earn to recite the months of the year b ackward as rapidly as possible. Why is some unlikely task where you have to l this going to be hard? Because there will e way that you've done your recite the months in th repeatedly be the pull to whole life, which is forward; the previous, overlearned version of the task interferes with this new reversal task. Who would excel at this task? Someone who has never learned to do January, February, March, etc., automatically in that t's equivalent of a reversal task, they do better than do direction. If you sleep deprive some rats and give them a ra control animals. Why? Because they can 't remember the prior overlearned vers ion of the task we ll enough for it to intrude now. stress. So now we have the basics of sleep and what it might be good for. Entrez SLEEP DEPRIVATION AS A STRESSOR As we glide down into slow wave sl ress-response system. For occur to facets of the st eep, some obvious things starters, the sympathetic nervous system shuts down, in favor of that calm, vegetative parasympathetic nervous system. In addition, glucocorticoid levels go down. As introduced back in chapter 2, CRH is the hypothalamic hormone that gets the pituitary to release ACTH in order to trigger adrenal release of gl ucocorticoids. Some of the or and a brake—a releasing factor and an itary hormone release consists of an accelerat hypothalamic control of pitu inhibiting inhibiting factor. For year "corticotropin s, there's been evidence floating aroun d for a hypothalamic e effects of CRH. No one's sure what CIF is, or ease of ACTH, counteracting th factor" (CIF) that would inhibit the rel t evidence that CIF is a brain chemical that helps bring on slow wave sleep if it really exists, but there's some decen (called "delta sleep-inducing factor"). Thus, sleep deeply, and you turn off glucocorticoid secretion. dream imagery and to move In contrast, during REM, as you're mob ilizing all that energy to generate that outlandish your eyes rapidly, glucocorticoid secretion and the sympathetic nervous system rev up again. But given that most of ely a time when the stress- ve sleep, sleep is predominat what counts as a good night's sleep consists of slow wa 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

122 Pa g e 122 of 212 response is turned off. This is seen in species whether they're nocturnal or diurnal (that is, sleeping during the dark of CRH, ACTH, and glucocorticoids begin to rise. This is hours, like us). About an hour before you wake up, levels of some energy, but because not just because merely rousing from slumber is a mini-str essor, requiring mobilization those rising stress hormone levels play a role in terminating sleep. So deprive yourself of sleep, and the sleep-induced decline in the levels of those stress hormones doesn't occur. And, athetic nervous system is activated; orticoid levels increase and the symp no surprise, they rise instead. Glucoc commensurate with everything that's been reviewed in previous chapters, down go levels of growth hormone and of es glucocorticoid secretion, although not to a massive various sex hormones. Sleep deprivation definitely stimulat extent in most studies (unless the sleep deprivation is really prolonged; however, "it deprivation] are due to the st ress of dying rather than to is postulated that these increases [in response to severe sleep sleep loss," dryly noted one journal article). me of the stored forms of ay a role in breaking down so The elevated glucocorticoid levels during sleep deprivation pl energy in the brain. This, along with many of the glucocorticoid effects on memory, could have something to do with That's something we all l why learning and memory are so lousy wh en you're sleep-deprived. earned when doing an all ecall what month it was, let alone ing the next morning during the fi nal exam that we can barely r -nighter and discover A recent study beautifully eads the previous night. any of the factoids crammed in our h demonstrated one way in which our brains become impaired when we try to think hard on no sleep. Take a normally rested subject, stick her in a brain imager, and ask her to solve some "working memory" problems (holding on to some facts and manipulating git numbers). As a result, her frontal cortex lights up metabolically. Now, them—like adding sequences of three-di take someone who is sleep deprived and he's awful at the working memory task. And what's going on in his brain? What you might have guessed is that frontal metabolism woul d be inhibited, too groggy to get activated in response to e parts of the rest of the cortex. It's ontal cortex is activated, but so are larg the task. Instead, the opposite occurs—the fr is gleaming computer of a frontal cortex to a bunc as if sleep deprivation has reduced th h of unshaven gibbering neurons counting on their toes, having to ask the rest of their cortical buddies to help out with this tough math problem. ressor? It's obvious. We're accustomed to So why care if sleep deprivation is a st all sorts of amenities in our modern , advice nurses who can be called at two in the morning, round-the-clock lives: overnight deliveries of packages technical support staff. Therefore, people are required to work under conditions of sleep deprivation. We're not a nocturnal species and if a person works at night or works swing shifts, regardless of how many total hours of sleep she's getting, it's going against her biological nature. People who work those sorts of hours tend to overactivate the stress-response, and there's little habituation that goes on. Given that an overactive stress-response makes every page sk of cardiovascular disease, or shift work increases the ri of this book relevant, it is not surprising that night work suppression, and fertility problems. gastrointestinal disorders, immune A widely reported study a few years back really brought th is into focus. Recall how prolonged stress and glucocorticoids can damage the ry. Kei Cho of the University of Bristol studied flight hippocampus and impair hippocampal-dependent explicit memo attendants working for two different airlin es. On one airline, after you worked a transcontinental flight with major jet lag, you'd have a 15-day break until being scheduled for the next transcontinental flight. In contrast, on Airline #2, presumably with a weaker union, you got a 5-day break before the next transcontinental flight.* Cho controlled for total amount of flying time and total number of time zones sh ifted in the course of flying. Thus, Airline #2's crews ecover. Finally, Cho considered didn't experience more total jet lag, just less time to r only employees who had been e, impaired explicit memory, #2's attendants had, on averag doing this for more than five years. He found that Airline higher glucocorticoid levels, and a smaller temporal lobe (the part of the brain that contains the hippocampus). (This study was briefly alluded to in chapter 10). This is obviously not a good thing for the employees working under these attendant will remember that 17C requested a mixture of conditions. And this may make it less likely that the flight ginger ale and skim milk with ice. But it kind of ma kes one wonder whether the b ack-to-the-grind-after-5-days pilot is having trouble remembering whether or not this little ol' switch turns the engine on or off. These worries about sleep deprivation are relevant to even those whose 9-to-5 job is 9-to-5 during daylight hours. We deprived, beginning with some le as indoor thing as simp have an unprecedented number of ways to make us sleep by the occasional Model T backfiring. the average American slep lighting. In 1910, t nine hours a night, disturbed only We now average 7.5 and declining. When there's the lure of 24-hour-a-day fu n, activities, and entertainment or, for meone else is working while you indulge that somewhere, in some time zone, so the workaholic, the knowledge + yourself in sleep, that pull of "just a few more minutes," of pushing yourself, becomes irresistible. And damaging. * Either out of good manners or identify the airlines. ter sued, Cho did not fear of getting his keis + Just to be perfectly up front, I'm being that I even have the nerve to spout off about this. For the a complete hypocrite here and it's scandalous 't eat meat or drink tea or c offee. But I'm most part I'm without vices— I don't smoke, have never had a dr ink or illicit drug in my life, don ent, who is tion. I've got this colleague, William Dem needed a nap since the Carter administra incredibly bad at getting enough sleep; I've 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

123 Pa g e 123 of 212 considered the dean of sleep res really a mess from earch, absolutely evangelical abou t the health risks of sleep deprivation, and on days when I'm So on this one, do as I say, not as I do. lack of sleep, I live in dread of running into him. AND STRESS AS A DISRUPTOR OF SLEEP What should happen to sleep during stress? This one's simple, given a zebra-o-centric view of the world: lion coming, don't nap (or, as the old joke goes, "The lion and the lamb shall lie down together. But the lamb won't get much sleep."). The hormone CRH seems to be most responsible for this effect. As you'll recall, the hormone not only starts timulating ACTH release from the pituitary, but it is also the neurotransmitter that the glucocorticoid cascade by s activates all sorts of fear, an a sleeping rat's brain and you the brain. Infuse CRH into xiety, and arousal pathways in suppress sleep—it's like throwing ice water onto those happily dozing neurons. Part of this is due to the direct effects of CRH in the brain, but part is probably due to CRH activating the sympathetic nervous system. If you go up to high altitude without acclimating, your heart is going to be racing, even when you're not exerting yourself. This is not nxious, but simply because your heart has to beat because you are stressed or a more often to delive r sufficient oxygen. ing rhythmically 110 times a Suddenly you discover that it's awfully hard to fall as leep with your eyeballs throbb ivation make sleeping hard. sympathetic act minute. So the bodily consequences of Not surprisingly, about 75 percent of cases of insomnia are triggered by some major stressor. Moreover, many (but levels of sympathetic arousal or of glucocorticoids in their not all) studies show that poor sleepers tend to have higher bloodstream. So, lots of stress and, potentially, little sleep. But stress not only can decrease the total amount of sleep but can e, when CRH infusion decreases the total of whatever sleep you do manage. For exampl quality compromise the e to a decrease in slow wave sleep, ex actly the type of sleep you need for amount of sleep, it's predominantly du more shallow sleep stages, meaning you wake up more energy restoration. Instead, your sleep is dominated by easily—fragmented sleep. Moreover, when you do manage to get some slow wave sleep, you don't even get the ve sleep is ideal, really restoring thos e energy stores, ther normal benefits from it. When slow wa e's a characteristic EEG (electroencephalogram) recording. er range that can be detected on an pattern in what is called the delta pow e infused with glucocorticoids during sleep, you get less of that helpful sleep When people are stressed pre-sleep, or ar pattern during slow wave sleep. Glucocorticoids compromise something else that occurs during good quality sleep. Jan Born of the University of Lubeck in Germany has shown that if you infuse glucocorticoids into someone while Jeff Wall, Insomnia, transparency in lightbox, 1994. they're sleeping, you impair the memory consolidation that would normally be occurring during slow wave sleep. ES B CAUSES . . . A CAUSES B CAUSES A CAUS 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

124 Pa g e 124 of 212 We have the potential for some real problems here, insofar as lack of sleep or poor-quality sleep activates the stress- response, and an activated stress-response makes for less sl ach feeds on the other. Does eep or lower-quality sleep. E even a smidgen of stress, or staying up late once to see Ted Koppel interview Britney that mean that experiencing Spears about the evidence for and agains t global warming, and—that's it, you're finished—downward spiral of stress and sleep deprivation? Obviously not. For one thing, as mentioned, sleep deprivation doesn't cause all that massive of a stress-response. ill eventually over come the most stre ssful of stressors. Moreover, the need to sleep w the lines that the expectation that how the two halves might interact, along Nonetheless, a fascinating study suggests you're going to sleep poorly makes you stressed enough to get poor-quality sleep. In the study, one group of volunteers was allowed to sleep for as long as they wanted, which turned out to be until around nine in the morning. As would be expected, their stress hormone levels began to rise around eight. How might you interpret that? These folks had enough sleep, brains knew it. Start secreting those stress happily restored and reenergized , and by about eight in the morning, their hormones to prepare to end the sleep. But the second group of volunteers went to sleep at the same time but were told that they would be woken up at six in the morning. And what happened with them? At five in the morning, their stress hormone levels began to rise. eir stress hormone levels rise This is important. Did th an the other group because they needed three hours earlier th three hours less sleep? Obviously not. The rise wasn't about th em feeling rejuvenated. It was about the stressfulness of lier than desirable. Their br patory stress while sleeping, anticipating being woken up ear ains were feeling that antici demonstrating that a sleeping brain is still a working brain. What might be happening, then, if you go to sleep thinking that not only will you be woken up earlier than you would time? Where any minute could be unpredictable your last minute of sleep for the night? It's quite like, but at an possible that stress hormone levels will be elevated throughout the night, in nervous anticipation of that wake-up call. ss-response during sleep, the quality of the sleep is going to be compromised. As we've seen, with an elevated stre to what counts as miserable sleep. Continuous, uninterrupted sleep, but too little of it— Thus, there is a hierarchy as deadline looming, go to sleep late, get up early, not good. Even worse is too little sleep that is fragmented. As an nt where every three hours for days I had to take blood samples from some animals. example, I once did an experime Even though I did next to nothing on these nights and days other than sleep, in fact I got more total sleep per day than fragmented. You finally get was usual for me, I was a wreck. But worst of all is too little sleep that is unpredictably back to sleep, but with the corrosive knowledge that five hours or five minutes from now, another patient will come ack to the fire truck, or so into the emergency room, or the alarms will go off and it's b meone's diaper will slowly but surely fill up. This teaches us a lot about what counts as good sleep and how stress can prevent it. But as we'll see in a couple of chapters, this generalizes beyond sleep. When it comes to what makes for psychological stress, a lack of predictability and control are at the top of the list of things you want to avoid. 12 AGING AND DEATH Predictably, it comes at the most unpr edictable times. I'll be lecturing, bored, telling the same story about neurons I , and then it hits, producing itat-ingly young undergraduates looking at the ocean of irr did last year, daydreaming, almost a sense of wonderment. "How can you just sit there? Am I the only one wh o realizes that we're all going to die someday?" Or I'll be at a scientific conference, this time barely understanding someone else's lecture, and amid the roomful of savants, the wave of bitterness will sweep over me. "All of you damned medical experts, and not one of you can make me live forever." It first really dawns on us emotionally sometime around puberty. Woody Allen, once our untarnished high priest of death and love, captures its roundabout assault perfectly in n, in flashback, as a The protagonist is show Annie Hall. young adolescent. He is sufficiently depressed for the worried mother to drag him to the family doctor—"Listen to nesque adolescent, glazed with despair what he keeps saying, what's wrong with him, does he have the flu?" The Alle nding." It's all there—the universe is expanding; look how and panic, announces in a monotone: "The universe is expa 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

125 Pa g e 125 of 212 big infinity is and how finite we are—and he has been initia ted into the great secret of ou r species: we will die and we know it. With that rite of passage, he has found the mother lode of psychic energy that fuels our most irrational and violent moments, our most selfish and our most altruistic ones, our neurotic dialectic of simultaneously mourning and denying, our diets and exercising, our myths of paradise and resurrection. It's as if we were trapped in a mine, shouting out for rescuers, Save us, we're alive but we're getting old and we're going to die. Morris Zlapo, collage, 1987. Gepetto's Dementia, And, of course, before dying, most of us will become old, a process aptly described as not for sissies: wracking pain. Dementia so severe we can't recognize our children. Cat fo od for dinner. Forced retirement. Colostomy bags. Muscles that no longer listen to our commands, organs that betray us, children who ignore us. Mostly that aching sense that just when we finally grow up and learn to like ourselves and to love and play, the shadows lengthen. There is so little time. r many years I have spent part of each y ear doing stress resear ch on wild baboons Oh, it doesn't have to be that bad. Fo in East Africa. The people living there, like many people in the nonwesternized world, cl early think differently about these issues than we do. No one seems to find getting old depressing. How could they?—they wait their whole lives to become powerful elders. My nearest neighbors are of the Masai tribe, nomadic pastoralists. I often patch up their various minor injuries and ills. One day, ears old) tottered age (perhaps sixty y one of the extremely old men of the vill -lobes, long-forgotten ed beyond measure, tips missing from a fe into our camp. Ancient, wrinkl w fingers, frayed ear battle scars. He spoke only Masai and not Swahili, the lingua franca of East Africa, so he was accompanied by 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

126 Pa g e 126 of 212 An elderly hunter-gatherer shaman in the Kalahari Desert. his more worldly, middle-aged neighbor, who translated for him. He had an infected sore on his leg, which I washed educated guess—and I "cataracts" was my barely also had trouble seeing— and treated with antibiotic ointment. He explained that they were beyond my meager curative powers. He seemed resigned, but not particularly disappointed, and as he sat there cross-legged, naked except for the blanket wrapped around him, basking in the sun, the woman stood behind him and stroked his head. In a voice as if describing last year's weather she said, "Oh, when he was younger, he was beautiful and strong. Soon he will die." That night in my tent, sleepless and jealous of the Masai, I appalling infant mortality rates, I'll take the chances of thought, "I'll take your malaria and parasites, I'll take your being attacked by buffalo and lions. Just let me be as unafraid of dying as you are." Maybe we will luck out and wind up as respected village elders. Perhap s we will grow old with grace and wisdom. Perhaps we will be honored, surrounded by strong, happy children whose health and fecundity will feel like st of us will age with a find increasing evidence that mo immortality to us. Gerontologists studying the aging process fair degree of success. There's far less institutionalization and disability than one might have guessed. While the size of social networks shrink with age, the quality of the re lationships improves. There are types of cognitive skills that improve in old age (these are related to social intelligence and to making good strategic use of facts, rather than r health is above average, and takes age elderly individual thinks his or he merely remembering them easily). The aver st important, the average level pleasure from that. And mo age; fewer negative emotions of happiness increases in old occur and, when they do, they don't persist as long. Connected to this, brain-imaging studies show that negative more of an impact on brain metabolism in older people, as images have less of an impact, and positive images have compared to young. So maybe old age is not so bad. The final chapter of this book reviews some of the patterns seen in aged people who are particularly 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

127 Pa g e 127 of 212 successful in their aging. The purpose of this chapter is to review what stress has to do with the aging process and whether we wind up with the honored village elder model of aging, or the cat food variant. AGED ORGANISMS AND STRESS How do aged organisms deal with stress? Not very well, it turns out. In many ways, aging can be defined as the certainly fits our perception of aged individuals as fragile progressive loss of the ability to deal with stress, and that and vulnerable. This can be stated more rigorously by saying that many aspects of the bodies and minds of old organisms work fine, just as they do in young ones, so long as they aren't pushed. Throw in an exercise challenge, an physical, cognitive, or psyc hological stressors—and aged injury or illness, time pressure, novelty—any of a variety of organisms don't do so well. "Not doing so well" in the stress-response department can take at least two forms that should be familiar by now. The first is failing to activate a sufficient stress-response when it is needed. This occurs at many levels during aging. For a variety of defenses they can mobilize in resp onse to a challenge th example, individual cells have at can be viewed as a cellular stress-response. Heat a cell to an unhealthy extent and "heat shock prot eins" are synthesized to help stabilize cellular function during a crisis. Damage DNA and DNA re pair enzymes are activated. Generate oxygen radicals and -responses become less responsive to ponse. And all of these cellular stress antioxidant enzymes are made in res challenge during aging. vel of how whole organ systems respond to stress. For example, after you A similar theme comes through at the le eliminate from your study elderly people who have heart disease and look only at healthy subjects of different ages (so as to study aging, instead of inadvertently studying disease), many aspects of car diac function are unchanged by not respond as adequately as do young cise, for example, and old hearts do age. But challenge the system with exer ones, in that the maximal work capacity and the maximal heart rate that can be achieved are nowhere near as great as in a young person.* Similarly, in ey secrete plenty, more pinephrine during exercise. Th * The problem here is not that elderly individuals fail to secret e sufficient epinephrine or nore e epinephrine and than young individuals, in fact. But the heart and various blood vessels in an aged organism do not respond as vigorously to th norepinephrine. the absence of stress, old and young rat brains contain roughly the same amount of energy But when you stress the levels decline faster in the old brains.. Or, as a classic system by cutting off the flow of oxygen and nutrients, energy example, normal body temperature, 98.6 degrees, does not chan ge with age. Nevertheless, ag ed bodies are impaired in mounting a thermoregulatory stress-response, and thus it takes the bodies of the elderly longer to restore a normal temperature after being warmed or chilled. to IQ test scores as people get older? (You'll notice that The idea also applies to measures of cognition. What happens I didn't say "intelligence." What that has to do with IQ test scores is a controversy I don't want to touch.) The dogma 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

128 Pa g e 128 of 212 in the field was once that IQ declined wi th age. Then it was that it did not decline. It depends on how you test it. If complete the test, there is little difference. As you stress you test young and old people and give them lots of time to s fall for all ages, but much further subjects race against a time limit—score the system—in this case, by making the among older people. So sometimes the problem in aging is not enough of a stress-r esponse. Predictably, in some realms, the problem is too too long to turn off at the end of a much of a stress-response—either one tu rned on all the time, or one that takes stressor. As an example, older individuals are im paired at turning off epinephrine, norepinephrine, or glucocorticoid secretion seline. Moreover, even in the ese substances to return to ba after a stressor has finished; it takes longer for levels of th are typically elevated in aged rats, absence of the stressor, epinephrine, no repinephrine, and glucocorticoid levels nonhuman primates, and humans as well.* Do aged organisms pay a price for having these components of the stress-response turned on too often? This seems to s discussed in the chapter on memory, stress and glucocorticoids inhibit the be the case. As one example, which wa birth of new neurons in the adult hippocampus and inhibit the growth of new processes in preexisting neurons. Is the birth of new neurons and the elaboration of neuronal proce sses preferentially inhibited in old rats? Yes, and if their gluco- rom a time when age in humans. However, * The literature used to show th at resting glucocorticoid levels did not rise with those studies came f or eighties, and til the late seventies ider someone aged un lderly." Modern gerontologists do not cons someone age sixty would be classified as "e ting glucocorticoid levels in that age group. more recent studies show a big jump in res ls seen in young animals. cess growth increase to leve corticoid levels are lowered, neurogenesis and pro We know by now that, ideally, the hormones of the stress-response should be nice and quiet when nothing bad is happening, secreted in tiny amounts. When a stressful emergency hits, your body needs a huge and fast stress- precisely what old And these traits are erything should shut off immediately. response. At the end of the stressor, ev organisms typically lack.* WHY YOU SELDOM SEE REALLY OLD SALMON nship—not whether aged organisms can deal well with stress, We shift over to the other half of the aging-stress relatio that an excess of stress can increase aging. There is some decent evidence but whether stress can accelerate aspects of the risk of some of the diseases of ag es, glucocorticoid ing. Remarkably, it turns out that in mo re than a dozen speci excess is the cause of death during aging. als, a la Marlin Perkins: penguins who stan Pictures of heroic wild anim d all winter amid the Antarctic cold, keeping their eggs warm at their feet. Leopards dragging massive kills up trees with thei r teeth, in order to eat them free of miles. And then there's salm on, leaping over dams and harassment by lions. Desiccated camels marching scores of After which most of them stream of their birth. Wher waterfalls to return to the freshwater e they spawn a zillion eggs. die over the next few weeks. Why do salmon die so soon after spawning? No one is quite sure, but evolutionary biologists are rife with theories about why this and the rare other cases of "programmed die-offs" in the animal kingdom may make some evolutionary sense. What is known, however, is the proximal mechanism underlying the sudden die-off (not "How come they die, in terms of evolutionary patterns over the millennia?" but "How come they die, in the sense of which parts of the body's functioning suddenly go crazy?"). It is glucocorticoid secretion. e called DHEA, which has gotten is some evidence e in the levels of a hormon * Aging also brings about a dramatic declin ntion. There tons of atte ects in aged ne, blocking the actions of that DHEA serves as an "anti-stress" hormo glucocorticoids, and that it can have some beneficial eff nvincing studies, in populations. I've buried DHEA in this footnot e, however, because the subject is quite co ntroversial and in need of some more co my view. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

129 Pa g e 129 of 212 A male sockeye salmon, after the onset of programmed aging. If you catch salmon right after they spawn, just when they are looking a little green around the gills, you find they collapsed, and they are s; their immune systems have have huge adrenal glands, peptic ulcers, and kidney lesion like Selye's rats way back teeming with parasites and infections. Aha, kind of sounds when.* Moreover, the salmon have stupendously high glucocorticoid concentrations in their bloodstreams. When salmon spawn, regulation of their glucocorticoid secretion break s down. Basically, the brain loses its ability to measure accurately the quantities of gnal to the adrenals to secrete more glucocorticoids can circulating hormones and keeps sending a si of them. Lots of certainly bring about all those diseases with which the salmon are festering. But is the glucocorticoid excess really and it will live for a year responsible for their death? Yup. Take a salmon right after spawning, remove its adrenals, afterward. on, but also among a dozen in five species of salm of events not only occurs The bizarre thing is that this sequence species of Australian marsupial mice. All the male mice of these species die shortly afte r seasonal mating; cut out ose relatives. At their adrenal glands, however, and they to o keep living. Pacific salmon and mars upial mice are not cl least twice in evolutionary histor y, completely independently, two at is found in the * As a very weird and provocative observation, these salmon even have deposits in their brains of the "beta-amyloid" protein th one is quite sure what to make of that. brains of people with Alzheimer's disease. No up with the identical trick: if you want to degenerate very fast, secrete a ton very different sets of species have come of glucocorticoids. PROCESS IN THE MAINSTREAM CHRONIC STRESS AND THE AGING That is all fine for the salmon looking for the fountain of youth, but we and most other mammals age gradually over time, not in catastrophic die-offs over the course of days. Does stress influence the rate of gradual mammalian aging? Intuitively, the idea that stress accelerates the aging process makes sense. We recognize that there is a connection between how we live and how we die. Around 1900, a madly inspired German physiologist, Max Rubner, tried to and calculated things like define this connection scientifically. He looked at all sort s of different domestic species lifetime number of heartbeats and lifetime metabolic rate ( not the sort of study that many scientists have tried to there is only so long a body can go on—only so many breaths, so many heartbeats, so replicate). He concluded that much metabolism that each pound of fl esh can carry out before the mechanis ms of life wear out. A rat, with ately two years) than an ent faster (after approxim es up its heartbeat allotm approximately 400 heartbeats a minute, us elephant (with approximately 35 beats per minute and a sixty-year life span). Such calculations lay behind ideas about why some species lived far longer than others. Soon the same sort of thinking was applied to how long different individuals within a species live—if you squander a lot of your heartbeats being nervous about blind dates when metabolic reserve available to you at eighty. you're sixteen, there would be that much less ecies have not held up well in their strictest versions, In general, Rubner's ideas about life spans among different sp while the "rate of living" hypotheses about individuals within a species that his ideas in spired have been even less tenable. Nevertheless, they led many people in the field to suggest that a lot of environmental perturbations can wear out the system prematurely. Su ch "wear and tear" thinking fit in naturally with the stress concept. As we have seen, excessive stress increases the risks of adult-onset diabetes, hypertension, cardiovascular disease, osteoporosis, on as we age. Moreover, e conditions become more comm reproductive decline, and immune suppression. All of thes ces of allostatic load, it increases your risk of Metabolic in chapter 4 it was shown that if you have a lot of the indi syndrome; that same study showed that it increased your mort ality risk as well. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

130 Pa g e 130 of 212 We return to the tendency of very old rats, humans, and primat es to have elevated resting levels of glucocorticoids in lation of normal glucocorticoid secretion is disrupted during aging. To get a the bloodstream. Some aspect of the regu interest about why the water tank on your toilet does not sense of why this happens, we must return to chapter l's overflow when it's refilling. Once ag ain, the process of refilling can trigger a sensor—the flotation device—to decrease the amount of water flowing in negative to the tank. Engineers who study this sort of thing term that process increasing amounts of water accumul end-product inhibition: feedback inhibition ating in the tank decrease the or likelihood of further release of water. CRH/ACTH/glucocorticoid axis, work by this feedback-inhibition process. The Most hormonal systems, including the brain triggers glucocorticoid release indirectly via CRH and pituitary release of ACTH. The brain needs to know CRH. It does this by sensing the levels of glucocorticoids in the circulation (sampling whether to keep secreting more coursing through the brain) to see if levels the hormone from the bloodstream are at, below, or above a "set point." If eting CRH—just as when water levels in the toilet tank are still low. Once levels are low, the brain keeps secr glucocorticoid levels reach or exceed that set point, there is a negative feedback signal and th e brain stops secreting CRH. As a fascinating complicati on, the set point can shift. In the absence of stress, the br ain wants different levels of something stressful is happen glucocorticoids in the bloodstream from those required when ing. (This implies that the turn off CRH secretion by the brain should vary with quantity of glucocorticoids in the bloodstream necessary to turns out to be the case.) different situations, which This is how the system works normally, as can be shown experimentally by injecting a person with a massive dose of ). The brain senses the sudden increase and says, in effect, "My God, I don't a synthetic glucocorticoid (dexamethasone know what is going on with those idiots in the adrenal, but they just secreted too many glucocorticoids." The way dexamethasone exerts a negative feedback signal, and soon the person has stopped secreting CRH, ACTH, and her sive." If negative feedback own glucocorticoids. This person would be characteri zed as "dexamethasone-respon regulation is not working very well, however, the pers on is "dexamethasone-resistant"—she keeps secreting the various hormones, despite the whopping glucocorticoid signal in the bloodstream. And that is precisely what happens in old people, old nonhuman primates, and old rats. Glucocorticoid feedback regulation no longer works very well. ce of stress and during the glucocorticoids (in the absen This may explain why very old organisms secrete excessive recovery period after the end of a stressor). Why the failure of feedback regulation? There is a fair amount of evidence that it is due to the degeneration during aging of one pa rt of the brain. The entire brain does not serve as a eas with very high numbers of receptors for instead, that role is served by only a few ar "glucocorticoid sensor"; glucocorticoids and the means to tell the hypothalamus whether or not to secret e CRH. In chapter 10, I described how one of the important negative As it turns out, it is also the hippocampus is famed for its role in learning and memory. feedback sites in the brain for controlling glucocorticoid secretion. It also turns out that during aging, hippocampal neurons may become dysfunctional. When this occurs, some nces include a tendency to of the deleterious conseque may have elevated resting d be the reason aged people secrete an excessive amount of glucocorticoids—this coul levels of the hormone, may have trouble turning off secretion after the end of stress, or may be dexamethasone- resistant. It is as if one of the brak es on the system has been damaged, and ho rmone secretion rushes forward, a little out of control. regulation in the oblem with feedback d age, therefore, arise because of a pr The elevated glucocorticoid levels of ol damaged hippocampus. Why are neurons damaged in the aging hippocampus? It's glucocorticoid exposure, as was discussed in chapter 10. If you've read carefully, you will begin to note somethin g truly insidious embedded in these findings. When the coids. Which should damage the hippocampus further. hippocampus is damaged, the rat secretes more glucocorti other worse, causing a degenerative ticoid secretion... Each makes the Which should cause even more glucocor cascade that appears to occur in many aging rats, and whose potential pathological consequences have been detailed throughout virtually every page of this book. levels rise with extreme old age in the occur in humans? As noted, glucocorticoid Does this degenerative cascade human, and chapter 10 outlines the first evidence that these hormones might have some bad effects on the human hippocampus. The primate and human hippocampus appear to be negative feedback regulators of glucocorticoid associated with glucocorti coid excess, just as in th e rodent. So the pieces of release, such that hippocampal damage is , raising the possibilities that histories of severe stress, or of heavy use of the cascade appear to be there in the human pects of this cascade. ease, might accelerate as synthetic glucocorticoids to treat some dis 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

131 Pa g e 131 of 212 George Segal, Man in a Chair, wood and plaster, 1969. is sort of dysfunction is an obligatory part of aging? Certainly not. It was not by Does that mean that all is lost, that th y" aging rats, rather than in "all." chance that two paragraphs above, I desc ribed this cascade as occurring in "man spares them this cascade, as do many Some rats age successfully in a way that humans—these pleasing stories are part of the final chapter of this book. It is thus not yet clear whether the "glucocorticoid neurotoxicity" story applies to how our brains age. Unfortunately, the answer is not likely to be availabl e for years; the subject is difficult to study in humans. Nevertheless, from what and monkey, glucocorticoid toxicity stands as a striking example of ways in we know about this process in the rat our aging that will will be an aspect of which stress can accelerate aging. Should it turn out to apply to us as well, it harbor a special threat. If we ar e crippled by an accide nt, if we lose our si ght or hearing, if we are so weakened by living. But when it heart disease as to be bed-bound, we ceas e having so many of the things that make our lives worth when it is our ability to recall is our brains that are damaged, old memories or to form new ones that is destroyed, we fear we'll cease to exist as sentient, unique individuals—the version of aging that haunts us most. pretty frazzled by now, given the detai ling in the twelve chapters so far about Even the most stoic of readers should be is time to shift to the second half of the book, which the sheer number of things that can go wrong with stress. It in the stress-response. It is time to begin to get some examines stress management, coping, and individual differences good news. 13 WHY IS PSYCHOLOGICAL STRESS STRESSFUL? Some people are born to biology. You can spot them instantly as kids—they're the ones comfortably lugging dissecting some dead animal around the toy microscopes, on the dining room table, being ostracized at school for their obsession with geckos.* But all sorts of folks migrate to biology from other fields—chemists, psychologists, physicists, mathematicians. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

132 Pa g e 132 of 212 Several decades after stress physiology t their formative began, the discipline was inundated by people who had spen years as engineers. Like physiologists, they thought there was a ferocious logic to how the body worked, but for bioengineers, that tended to mean viewing the body a bit like the circuitry diagram that you get with a radio: input- to write such words, as I barely output ratios, impedance, feedback lo ops, servomechanisms. I shudder even understand them; but the bioengineers did wonders for the field, adding a tremendous vigor. Suppose you wonder how the brain knows when to stop glucocorticoid secretion—when enough is enough. In a vague sort of way, ay-night dinner table, clean them with my knife, and pr * I used to collect the leftover chicken bo oudly display an nes from everyone at the Frid articulated skeleton by the end of dessert. In retrospect, I think cal quest. A biography of to begin an anatomi itate my sister than this was more to irr to appreciate that the worl ntial zoologists when he la psed into politics. At Teddy Roosevelt, however, recently helped me d lost one of its great pote that age, he reacted to the news that hi age eighteen, he had already published professi onally in ornithology; when he was half s mother had thrown out his collection of field mice, stored in the family icebox, by moping around the house, proclaiming, "The loss to science! T he loss to science!" everyone knew that somehow the brain must be able to measure the amount of glucocorticoids in the circulation, ether to continue secreting compare that to some desired set point, and then decide wh CRH or turn off the faucet came in and showed that th (returning to the toilet tank model). The bioengi-neers e process was vastly more interesting and complicated th an anyone had imagined. There are "multiple feedback domain s"; some of the time the at which the level is quantity brain measures the of glucocorticoids in the bloodstream, and sometimes the rate hing? Epinephrine, linear or all-or-not critical issue: Is the stress-response changing. The bioengineers solved another nces are all secreted during stress; but glucocorticoids, prolactin, and other substa are they secreted to the same extent turns out to be incredibly responsiveness)? The system regardless of the intensity of the stressor (all-or-nothing lationship between, for example, sensitive to the size of the stressor, demonstrating a linear re the extent of the drop in blood pressure and the extent of epinephrine secretion, between the degree of hypoglycemia (drop in blood sugar) and sense something stressful, but it also is amazingly accurate at measuring just glucagon release. The body not only can how far and how fast that stressor is throwing the body out of allostatic balance. ineers, which makes perfect sense, since in his time the Beautiful stuff, and important. Hans Selye loved the bioeng eemed a bit soft-headed to some mainst whole stress field must have still s ream physiologists. Those physiologists set when it is too hot, but ld, and a diametrically opposite knew that the body does one set of things when it is too co here were Selye and his crew insisting that there were and hot? physiological mechanisms that respond equally to cold hypoglycemia and hypotension? The beleaguered stress experts welcomed the bioengineers with And to injury and s, formulas. ..." charts, feedback loop can do math about stress, construct flow open arms. "You see, it's for real; you Golden days for the business. If the system was turning out an ever anticipated, it was to be far more complicated th ogical, mechanistic. Soon it would be possible to model the body as one big complicated in a way that was precise, l input-output relationship: you tell me exactly to what degree a stressor impinges on an organism (how much it disrupts the allostasis of blood sugar, fluid volume, optim al temperature, and so on), and I'll tell you exactly how much of a stress-response will occur. This approach, fine for most of the gr ll probably allow us to estimate quite ound that we've covered up until now, wi is doing when the organism is sprintin g from a lion. But th e approach is not accurately what the pancreas of that zebra going to tell us which of us will get an down. Starring in the late 1950s, a new style of experiments in stress physiology began ulcer when the factory closes at lucid, mechanistic bioengin eering bubble. A single example will suffice. An organism to be conducted that burst th is subjected to a painful stimulus, and you are interested in how great a stress-response will be triggered. The bio- engineers had been all over that one, mapping the relations hip between the intensity and duration of the stimulus and dy can reach out for its mommy the response. But this time, when the painful stimulus o ccurs, the organism under stu circumstances, this organism shows less of a stress-response. and cry in her arms. Under these istic world of the bioengineers could explain this phenomenon. The input was still the Nothing in that clean, mechan should have been firing while the child underwent some painful procedure. same; the same number of pain receptors ch community: the Yet the output was completely different. A critical r ealization roared through the resear tical stressors with the same extent l factors. Two iden physiological stress-response can be modulated by psychologica differently, and the whole show changes from there. of allostatic disruption can be appraised perceived, can be Suddenly the stress-response could be made bigger or smaller, depending on psychological factors. In other words, step was demonstrated: in the absence modulate psychological variables could the stress-response. Inevitably, the next of any change in physiological reality—any actual disrup tion of allostasis—psycholog ical variables alone could trigger the stress-response. Flushed with excitement, Yale p hysiologist John Mason, one of the leaders in this proclaim that all stress-responses approach, even went so far as to were psychological stress-responses. The old guard was not amused. Just wh en the conception of stress was beco ming systematized, rigorous, credible, along came this rabble of psychologists muddying up the picture. In a series of published exchanges in which they e and Mason attempted to shred each other's work. Mason first praised each other's achievements and ancestors, Sely 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

133 Pa g e 133 of 212 smugly pointed to the growing literature on psychological initiation and modulation of the stress-response. Selye, facing defeat, insisted that all stress-responses couldn't be psychological and perceptual: if an organism is ponse when a surgical incision is made. anesthetized, it still gets a stress-res place at the table, and as they have acquired some table manners and a few The psychologists succeeded in getting a gray hairs, they have been treated less like barbarians. We now have to consider which psychological variables are logical stress stressful? critical. Why is psycho THE BUILDING BLOCKS 0F PSYCHOLOGICAL STRESSORS You would expect key psychological variables to be mushy concepts to uncover, but in a Outlets for frustration then at Rockefeller University series of elegant experiments, the physiologist Jay Weiss, , demonstrated exactly what equivalent to the static ocks (roughly is a rat that receives mild electric sh is involved. The subject of one experiment shock you might get from scuffing your foot on a carpet). Over a series of these, the rat develops a prolonged stress- nce, we can express the long response: its heart rate and glucocorticoid secretion rate go up, for example. For convenie -term consequences by how likely the rat is to get an ulcer, a nd in this situation, the probability soars. In the next pattern and intensity; its allostatic balance is challenged room, a different rat gets the same series of shocks—identical gets a shock, it can run over to a bar of wood and gnaw on to exactly the same extent. But this time, whenever the rat it. The rat in this situation is far less likely to get an ulcer. You have given it an outlet for frustration. Other types of outlets work as well—let the stressed rat eat something, drin k water, or sprint on a running wheel, and it is less likely to develop an ulcer. We humans also deal better with stressors when we have outlets for frustration—punch a wall, take a run, find solace in a hobby. We are ev imagine those outlets and derive some relief: consider the prisoner of war en cerebral enough to who spends hours imagining a golf game in tremendous detail. I have a friend who passed a prolonged and very stressful illness lying in bed with a mechanical pencil and a notepad, drawing topographic maps of imaginary mountain ranges and taking hikes through them. ng effective is if it distracts A central feature of an outlet bei from the stressor. But, obviously, more important is that it also be something positive for you—a re minder that there is more to life th an whatever is ma king you crazed and ercise provide an additional layer of benefit, one harking tration-reducing effects of ex stressed at the time. The frus nauseam, between the zebra running for it s life and the psychologically stressed back to my dichotomy, repeated ad human. The stress-response is about preparing your body for an explosive burst of energy consumption right now; psychological stress is about doing all the same things to your body for no physical reason whatsoever. Exercise finally provides your body for the outlet that it was preparing for. eaction. This time, when the the outlet-for-frustration r A variant of Weiss's experiment uncovers a special feature of rat gets the identical series of electric shocks and is upset, it can run across the cage, sit actice works wonders aggression: the pr induced displacement of next to another rat and ... bite the hell out of it. Stress- at minimizing the stressfulness of a stressor. It's a real primate specialty as well. A male baboon loses a fight. s a subordinate male who was minding his own business. An extremely high Frustrated, he spins around and attack nders. Humans are pretty good at ts frustration displaced on percentage of primate aggression represen to innocent bysta omenon in the contex t of stress-related disease: "He's one it, too, and we have a technical way of describing the phen of those guys who doesn't get ulcers, he gives them." Taking it out on someone else—how well it works at minimizing the impact of a stressor. th another organism to minimize th e impact of a stressor on us is An additional way we can interact wi Social support considerably more encouragi ng for the future of our planet than is di splacement aggression. Rats only occasionally use it, but primates are great at it. Put a primate through something unpleasant: it gets a stress-response. Put it through those primates are strangers, the stress- other primates and ... it depends. If the same stressor while in a room full of response gets worse. But if they are friends, the stress-re sponse is decreased. Social support networks—it helps to have a shoulder to cry on, a hand to hold, an ear to listen to you, someone to cradle you and to tell you it will be okay. ly do laboratory research on how stress and glucocorticoids The same is seen with primates in the wild. While I most affect the brain, I spend my summers in Kenya studying patterns of stress-related physiology and disease among wild baboons living in a national park. The social life of a male baboon can be pretty stressful—you get beaten up as a victim of displaced aggression; you carefu it off, only to have it stolen by lly search for some tuber to eat and clean someone of higher rank; and so on. Glucocorticoid levels are elevated among low-ranking baboons and among the entire group if the dominance hierarchy is unstable, or if a new aggressive male has just joined the troop. But if you are a male baboon with a lot of friends, you are likely to have lower glucocorticoid concentrations than males of the same general rank who lack these outlets. And what counts as friends? You play with kids, have frequent nonsexual grooming bouts with females (and social grooming in nonhuman primates lowers blood pressure). 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

134 Pa g e 134 of 212 Social support is certainly protective fo r humans as well. This can be demonstr ated even in transient instances of d to a stressor such as having to give a public speech or support. In a number of subtle studies, subjects were expose perform a mental arithmetic task, or having Landscape with Figures, egg tempera on gesso, 1966. George Tooker, two strangers argue with them, with or wi thout a supportive friend pres support translated into ent. In each case, social nt differences in degrees of social support can influence less of a cardiovascular stress-response. Profound and persiste human physiology as well: within the same family, th ere are significantly higher glucocorticoid levels among other example, among women with stepchildren than among biologi cal children. Or, as an metastatic breast cancer, the more social support, the lower the resting Cortisol levels. s have longer life expectanci es. When the spouse dies, the As noted in chapter 8, people with spouses or close friend risk of dying rises. Recall also from that chapter the study of parents of Israeli soldiers killed in the Lebanon war: in s no notable increase in risk of diseas the aftermath of this stressor, there wa es or mortality, except among those who cardiovascular system. People who are me additional examples concern the were already divorced or widowed. So mpathetic nervous systems. Given the likelihood that this will lead to higher socially isolated have overly active sy blood pressure and more platel r blood vessels (remember that fr om chapter 3?), they are more et aggregation in thei likely to have heart disease—two to five times as likely, as it turns out. And once they have the heart disease, they are more likely to die at a younger age. In a study of patients Duke University and colleagues found that half of those with severe coronary heart disease, Redford Williams of five years— a rate three times higher lacking social support were dead within than was seen in patients who had a spouse or close friend, afte r controlling for the severi ty of the heart disease.* Finally, support can exist at the broad community level (stay tuned for chapter 17). If you are a member of an ethnic minority, the fewer members there are of your group in your neighborhood, the higher your risks of mental illness, psychiatric hospitalization, and suicide. Predictability Weiss's rat studies uncovered another variable modulating the stress-response. The rat gets the same each shock, it hears a wa rning bell. Fewer ulcers. pattern of electric shocks, but this time, just before Predictability It learns when something two pieces of information. makes stressors less stressful. The rat with the warning gets not about to happen. It can relax. dreadful is about to happen. Th e rest of the time, it learns that something dreadful is a half-second away from the next shock. The rat without a warning can always be In effect, information that increases you that it's not going to be worse—you are going to get predictability tells you that there is bad news, but comforts shocked soon, but it's never going to be sprung on you without warning. We all know a human equivalent of this principle: you're in the dentist's chair, no novocaine, the dentist drilling away. Ten seconds of 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

135 Pa g e 135 of 212 * Recently, I learned about the protective e on how stressful ffects of social support in an unexpected way. A local TV station was doing a piece way we a 15-second sound bite g this chapter into rush-hour traffic was, and I wound up giving them advice—turnin . Somewhere along the y clinic) who did e eventually found one through a local Type-A cardiolog stumbled onto the great idea of getting a certified Type-A individual (w and during a commute. The film crew would take some saliva the commute each day and measuring his stress hormone levels before samples from which glucocorticoid levels would be measur st tube. Then into re his commute, collect some spit in a te ed. Great. Get to the guy's house just befo mper to bumper. ssed by the worry that there wouldn't be traffic—with the film crew increasingly stre any tie-ups. But soon the snarls began, bu ighly elevated Then the second saliva sample was taken. Laboratory analysis, a nxious TV producers awaiting results. Baseline sample at home: h e outcome of that unscientific experiment was Oh no. I'm convinced that the explanation for th glucocorticoid levels. Rush-hour level: way down. sh hour each day, this was fabulous. A chance to be on televis ion, a bunch of the social support. For this guy, who Type-A's his way through ru people there with him to document what a stressful commute he e ndures, getting to feel he's the chosen representative of all Ty pe A's, their de cheerfully pointing out how horrible it was, how much worse he's seen ("You think this is bad?! This anointed. He apparently spent the entire ri crew in tow when isn't bad. You should have been in Troy in '47."). He had a fabulous time. The punch line? Everyone should have a friendly film they're stuck in traffic. nerve-curling pain, some rinsing, five seconds of drilling, a pause while the dentist fumbles a bit, fifteen seconds of whimper, you gasp, "Almost done?" e pauses, frazzled and trying not to drilling, and so on. In one of th ittent drilling. Think how grateful we are for the dentist "Hard to say," the dentist mumbles, returning to the interm who, instead, says, "Two more and we're done." The instant the second burst of drilling ends, down goes blood pressure. By being given news about the stressor to come, you are also implicitly being comforted by now knowing what stressors are not coming. sms will eventually habituate to a stressor if it is applied As another variant on the helpfulness of predictability, organi over and over; it may knock physiological allostasis equally out of balance the umpteenth time that it happens, but it is a familiar, predictable stressor by then, d. One classic demonstration involved and a smaller stress-response is triggere men in the Norwegian military going through parachute training—as the process went from being hair-raisingly novel r sleep, their anticipatory stress-resp onse went from being gargantuan to to something they could do in thei nonexistent. is shown in an elegant, subtle study. A rat is going The power of loss of predictability as a psychological stressor easured intervals the experimenter delive rs a piece of food down a chute into about its business in its cage, and at m the cage; rat eats happily. This is called an intermittent reinforcement schedule. Now, change the pattern of food delivery so that the rat gets exactly the same total amount of food over the course of an hour, but at a random rate. The rat receives just as much reward, but le ss predictably, and up go gl ucocorticoid levels. There is not a single physically , pained, running for its life—nothing is out of allostatic stressful thing going on in the rat's world. It's not hungry balance. In the absence of any stressor, loss of predictability triggers a stress-response. There are even circumstances in which a stress-response can be more likely to occur in someone despite the reality stressful. Work by the zoologist John Wingfield of the University of Washington has less that the outside world is es between the Arctic and the tropics. rds. Consider some species that migrat shown an example of this with wild bi Bird #1 is in the Arctic, where the te and where it is, indeed, 5 degrees outside that day. mperature averages 5 degrees grees, but today it has dropped down to where the average temperature is 80 de In contrast, Bird #2 is in the tropics, 60. Who has the bigger stress-response? Amazingly, Bird #2. The point isn't that the temperature in the tropics is 55 degrees warmer than in the Arctic (what kind of stressor would that be?). It's that the temperature in the tr opics is 20 degrees colder than anticipated. ring the onset of the Nazi blitzkrieg bombings of A human version of the same idea has been documented. Du England, London was hit every night like clockwork. Lots of stress. In the suburbs the bombings were far more sporadic, occurring perhaps once a week . Fewer stressors, but much less pred ictability. There was a significant increase in the incidence of ulcers du ring that time. Who developed more ulcers? The suburban population. (As ance of unpredictability, by the third month of the bombing, ulcer rates in all the another measure of the import hospitals had dropped back to normal.) Despite the similarity between the responses of humans and of predictability, I suspect that other animals to a lack of there they are not identical, and in an important way. The warning of impending shocks to a rat has little effect on the feel more confid ent about when it doesn't size of the stress-response during the shocks; instead, allowing the rat to the rest of the time. Analogously, when the dentist says, have to worry reduces the rat's anticipatory stress-response at the end "Only two more times and then we're done," it allows us to relax of the second burst of drilling. But I suggest, although I cannot prove it, th at unlike the case for the rat, proper information will also lower our stress- during the pain. If you were told "only two times more" versus "only ten times more," wouldn't you use response different mental strategies to try to cope? With either scenario, you would pull out the comforting thought of "only one more and then it's the last one" at different times; yo u would save your most distracting fantasy for a different point; you would try counting to zero from different numbers. Predictive information lets us know what internal coping strategy is likely to work best during a stressor. se it aids our strategizing about how e course of some medical problem becau We often wish for information about th we will cope. A simple example: you have some minor surgery, and you're given predictive information—the first 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

136 Pa g e 136 of 212 post-surgical day, there is going to be a lot of pain, pretty constant, whereas by the second day, you'll just feel a bit achy. Armed with that information, you are more likely to plan on watching the eight distracting videos on day one and to devote day two to writing delicate haikus than the other way around. Among other reasons, we wish to es when we request the most devastating piece optimize our coping strategi any of us will ever of medical information face: "How much time do I have left?" the rat the same series of shocks. facet of psychological stress. Give Rat studies also demonstrate a related Control This time, however, you ss a lever to avoid electric shocks. Take study a rat that has been trained to pre away the lever, shock it, and the rat thinking, "I can't believe this. I know what to do about develops a massive stress-response. It's as if the rat were this. This isn't fair." Ulceration city (as well as higher electric shocks; give me a damned lever and I could handle glucocorticoid levels, poorer immune function, and faster tumor growth). Give the trained rat a lever to press; even if So long as the rat has been it is disconnected from the shock mechanism, it still helps: down goes the stress-response. exposed to a higher rate of shocks previously, it will think that the lower rate now is due to its having control over the situation. This is an extraordinarily powerful variable in modulating the stress-response. ople in adjoining rooms, and expose humans yields similar results. Place two pe The identical style of experiment with both to intermittent noxious, loud noises; the person who ha s a button and believes that pressing it decreases the likelihood of more noise is less hypertensive. In one variant on this experiment, subjects with the button who did not exercise of control is not critical; bother to press it did just as well as those who actually pressed the button. Thus, the s, yet more of us are phobic rather, it is the belief that you have it. An everyday ex ample: airplanes are safer than car re in control. ge driver, thus mo lieves that he is a better-than-avera your average driver be about flying. Why? Because all. My wife and I tease each other on pl ng control: "Okay, ane flights, exchangi In an airplane, we have no control at you rest for a while, I'll take over concentrating on keeping the pilot from having a stroke." The issue of control runs through the literature on the psychol ogy of stress. As will be discussed in the final chapter on coping, exercise can be a great st ress reducer, but only so long as it is something that seems even remotely run voluntarily in a running wheel, and it makes it feel great. desirable. Amazingly, the same is seen in a rat— let a rat and it gets a massive stress-response. a rat to do the same amount of exercise Force The issue of control runs through the extensive literature on occupational stress. Sure , there are some jobs where stress comes in the form of someone having too much cont rol and responsibility—that rare occupation where, over the course of an average workday, you might find yourself having to direct the landing pattern of an array of circling , and make the final decision as to onally excise someone's cerebral aneurysm jumbo jets at the local airport, pers whether taffeta is going to be in at the fall runway show in Milan. For most, though, occupational stress is built more around lack of contro l, work life spent ies have shown that the link between o as a piece of the machine. Endless stud ccupational stress and increased risk of cardiovascular and metabolic diseases is anchored in the killer combination of high demand and low control—you have to work hard, a lot is expected of you, and you have minimal control over the process. This is the epitome of the ers. The control element is Marx's alienation of the work assembly line, the combination of stressors that makes for more powerful than the demand one—low demand and low control is more damaging to one's health than high demand and high control. only certain domains, however . For example, there is the The stressfulness of lack of control on the job applies in issue of what product is made, and lack of control in this realm tends not to be all that stressful—few people are on that all of their capab ulcerating because of their deep convicti le and motivated fellow wo rkers should be cranking vast numbers of stuffed Snoopys out of this factory instead of ball bearings. Instead, it is stress about lack of control over the process—what work rate is expected and how much flexibility there is about it, what amenities there are and how authoritarian the authorities are. how much control you have over them, These issues can apply just as readily to some less ex can be highly prestigious and pected workplaces, ones that sicians in orchestras generally have lower job satisfaction and more stress desirable. For example, professional mu of researchers suggest that this is h as a string quartet). Why? One pair than those in small chamber groups (suc because of the lack of autonom orchestras are subservient to y in an orchestra, where centu ries of tradition hold that ears that orchestra unions ample, it was only in recent y onducting them. For ex the dictatorial whims of the maestro c won the right for regularly scheduled bathroom breaks during rehearsals, instead of having to wait until the conductor cared to note how squirmy th e reed players had become.* So the variable of control is extremel y important; controlling the rewards that you get can be more desirable than getting them for nothing. As an extraordinary example, both pigeons and rats prefer to press a lever in order to obtain eme found in the activities and the food delivered freely—a th food (so long as the task is not too difficult) over having statements of many scions of great fortunes, who regret the contingency-free nature of their lives, without purpose or striving. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

137 Pa g e 137 of 212 * Interestingly, the paper was written by Se orchestra musician. ymour Levine, one of the gian ts in this field, and his son, Robert, a professional researchers have emphasized this, information are closely related. Some Loss of control and lack of predictive is subjected to novelty. You thought you knew how to pointing out that the common theme is that the organism manage things, you thought you knew what would happen next, and it turns out you are wrong in this novel situation. The potency of this is demonstrated in primate studies in which merely placing the animal into a novel cage arousal and vigilance, as these types of stressors cause suppresses its immune system. Others have emphasized that you search for the new rules of control and prediction aspects of the same issue. . Both views are different Yet another critical psychological variable in the stress-response has been ings worsening A perception of th uncovered. A hypothetical example: two rats get a series of electric shocks. On the first day, one gets ten shocks an ks an hour. Who becomes hypertensive? Obviously, the one hour; the other, fifty. Next day, both get twenty-five shoc eese, no problem; I can handle king, "Twenty-five? Piece of ch going from ten to twen ty-five. The other rat is thin a perception that events are improving helps tremendously. that." Given the same degree of disruption of allostasis, ecall in chapter 9 the scenario where pain is less stressful, The principle often pops up in the realm of human illness. R r example, that the drugs can even be welcome, when it means, fo are working, the tumor is shrinking. One classic 25 percent chance of dying of cancer. study demonstrated that in examin ing parents of children who had a Astonishingly, these parents showed only a moderate rise in glucocorticoid levels in the bloodstream. How could that of death had been far higher. Twenty- mission after a period in which the odds be? Because the children were all in re racle. Twenty-five shocks an hour, a certain degree of social instability, a one- five percent must have seemed like a mi in-four chance of your child dying—each can imply either good news or bad, and only the latter seems to stimulate a reality; it's the meaning you attach to it. stress-response. It's not just the external en dominance hierarchies are y in Kenya. In general, wh A version of this can be observed among the baboons I stud unstable, resting glucocorticoid levels rise. This makes sense, because such instabilities make for stressful times. Looking at individual baboons, however, shows a more subtle pattern: given the same degree of instability, males have elevated glucocorticoid leve amid the tumult whose ranks are dropping ls, while males whose ranks are rising don't show this endocrine trait. NOT SO FAST Thus, some powerful psychological factors can trigger a stress-response on their own or make another stressor seem lets for frustration or sources of support, a perception that more stressful: loss of control or predictability, loss of out in the meaning of these different factors. As we saw, things are getting worse. There are obviously some overlaps worsening, and you have the with a perception of things control and predictability are closely aligned; combine them situation of bad things happening, out of your control, an d utterly unpredictable. The primatologist Joan Silk of UCLA has emphasized how, among primates , a great way to maintain dominance is for the alpha individual to mete out aggression in a randomly brutal way. This is our primate essence of terrorism. Sometimes these different variables conf lict and it becomes a question as to which is more powerful. This often involves a dichotomy between control/predictability issues and the perception of whether things are improving or worsening. For example, someone unexpectedly wins the lotte ry big-time. Is this a stressor? It depends on what is more powerful, the beneficial "perception of things getting better" part or the stressful "lack of predictability" part. Not surprisingly, if the lottery win is big enough, most people's psyches can handle some unpredictability. Nonetheless, some nonhuman primate studies in which rank was manipulated by the experimenters show that it can go in the other way, that if the change is sufficiently une xpected, it can be stressful, ev en if it is good change (and sometimes find change for the good to be less desirable psychotherapy often must delve into the reasons why people ion is sufficiently awful, the fact that it may have been than persisting with a known misery). Conversely, if a situat predictable offers little comfort. These factors play a major role in explaining how we all go through lives full of stressors, yet differ so dramatically in vidual differences in greater amines the bases of these indi our vulnerability to them. The final chapter of this book ex detail. This will serve as a blueprint for analyzing how to hological variables—how, in learn to exploit these psyc effect, to manage stress better. interact brings up a key point, one that will dominate The ways in which these different psychological variables can the final chapter. This is that stress management cannot consist merely of the simple-minded solution of "Maximize ustration." As we will now see, it is considerably control. Maximize predictability. Maximize outlets for fr 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

138 Pa g e 138 of 212 more complicated than that. As the most obvious first pass at this, some lack of control and predictability can be a great thing—a good roller-coaster ride, a superbly terrifying movie, a mystery novel with a great surprise ending, And sometimes, an overabundance of predictability is a winning a lottery, being subject to a random act of kindness. control and predictability are what we call stimulation. In disaster—boredom on the job. The right amounts of loss of chapter 16, we will look at the biology of why stimulation makes us happy, rather than stressed. The goal is never to this chapter considers when stasis. And the remainder of generate lives in which there is never a challenge to allo increasing a sense of control and predictability reduces stress. SOME SUBTLETIES OF PREDICTABILITY can ameliorate the consequences of stress: one rat gets a series of shocks and We have already seen how predictability develops a higher risk for an ulcer th an the rat who gets warnings beforehand. Predictability doesn't always help, however. The experimental literature on this is pretty dense; some human examples of this point make it more ange the stressor, just the inevitable; the warning cannot ch accessible. (Remember, in these scenarios, the stressor is perception of it.) How predictable is the stressor, in the absence of a warning? What if, one morning, an omnipotent voice says, "There is no way out of it; a meteor is going to crush your car while you're at work today (but it's the only time it will happen this year)." Not soothing. There's the good news that it's not going to happen again tomorrow, but that's hardly comforting; this is not an event that you anxiously fret ov er often. At the other extrem e, what if one morning an on the freeway—lots of traffi c, stops and go's. Tomorrow, omnipotent voice whispers, "Today it's going to be stressful too. In fact, every day this year, except November 9, when there'll hardly be any traffic, people will wave to each other, and a highway patrol cop will stop you in order to share his coffee cake with you." Who needs predictive information about the obvious fact that driving to work is going to be stressful? Thus, warnings are less effective for very rare stressors (you don't usually worry much about meteors) and very frequent ones (they approach being ithout the warning). predictable even w ssor does the warning come? Each day, you go for a mysterious appointment: you are How far in advance of the stre led into a room with your eyes closed and are seated in a deep, comfortable chair. Then, with roughly even probabilities but no warning, either a rich, avuncular voice reads you to sleep with your favorite childhood stories, or 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

139 Pa g e 139 of 212 a bucket of ice water is sloshed over your head. Not a pleasing prospect, I would bet. Would the whole thing be any less unsettling if you were told which treatment you were going to get five seconds before the event? Probably not— there is not enough time to derive any psychological benefits from the information. At the other extreme, how about predictive information long in the future? Would you wish for an omnipotent voice to tell you, "Eleven years and n full minutes"? Information either just before or long twenty-seven days from now your ice-water bath will last te before the stressor does little good to alleviate the psychological anticipation. atory stressor. For example, if the can even increase the cumulative anticip Some types of predictive information be comforted by the omnipotent messa stressor is truly terrible. Would you ge: "Tomorrow an unavoidable accident will mangle your left leg, although your right leg will remain in great shape"? the information is vague. As I write this section, we Likewise, predictive information can make things worse if ing vagueness of predictive information continue to be stressed by the madden in our post-9/11 world, when we are reat is, but be extra alert given warnings that read like horoscopes from hell: "Orange Al ert: We don't know what the th about everything for the next few days."* not always work to protect us from stress. The much more Collectively, these scenarios tell us that predictability does that it works only in a midrange of frequencies and intensities of stressors, systematic studies with animals suggest and with certain lag times and levels of accurate information. SUBTLETIES OF CONTROL of the effects of control on stress, we need to return to the paradigm of the To understand some important subtleties rat being shocked. It had been previously trained to press a lever to avoid shocks, and now it's pounding away like crazy on a lever. The lever does nothing; the rat is still get ting shocked, but with less ch ance of an ulcer because the decreases the stress-response rat thinks it has control. To introduce a sense of control into the experimental design because, in effect, the rat is thinking, "T en shocks an hour. Not bad; just imag ine how bad it would be if I wasn't on top of it with my lever here." But what if things backfire, and adding a sense of control makes the rat think, "Ten shocks an hour, what's wrong with me? I have a lever here, I should have avoided the shocks, it's my fault." If you believe you have control over stressors that are, in fact, beyond your control, you may consider it somehow to be your fault that the inevitable occurred. acetious article in which Tom Ridge, secretary of * The satirical newspaper The Onion mocked the imprecision of this information with a f roon Alert, Homeland Security, supposedly announ ces new levels of alert. "The newly added levels are Orange-Red Alert, Red-Orange Alert, Ma said. "They indicate, in ascending order of fear: concern, deep dread, severe appre hension, near- Burnt Sienna Alert, and Ochre Alert," Ridge 39, no. 7,26 February 2003) crippling fright, and pants-shitting terr or. Please make a note of this." (The Onion me of our most feel terrible. So the face of awful events can make us An inappropriate sense of control in compassionate words to people experienci ng tragedy involve minimizing their perceived sense of control. "It's not your fault, no one could have stopped in time; she just darted out from between the cars." "It's not something you could have done anything about; you tried your best, the economy's just lousy now." "Honey, getting him the best doctor in the world couldn't have cured him." And some of the most brutally callous of society's attempts to shift blame attribute more personal control during a stressor than exists. "She was asking for it if she was going to dress that way" (rape victims have the cont d's schizophrenia was caused by your rol to prevent the rape). "Your chil tive belief that dominated psychiatry for decades before the disease was mothering style" (this was a destruc the effort to assimilate, they wouldn't have these recognized to be neurochemical). "If they'd only made problems" (minorities have the power to prevent their persecution). ress are highly dependent on context. In general, if the stressor is of a sort The effects of the sense of control on st where it is easy to imagine how much worse it could have b een, inserting an artificial sense of control helps. "That was awful, but think of how bad it would have been if I ha dn't done X." But when the stressor is truly awful, an at you managed to avoid, but onceive a yet-worse scenario th artificial sense of control is damaging—it is difficult to c easy to be appalled by the disaster you didn't prevent. You don't want to feel as if you could have controlled the uncontrollable when the outcome is awful. People with a strong internal locus of control (in other words, people who think they are the masters of their ow n ship—that what goes on around them reflects their actions) have far greater with external loci when confronted with something uncontrollable. This is a particular stress-responses than do those elderly men) as life generates more and more things beyond their control. As we will risk for the elderly (especially a personality type whose tendency to internalize co see in the final chapter, there is even ntrol in the face of bad, uncontrollable things great ly increases the risk of a particular disease. These subtleties about control and predictability help to explain a confusing feature about the studies of stress. In general, the less control or predictability, the more at ri sk you are for a stress-induced disease. Yet an experiment conducted by Joseph Brady in 1958 with monkeys gave rise to the view that more control and more predictability could press a bar to delay shocks ("executive" monkeys); the other half were passively cause ulcers. Half the animals k whenever the first they received a shoc yoked to one of the "executives" such that 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

140 Pa g e 140 of 212 one did. In this widely reported study, the executive monkey s were more likely to develop ulcers. Out of these studies ve humans weighed images of executi tive stress syndrome" and associated came the popular concept of the "execu down with the stressful burdens of control, leadership, and responsibility. Ben Natelson, of the VA Medical Center in East Orange, New Jersey, along with Jay Weiss, noted some problems with that study. First, it was conducted with "nonexecutive" monkeys were . Second, the "executive" and parameters where control and predictability are bad news ess the bar first in pilot studies were selected to be not chosen randomly; instead, the monkeys that tended to pr since been shown to be more emotio executives. Monkeys that press sooner have nally reactive animals, so Brady was ne monkeys. In general, executives of all tive side with the more reactive, ulcer-pro inadvertently stacking the execu species are more likely to be givi , as we will see in chapter 17. ng ulcers than to be getting them modulated or even caused by psychologi To summarize, stress-responses can be cal factors, including loss of outlets support, a perception of things worsening, and under some circumstances, a loss of control for frustration and of social and of predictability. These ideas have vastly expanded our ability to answer the question: Why do only some of us mber of stressors that befall us. After all the chapters on get stress-related diseases? Obviously we differ as to the nu physiology, you can guess that we differ in how fast our adrenals make glucocorticoids, how many insulin receptors we have in our fat cells, the thickness of our stomach walls, and so on. But in addition to those physiological differences, we can now add another dimension. We differ in the psychological filters through which we perceive the stressors in our world. Two people participating in the sa me event—a long wait at the supermarket checkout, public —may differ dramatically tion of the event. "Oh, speaking, parachuting out of an airplane in their psychological percep I'll just read a magazine while I wait" (outlet for frustration); "I'm nervous as hell, but by giving this after-dinner talk, I'm a shoo-in for that promotion" (things are getting better); "This is great—I've always wanted to try sky-diving" (this is something I'm in control of). ider psychiatric disorders such as de In the next two chapters we will cons pression and anxiety, and personality disorders, in which there's a bad match between how stressful the real world is and how st ressful the person perceives ch between the two can take a variet y of forms, but the thing in common it to be. As we'll see, the mismat that, in chapter 16, we is the fact that a potentially considerable price is pa id by the sufferer. Following has to do with the process of addict ion. Following that is a chapter consider what psychological stress society it is, can have profound effects on stress examining how your place in society, and the type of ress-management techniques apter we will examine how st physiology and patterns of disease. In the final ch can aid us by teaching how to exploit these psychological defenses. 14 STRESS AND DEPRESSION exotica of disease. They fill our ma We are morbidly fascinated with the de-for-television movies, our tabloids, and the book reports of adolescents hoping to become doc-tors someday. Victorians with Elephant Man's disease, murderers with multiple personality disorders, ten-year-old s with progeria, idiot savants with autism, cannibals with ry, try a major depression. It can be s to the bread and butter of human mise kuru. Who could resist? But when it come life-threatening, it can destroy lives, demolish the families of sufferers. And it is dizzyingly common—the it the common cold of psychopathology. Best estimates are that from 5 to 20 psychologist Martin Seligman has called percent of us will suffer a major, incapacitating depression at some point in our lives, causing us to be hospitalized or increasing for decades—by incidence has been steadily icant length of time. Its medicated or nonfunctional for a signif the year 2020, depression is projected to be the s econd leading cause of medi cal disability on earth. This chapter differs a bit from those that preceded it in which the concept of "stress" was at the forefront. Initially, that may not seem to be the case in our focus on depression. Th e two appear to be inextricab ly linked, however, and the concept of stress will run through every page of this chapter. It is impossible to understand either the biology or the critical role played in the disease by stress. psychology of major depressions without recognizing To begin to understand this connection, it is necessary to get some sense of the disorder's characteristics. We have first is a term that we all use in an Depression to wrestle with a semantic problem. everyday sense. Something mildly or fairly upsetting happens to us, and we get sue is chronicity— "the blues" for a while, followed by r ecovery. This is not what occurs in a ma jor depression. One is ve persisted for at least two weeks. The other is severity— for a major depression to be occurring, the symptoms to ha 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

141 Pa g e 141 of 212 this is a vastly crippling disorder that leads people to attempt suicide; its victims may lose their jobs, family, and all social contact because they can of bed, or refuse to go to a psychiatrist because they not force themselves to get out ease, and throughout this chapter I will be referring to this feel they don't deserve to get better. It is a horrific dis ansient blues that we may casually signify with the term major, devastating form of depression, rather than the tr "feeling depressed." THE SYMPTOMS The defining feature of a major depression is loss of pleasure. If I had to define a major depression in a single sentence, I would describe it as a "gen er requiring a strong environmental trigger whose eric/neurochemical disord Depression can be as tragic as cancer or a spinal characteristic manifestation is an inabi lity to appreciate sunsets." on occasion we actually believe it; None of us will live forever, and cord injury. Think about what our lives are about. our days are filled with disappointments, failures, unrequited loves. Despite this, almost inconceivably, we not only for example, am resounding cope but even feel vast pleasures. I, ly mediocre at soccer, but nothing keeps me from my up someone more adept than I; I'm twice-weekly game. Invariably there co mes a moment when I manage to gum ere's still plenty more time to play and a breeze blows and I suddenly feel panting and heaving and pleased, and th at could be more tragic than a dis my animal existence. Wh dizzy with gratitude for ease that, as its defining symptom, robs us of that capacity? This trait is called anhedonia: hedonism is "the pursuit of pleasure," anhedonia is "the inability to feel pleasure" (also eably). Anhedonia is consistent among depressives. A often called dysphoria—I'll be using the terms interchang engaged to the woman of his dreams— promotion; a man has just become woman has just received the long-sought and, amid their depression, they will tell you how they feel nothing, how it really doesn't count, how they don't food, humor—none can bring any pleasure. deserve it. Friendship, achievement, sex, built around work of the psychologist This is the classic picture of depressi on, and some recent research, much of it Alex Zautra of the George looker, Woman at the Wall, egg tempera on gesso, 1974. mplex. Specifically, positive an d negative emotions are not University of Arizona, shows that the story is more co mere opposites. If you take subjects and, at random times throughout the day, have them record how they are feeling ere's normally not rsely correlated. Th eeling good and feeling bad are not inve at that moment, the frequencies of f much of a connection between how much your life is filled with strongly positive emotions and how much with esents a state where those two independe strongly negative ones. Depression repr nt axes tend toward collapsing into one inverse relationship—too few positive emotions and too many negative ones. Naturally, the inverse correlation ession characterized ent subtypes of depr isn't perfect, and a lot of current resear ch focuses on questions like: Are differ more by the absence of positive emotions or the overabundance of negatives? 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

142 Pa g e 142 of 212 Accompanying major depression are great grief and great guilt. We often f eel grief and guilt in the everyday acitating, as the person is depression, they can be incap sadnesses that we refer to as "depression." But in a major r. There can be complex overwhelmed with the despai layers of these feelings: not just obsessive guilt, for exam ple, about something that has contributed to the depression, but obsessive guilt about the depression itself—what it has done to the sufferer's family, the guilt of not being able to l wonder that, worl dwide, depression overcome depression, a life lived but on ce and wasted amid this disease. Smal accounts for 800,000 suicides per year.* In a subset of such patients, the sense of grief and guilt can take on the quality of a delusion. By this, I do not mean the thought-disordered delusions of schizophrenics; instead, delusional thinking in depressives is of the sort where ings are terrible and getting ere one must conclude that th facts are distorted, over- or underin-terpreted to the point wh worse, hopeless. whelmed by his implied mortality, the An example: a middle-aged man, out of the blue, has a major heart attack. Over from the attack reasonably transformation of his life, he slips into a major depression. Despite this, he is recovering normal life. But each day he's sure he's getting worse. well, and there is every chance that he will resume a The hospital in which he is staying is circular in constructio n, with a corridor that forms a loop. One day, the nurses walk him once around the hospital before he collapses back in bed. The next day, he does two laps; he is getting stronger. That evening, when his family visits, he explains to them that he is sinking. "What are you talking about? The nurses said that you did two loops today; yesterday you only did one." No, no, he shakes his head sadly, you don't understand. He explains that the hospital is being renovated and, um, well, last night they closed off the old corridor is less than half the distance of the and opened a newer, smaller one. And, yo u see, the distance around the new loop old one, so two laps today is still less than I could do yesterday. ith the father of a friend, an engi This particular incident occurred w neer who lucidly described radii and believe that the hospital had opened up a new corridor through the core of the circumferences, expecting his family to building in one day. This is delusional thinking; the emotional energies behind the analysis and evaluation are interpreted in a way that leads to depressive conclusions—it's awful, getting disordered so that the everyday world is worse, and this is what I deserve. * Some suicide statistics: women are more lik ely to attempt suicide when depressed than are men; men are mo re likely to be succ essful. The group e with, naturally, access to guns. les over sixty-five years of ag most at risk are single white ma Cognitive therapists, like Aaron Beck of the University of Pennsylvania, even consider depression to be primarily a disorder of thought, rather than emotion, in that sufferers tend to see the world in a dist orted, negative way. Beck and show a subject two ample, they might s that provide evidence for this. For ex colleagues have conducted striking studie pictures. In the first, a group of peopl ble, feasting. In the second, the same e are gathered happily around a dinner ta ltaneously; which one is remembered? how the two pictures rapidly or simu people are gathered around a coffin. S Depressives see the funeral scene at rate are not only depressed about something, but see s higher than chance. They glasses are always half empty. inforces that feeling. Their the goings-on around them in a distorted way that always re Another frequent feature of a major depression is called psychomotor retardation. The person moves and speaks tion. She finds the act of me rely arranging a doctor's slowly. Everything requires tremendous effort and concentra appointment exhausting. Soon it is too much even to get out of bed and get dressed. (It should be noted that not all the opposite pattern, termed psychomotor agitation.) The depressives show psychomotor retardation; some may show on, which is that severely, psychomotor retardation accounts for one of the important cl inical features of depressi profoundly depressed people rarely attempt suicide. It's not until they begin to feel a bit better. If the psychomotor aspects make it too much for this person to get out of bed, they sure aren't going to find the often considerable energy needed to kill themselves. A key point: many of us tend to think of depressives as people who get the same everyday blahs as you and I, but that for them it just spirals out of control. We may also have hot, that these are people who the sense, whispered out of ears just can't handle normal ups and downs, who are indulging th emselves. (Why can't they just get themselves together?) pports that view. pressive symptoms su a disease as diabetes. Another set of de A major depression, however, is as real peculiarly; these are called Basically, many things in the bodies of depressives work vegetative symptoms. You and I at do we do? Typically, we sleep more than usual, probably eat more than usual, get an everyday depression. Wh comforts will make us feel better. These tr aits are just the opposite of the vegetative convinced in some way that such ll, and in a distinctive symptoms seen in most people with ma jor depressions. Eating decl ines. Sleeping does as we falling asleep, they have the problem of "early morning manner. While depressives don't necessarily have trouble wakening," spending months on 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

143 Pa g e 143 of 212 end sleepless and exhausted from three-th hortened but, as mentioned in irty or so each mo rning. Not only is sleep s —the normal pattern of shifting between deep and shallow of sleep is different as well chapter 11, the "architecture" of dream states, are disturbed. sleep, the rhythm of the onset An additional vegetative symptom is extremely relevant to this chapter, namely that major depressives often tical for a number of reasons that will be returned to, and experience elevated levels of glucocorticoids. This is cri ve sitting on the edge of the bed, barely helps to clarify what the diseas e is actually about. When looking at a depressi person as energy-less, enervated. A more able to move, it is easy to think of the accurate picture is of the depressive as a psycho-dynamic view of t all inside. As we will see, a tightly coiled spool of wire, tense, straining, active—bu depression shows the person fighting an enormous, aggressive mental battle—no wonder they have elevated levels of stress hormones. Chapter 10 reviewed how glucocorticoids can impair aspects of memory that depend on the hippocampus, and the y help explain another feature of the disease, which is frequently elevated glucocorticoid levels in depression ma problems with hippocampal-dependent memory. The memory problems may reflect, in part, a lack of motivation on the part of the depressed person (why work hard on some shrink's memory test when everything, everything, is hopeless and pointless?), or an anhedonic inability to respond to the rewards of remembering something in a task. actors, the pure process of storing and retrieving memories via the hippocampus Nonetheless, amid those additional f is often impaired. As we'll s ee shortly, this fits extraordin arily well with recent findings showing that the hippocampus is smaller than average in many depressives. an merely the situation of someone who Another feature of depression also confirms that it is a real disease, rather th ups and downs. There are multiple types simply cannot handle everyday of depressions, and they can look quite tuates from feeling extrem pression, the sufferer fluc different. In one variant, unipolar de ely depressed to feeling ates between deep depressi reasonably normal. In another form, the person fluctu on and wild, disorganized familiarly, manic depression. Here we run into another hyperactivity. This is called bipolar depression or, more ession in an everyday sense that is complication because, just as we use depr different from the medical sense, mania may use the term to refer to madness, as in made-for-tel has an everyday connotation as well. We evision homicidal maniacs. Or we could describe someone as being in a manic state when he is buoyed by some ating. But the mania found in manic depression is of a unexpected good news—talking quickly, laughing, gesticul completely different magnitude. Let me give an example of the disorder: a woman comes into the emergency room; she's bipolar, completely manic, hasn't been taking her medication. She's on welfare, doesn't have a cent to her name, and in the last week she's bought thr ee Cadillacs with money from loan sharks . And, get this, she doesn't even know ee hours of sleep a night and feel rested, will talk nonstop how to drive. People in manic states will go for days on thr concentrate amid their raci for hours at a time, will be vastly distractible, unable to ng thoughts. In outbursts of irrational grandiosity, they will behave in ways that are foolhardy or dangerous to themselves and others—at the lves in attempting to prove their immortality, burning down their homes, giving away their extreme, poisoning themse a profoundly destructive disease. life savings to strangers. It is The strikingly different subtypes of depression and their variability suggest not just a single disease, but a heterogeneity of diseases that have different underlying biologies. Another feature of the disorder also indicates a biological abnormality. Suppose a patient comes to a doctor in the tropics. The patient is running a high fever that n, and so on every 48 to 72 hours. The doctor will r, abate again, return agai abates, only to come back a day or two late recognize this instantly as malaria, becau has to do with the life cycle of the se of the rhythmicity of the disorder. It e liver and spleen. The rhythm icity screams biology. In the malarial parasite as it moves from red blood cells to th A manic-depressive may be manic for five days, severely same way, certain subtypes of depression have a rhythm. nally, symptom-free for a few depressed for the following week, then mildly depressed for half a week or so, and, fi weeks. Then the pattern starts up again, and may have been things and bad things happen, doing so for a decade. Good but the same cyclic rhythm continues, which suggests just as much deterministic biology as in the life cycle of the malarial parasite. In another subset of depression the rhythm is annual, where sufferers get depressed during the winter. These are called seasonal aff ective disorders (SADs; "affective" is the psychiatric term for emotional responses), and are thought to be related to patterns of exposure to light; recent work has uncovered a class of retinal send their information directly into the limbic system, the cells that respond to light intensity and, surprisingly, emotional part of the brain. Again, the rhythmicity appears independent of external life ev ents; a biological clock is ticking away in there that has something to do with mood, and something is seriously wrong with its ticking. Neurochemistry and Depression THE BIOLOGY OF DEPRESSION at something is awry with the chemistry of the brains of depressives. In order to Considerable evidence exists th appreciate that, it is necessary to lear n a bit about how brain cells communicate with one another. The illustration on page 279 shows a schematic version of two neurons, the principal type of brain cell. If a neuron has become excited with some thought or memory (metaphorically speaking), it s excitement is electrical—a wave of electricity sweeps from the dendrites over the cell body, down the axon to the axon terminals. When the wave of electrical excitation oss the synapse. These messengers— chemical messengers that float acr reaches the axon terminal, it releases 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

144 Pa g e 144 of 212 neurotransmitters— bind to specialized receptors on the adjacent dendri te, causing the second neuron to become electrically excited. ing, however: What happens to the neurotrans A minor piece of housekeep mitter molecule after it has done its job and floats off the receptor? In inal of the first neuron and some cases, it is recycled—tak en back up by the axon term flushed out to sea (the cerebrospinal degraded in the synapse and the debris repackaged for future use. Or it can be neurotransmitters out of the way fail e urine). If these processes of clearing fluid, then to the blood, and then th stops or both), sudden ly a lot more neurotransmitter re mains in the synapse, giving a (reuptake ceases or degradation stronger signal to the second neuron than usual. Thus, the proper disposal of these powerful messengers is integral to normal neuronal communication. trillions of chemically unique neurotransmitters? Certainly There are trillions of synapses in the brain. Do we need not. You can generate a seemingly infinite number of messages with a finite number of messengers; consider how many words we can form with the mere twenty-six letters in our alphabet. All you need are rules that allow for the same messenger to convey different meanings, metaphori cally speaking, in different contexts. At one synapse, neurotransmitter A sends a message relevant to pancreatic regulation, while at another synapse the same neurotransmitter substance may pertain to adolescent crus nsmitters, probably on the hes. There are many neurotra order of a few hundred, but certainly not trillions. neurons talk to each other with neurotra So that's a primer on how nsmitters. The best evidence suggests that depression involves abnormal levels of the neurotransmitters norepinephrine, serotonin, A neuron that has been excited conveys information to other neurons by means of chemical signals at synapses, the contact points between neurons. When the impulse reaches the axon terminal of the signaling neuron, it induces the cleft and bind to receptors in the release of neurotransmitter molecule s. Transmitters diffuse across a narrow adjacent neuron's dendritic spine. and dopamine. Before reviewing the evid ence, it's important to clear up a point. You are no doubt thinking, "Wasn't there something about norepinephrine and the sympathetic ago?" Absolutely, and that nervous system many chapters proves the point about the varied roles played by any given neurotransmitter. In one part of the body (the heart, for cerning arousal and the Four F's, whil e in a different part of the nervous example), norepinephrine is a messenger con system, norepinephrine seems to have something to do with the symptoms of depression. Why is it likely that there is something wrong with norepinephrine, serotonin, or dopamine in depression? The best the amount of signaling by these neurotransmitters. lessen depression increase evidence is that most of the drugs that the recycling, or One class of antidepressants, called tric yclics (a reference to their biochemical structure), stops reuptake, of these neurotransmitters into the axon terminal s. The result is that the neurotransmitter remains in the her class of drugs, called MAO synapse longer and is likely to hit its respective r eceptor a second or third time. Anot 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

145 Pa g e 145 of 212 inhibitors, blocks the degradation of these neurotransmitte rs in the synapse by inhibiting the action of a crucial messenger remains in is that more of the monoamine oxidase, or MAO. The result, again, enzyme in that degradation, te a pretty straightforward dendrite of the recei the synapse to stimulate the ving neuron. These findings genera eases the amount of norepinephrine, serotonin, and dopamine in synapses conclusion: if you use a drug that incr gets better, there must have been too little of those throughout the brain, and as a result, someone's depression first place. Case closed. neurotransmitters in the the problem with serotonin, dopamine, or norepinephrine? The Naturally, not so fast. As a first issue of confusion, is mitter systems, making it impossible to tell which one is tricyclics and MAO inhibitors work on all three neurotrans it, when it was thought le used to think norepinephrine was the culpr critical to the disease. Peop that those classical antidepressant drugs worked only on the norepinephrine synapse. These days, most of the excitement centers on only on serotonin synapses (selective serotonin, mainly because of the effi cacy of reuptake inhibitors that work , of which Prozac is the most famous). serotonin reuptake inhibitors, or SSRIs However, there still remains some of the newest antidepressants reason to think that the other two neurotransmitters remain pa rt of the story, since some appear to work on them more than on serotonin.* ite major. Is the defect in depression A second piece of confusion is actually qu with these neurotransmitters really one of too little neurotransmitter in the synapse? You would th ink this was settled—the effective antidepressant drugs increase the amounts of these neurotrans mitters in the synapse and alleviate depression; thus, the problem had to be too little of the stuff to begin with. However, some clin ical data suggest that this might not be so simple. ressant, and the amount of The stumbling block has to do with timing. Expose the br ain to some tricyclic antidep signaling with these e uptake of serotonin, * The current herbal rage, St. John's wort, has been gaining some credibility in traditi onal scientific circles. It inhibits th e an antidepressant as Prozac. Mo taking any dopamine, and norepinephrine, and seems to be roughly as effectiv reover, in people who are not fects than do the SSRIs. Howeve that it can seriously additional medication, it appears to have somewhat fewer side ef r, there is increasing evidence disrupt the effectiveness of a wi de variety of other medications. neurotransmitters in the synapses changes within hours. However, give that same drug to a depressed person, and it ries have arisen in recent years that r. Something doesn't quite fit. Two theo takes weeks for the person to feel bette might reconcile this problem with timing, and they are both ex tremely complicated. Revisionist theory 1, the "it's not too little neurotransmitter, it's actually too much" hypothesis. First, some orientation. If somebody constantly yells at you, you stop listening. Analogously, if you inundate a cell with lots of a of receptors for neurotransmitter, the cell will not "liste n" as carefully—it will "down-regulate" (decrease) the number e, you double the amount of that messenger. If, for exampl that neurotransmitter, in order to decrease its sensitivity to serotonin reaching the dendrites of a cel l and that cell down-regulates its se rotonin receptors by 50 percent, the net result is more serotonin signaling wn-regulates less than 50 percent, the changes roughly cancel out. If the cell do lly less signaling in the synapse. In other words, how strong in the synapse; if more than 50 percent, the result is actua the signal is in a synapse is a function both of how loudly the first neuron yells (the amount of neurotransmitter released) and of how sensitively the s econd neuron listens (how r the neurotransmitter). many receptors it has fo Okay, ready. This revisionist th original problem is that there is actually too much norepinephrine, eory states that the serotonin, and/or dopamine in parts of the brains of depressives. What happens when you prescribe antidepressants that increase signaling of these neurotransmitters even furt her? At first, that should make the depressive symptoms this actually does occur.) Over the co urse of a few weeks, however, the worse. (Some psychiatrists argue that dendrites say, "This is intolerable, a ll this neurotransmitter; le t's down-regulate our recepto rs a whole lot." If this occurs and, critical to the for the increased neurotransmi theory, more than compensates tter signal, the depressive problem of excessive neurotransmitter signaling goes away: the person feels better. r all." This theory is even Revisionist theory 2, "It really is too little norepinephrine, serotonin, and/or dopamine afte more complicated than the fi rst, and also requires orientation. No t only do dendrites contain receptors for well there are receptors for the als of the "sending" neuron as turns out that on the axon termin neurotransmitters, but it by that neuron. What possible purpos e could these so-cal led autoreceptors very neurotransmitters being released serve? Neurotransmitters are released, float into the synaps tors on the second neuron. e, bind to the standard recep will float back and wind up bindin g to the autoreceptors. They serve as Some neurotransmitter molecules, however, some tors, the first neuron itter reaches the autorecep ; if, say, 5 percent of the released neurotransm sort of feedback signal neurotransmitter it has released. Then it can make some can count its toes, multiply by 20, and figure out how much decisions—should I release more neurotransmitter or stop now? Should I start synthesizing more? and so on. If this process lets the first neuron do its bookkeeping on neurotransmitter expenditures, what happens if the neuron down- amount of neurotransmitter it has released, the neuron will regulates a lot of these autoreceptors? Underestimating the ing the amount it synthesizes and discharges. inadvertently start increas 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

146 Pa g e 146 of 212 With this as background, here's the reasoning behind the s econd theory (that there really is too little norepinephrine, serotonin, or dopamine in a part of the brain of depressives). Give the antidepressant drugs that increase signaling of down-regulation of creased signaling, over the course of these neurotransmitters. Because of the in weeks there will be norepinephrine, serotonin, and dopamine r e idea that the autoreceptors on the first eceptors. Critical to this theory is th econd neuron. If that happens, the second a greater extent than the receptors on the s neuron will down-regulate to releasing sufficient extra neurotransmitter to more than neuron may not be listening as well, but the first one will be nced neurotransmitter signaling, and depressive symptoms abate. (This overcome that. The net result is enha T, or "shock therapy." ectroconvulsive therapy, EC mechanism may explain the efficacy of el For decades psychiatrists have used this technique to alleviate major depressions, and no one has quite known why it works. It turns out that rs, at least in experimental animal among its many effects ECT decreases th e number of norepinephrine autorecepto models.) If you are confused by now, you are in some good company, as the entire field is extremely unsettled. Norepinephrine, it is, for example, too little serotonin signaling, is it serotonin, or dopamine? Too much or too little signaling? If because too little serotoni fect blunting the es, or because there is some de n is being released into synaps sensitivity of serotonin receptors? (To give you a sense of how big a can of worms that one is, there ar e currently recognized more distributions in than a dozen different types of serotonin receptors, with diff ering functions, efficacies, and the brain.) for getting to a depression, and different pathways are Maybe there are a variety of different neurochemical routes associated with different subtypes of depression (unipolar versus manic depression, or one that is triggered by outside events versus one that runs with its own internal clockwork, or one sui-cidalism). This is a dominated by psychomotor retardation versus one dominated by very reasonable idea, but the evidence for it is still scant. Amid all those questions, another good one—why does having too much or too little of these neurotransmitters cause links between these neurotransmitters and fu a depression? There are a lot of nction. For example, serotonin is thought to have something to do with incessant ideation in depression, the uncontrollable wallowing in those dark thoughts. fective on people with obsessive-compuls Connected with this, SSRIs are often ef ive disorder. There is a commonality e, of doom, of despair, while in the latter case, it can be here: in the depressive case, it is the obsessive sense of failur obsessive worries that you left the gas on at home when yo u left, that your hands are dirty and need to be washed, and so on. Trapped in a mind that just circles and circles around the same thoughts or feelings. Norepinephrine is thought to play a different role in the symptoms of depression. The major pathway that utilizes norepinephrine is an array of projections from a brain region called the locus ceruleu s. That projection extends increasing their baseline level alerting other brain regions— diffusely throughout the brain and seems to play a role in of activation, lowering their threshold for responding to outside signals. Thus, a shortage of norepinephrine in this pathway might begin to explain the psychomotor retardation. n that will be reviewed at length in chapter 16. with pleasure, a connectio Dopamine, meanwhile, has something to do ental discovery. They had im Several decades ago, some neuroscientists made a fundam planted electrodes into the brains of rats and stimulated areas here and there, seeing what would happen. By doing so, they found an happy. So how can e rat became unbelievably e brain. Whenever this area was stimulated, th extraordinary area of th rat to tell you, by charting how-many times it is willing to one tell when a rat is unbelievably happy? You ask the press a lever in order to be rewarded with stimulation in that part of the brain. It turns out that rats will work t stimulation. They would rather be stim ulated there than ge themselves to death on that lever to ge t food when they ithdrawal. The region of dicted and going through w drugs even when they're ad are starving, or have sex, or receive the brain targeted in these studies was promptly called the "pleasure pathway" and has been famous since. That humans have a pleasure pathway was discovered shortly afterward by stimulating a similar part of the human brain during eels good. It's kind of neurosurgery.* The results are pretty am azing. Something along the li nes of "Aaaaah, boy, that f like getting your back rubbed but also sort of like sex or playing in the backyard in the leaves when you're a kid and Mom calling you in for hot chocolate and then you get into your pajamas with the feet..." Where can we sign up? as a neurotransmitter (and in chapter 16, we'll see how This pleasure pathway seems to make heavy use of dopamine gnals reward itself). The str ongest evidence for this is the dopamine signals the anticipation of reward more than it si to act as euphoriants. Suddenly, it seems plausible to ability of drugs that mimic dopamine, such as cocaine, hypothesize that depression, which is ch dysphoria, might involve too little dopamine and, aracterized above all by thus, dysfunction of those pleasure pathways. mes to the neurotransmitters implicated in depression, with attention these Thus, these are the big three when it co ressant drugs—the days probably being the most for sero tonin and the least for dopamine. All of the leading antidep such as tricyclics or MAO inhibitors—work by altering the levels of one or more of these SSRIs, and older classes 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

147 Pa g e 147 of 212 three neurotransmitters. At this point, there is nothing close to resembling a science as to which sort of person will respond best to which type of antidepressants. may be involved. One particularly interesting one is called Naturally, there's a spate of other neurotransmitters that in pain perception, with a major role in work have shown that Substance P plays a role Substance P. Decades of activating the spinal cord pathways disc indicate that drugs that ably, some recent studies ussed in chapter 9. Remark as antidepressants in some individuals. What's this about? Perhaps the sense block the action of Substance P can work of depression as a disease of "psychic pain" may be more than just a metaphor. Neuroanatomy and Depression I introduce an illustration here of what the brain looks like, to consider a second way in which brain function might be abnormal in rgery is done on patients who are awake (with their scalps anesth etized, of course). This * Because the brain is not sensitive to pain, a lot of such su to modern imaging techniques, surgeons often had to is helpful, because prior have the patient awake to guide what they were do ing. Place an electrode in the brain, stimulate, the pa the electrode, stimulate, and the patient flops her leg. Quick, tient flops her arm. Go a little deeper with mor. That sort of thing. ch deeper, hang a left past the third neuron, and there's the tu consult your brain road map, figure out where you are, go an in The triune brain. depressives, in addition to the neurochemistry discussed. On e region regulates processes like your breathing and heart ng hormones and instructing the autonomic nervous system. If rate. It includes the hypothalamus, which is busy releasi stress-response, it is the hypothalamus, midbrain, and your blood pressure drops drastically, causing a compensatory hindbrain that kick into gear. All sorts of vertebrates have roughly the same connections here. Layered on top of that is a region called the limbic system, the functioning of which is related to emotion. As relatively tiny limbic systems—they are not noted for the mammals, we have large limbic systems; lizards have complexity of their emotional lives. If you get a stress-resp onse from smelling the odor of a threatening rival, it's your limbic system that is involved. the animal kingdom has some, but it is a real primate specialty. The cortex does Above that is the cortex. Everyone in remembers where your car keys are. The stuff of the previous chapter. abstract cognition, invents philosophy, certain absence of pleasure afterward, gored by an elephant. You may feel a Now think for a second. Suppose you are maybe a sense of grief. Throw in a little psychomotor retardation—you're not as eager for your calisthenics as usual. Sleeping and feeding may be disrupted, glucocorticoid levels may be a bit on the high side. Sex may lose its appeal for a while. Hobbies are not as enticing; you don't jump up to go out with friends; you pass up that all-you-can-eat buffet. Sound like some of the symptoms of a depression? Now, what happens during a depression? You think a thought about your mortality or that of a loved one; you imagine e evaporating, late Beethoven string sts disappearing and endless species of lif children in refugee camps, the rain fore 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

148 Pa g e 148 of 212 quartets, and suddenly you experience so me of the same symptoms as after being gored by the elephant. On an thinks an abstract negative occurring when your cortex incredibly simplistic level, you can think of depression as the brain that this is as real as a physical stressor. In this view, people thought and manages to convince the rest of with chronic depressions are those whose cortex habitually whispers sad thoughts to the rest of the brain. Thus, an and the rest of a depressive's brain, and the onnections between the cortex astonishingly crude prediction: cut the c get the rest of the brain depressed. cortex will no longer be able to Remarkably, it actually works sometimes. Neurosurgeons may perform this procedure on people with vastly crippling depressions that are resistant to drugs, ECT, or other forms of therapy. Afterward, depressive symptoms seem to abate.* e rest of the brain. After ects the entire cortex from th Obviously, this is a simplified picture—no one actually disconn an mope around feeling bad about the final chapter of Of Mice and Men. The surgical all, the cortex does more th actually disconnects just one area toward the front of the procedure, called a cingulotomy, or a cingulum bundle cut, have all the characteristics of a brain rtex (ACC). The ACC is turning out to cortex, called the anterior cingulate co region you'd want to take offline in a major depression. It's a part of the brain that is very concerned with emotions. Show people arrays of pictures: in one case, ask them to pay attention to the emotions being expressed by people in the pictures; in another case, ask them to pay attention to details like whether these are indoor or outdoor photographs. In only the former case do you get activation of the ACC. * What else changes after this surgical procedure? If the cortex can no longer send abstract thoughts to the rest of the brain, the person should not s is a therapy employed only lose the capacity for abstr act misery but for abstract pleasure as well, and this is what happens; bu t surgery such as thi and clutching some state hospital, rocking d decades on the back ward of acitated by their illness, who spen only in patients completely incap attempting suicide with some regularity. themselves and feebly be negative ones. Induce a positive state in someone by And the emotions that the ACC is involved in seem to tabolism decreases. In contrast, if y showing something amusing, and ACC me ou electrically stimulate the ACC in people, they feel a shapeless sense of fear and forebo ding. Moreover, neurons in the ACC, including in humans, ly about the pain; it more concerns feelings about the pain. respond to pain of all sorts. But the ACC response isn't real As was discussed in chapter 9, give someone a hypnotic suggestion that they will not feel the pain of dipping their in projections from the spinal cord get just as active as if hand into ice water. The primary parts of the brain that get pa there were no hypnotic suggestion. But this time, the ACC doesn't activate. In addition, the ACC and adj acent brain regions activate when you show wi dows pictures of their lost loved ones (versus pictures of strangers). As an other example of this, put a volunteer in a brain-imaging machine and, from inside, ask them to play some game with two other people, via a computer console. Rig up the flow of the game so program) gradually begin just play that, over time, the other tw o (actually, a computer ing with each other, excluding e person feels, the more intensely the e ACC lights up, and the more left out th the test subject. Neuronal activity in th ACC activates. How do you know this has something to do with that dread junior high school feeling of being picked control in the study: set th the supposed other two last for the team? Because of a clever the person up to play wi time, though, is The difference, this e other two only play against each other. players. Once again, it winds up that th litch and that their computer console isn't working. Excluded that early on the subject is told there's been a technical g because of a snafu in the techno logy, there's no ACC activation. its resting level of activity tends to be elevated in people Given these functions of the ACC, it is not surprising that with a depression—this is the fear and pain and foreboding churning away at those neurons. Interestingly, another part depressives as well. We will hear lots about the role of of the brain, called the amygdala, seems to be hyperactive in the amygdala in fear and anxiety in th s, the amygdala seems to have been e next chapter. However, in depressive human face and his amygdala doesn't activate all that recruited into a different role. Show a depressed person a fearful much (in contrast to the response you' d see in the amygdala of a control su bject). But show him a sad face and the exaggerated activation. amygdala gets a highly as we saw in chapter 11, is one of the most distinctly Sitting just in front of the ACC is the frontal cortex which, human parts of the brain. Work by Richard Davidson of the University of Wisconsin has shown that one subregion called the prefrontal cortex (PFC) seems highly responsive to mood, and in a late ralized way. Specifically, activation of the left PFC is associated with positive moods, and activ For example, induce a positive state in ation of the right PFC, with negative. someone (by asking him to describe the happiest day of his life), and the left PFC lights up, in proportion to the person's subjective assessment of his pleasure. Ask him to remember a sad event, an d the right PFC dominates. d right PFC metabolism rises while left PFC decreases. Thus, Similarly, separate an infant monkey from its mother an not surprisingly, in depressives, there is decreased le ft PFC activity and elevated activity in the right PFC. the brain in depression, but to make sense of those, we have to consider There are a few other anatomical changes in what hormones have to do with the disease. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

149 Pa g e 149 of 212 Genetics and Depression It is hard to look at the biology of anything these days without genes coming into the picture, and depression is no onent. As a first observation, depression runs in families. For a long time, exception. Depression has a genetic comp for some folks that there is a genetic link, but this conclusion is undone by that would have been sufficient evidence the obvious fact that not only do genes run in families, environment does as well. Growing up in a poor family, an abusive family, a persecuted family, can all increase the risk of depression running through that family without genes having anything to do with it. So we look for a tighter relationship. The more closely related two individuals are, the more genes they share in of the most telling examples e a depressive trait. As one common and, as it turns out, the more likely they are to shar They share something like 50 percent of their genes. If one of this, take any two siblings (who are not identical twins). of them has a history of depression, the other has about a 25 percent likelihood, considerably higher than would be r genes in common. And if one of them is expected by chance. Now, comp are two identical twins, who share all of thei depressive, the other has a 50 percent chance. This is quite impressive—the more genes in common, the more s people share within a family, the likelihood of sharing the disease. But there remains a confound: the more gene rting with the fact that identical twins grow up treated more similarly than more environment they share as well (sta are non-identical twins). Tighten the relationship further. Look at children who were adopted at an early age. Consider those whose biological did not. They have an in creased risk of depression, mother had a history of depression, but whose adoptive mother eir biological mother. But the confound ther suggesting a genetic legacy shared with th e, as we saw in chapter 6, is that ier, with the circulatory envi "environment" does not begin at birth, but begins much earl ronment shared in utero with one's biological mother. For any card-carrying molecular biologist in the twenty-first century, if you want to prove that genes have something e specific genes, the specific st to do with depression, you're going to have to identify th retches of DNA that code for specific proteins that increase the risk for depression. As we'll s ee shortly, precisely that ha s occurred in recent years. Immunology and Depression book. Immunity is about fighting off pathogens, depression is This subsection did not exist in previous editions of this about feeling sad— unrelated subjects. Well, they can be related, but in an idiotically obvious way—like, duh, being sick can be depressing. But it's more complicated than that. Ch ronic illness that i nvolves overactivation of the im mune system (for example, chronic infections, or an autoimmune disease where the immune system has acci dentally activated and is attacking than other equally severe and prolonged illnesses that don't some part of your body) is more likely to cause depression onnection involve th involve the immune system. Some more threads of interc e cytokines that act as messengers to the brain, where they can stimulate om chapter 8, cytokines can also get in between immune cells. As you'll recall fr s becoming clear that they also interact wi CRH release. More recently, it' th norepinephrine, d opamine, and serotonin depression. This is shown in animal models of depression. Furthermore, systems. Critically, cytokines can cause eated with cytokines (to enhance immune certain types of cancers are sometimes tr function), and this typically results in depression. So this represents a new branch of study for biological psychiatry—the interactions between immune function and mood. Endocrinology and Depression Abnormal levels of a number of different hormones often go hand in hand with depression. To begin, people who secrete too little thyroid d, can be atypically resist ant to antidepressant drugs hormone can develop major depressions and, when depresse working. This is particularly important because many pe ople, seemingly with depressions of a purely psychiatric nature, turn out to have thyroid disease. There is another aspect of depression in which hormones may play a role. The incidence of major, unipolar depression Even when you consider mani c depression, where there is differs greatly, with women suffering far more than men. no sex difference in its incidence, bipolar women have more depressive episodes than do bipolar men. first guess, which is that wo men are more likely to see a Why this female bias? It has nothing to do with the obvious an are men. The difference holds up ev en when such reporting biases are health professional for depression th om the school of cognitive therapy, concentrates on the ways in which women and men controlled for. One theory, fr , women are more likely to ruminate over it—think about tend to think differently. When something upsetting happens it or want to talk about it with someone else. And men, terr ible communicators that they so often are, are more likely to want to think about anything but the problem, or even better, go and do something—exercise, use power tools, get 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

150 Pa g e 150 of 212 drunk, start a war. A ruminative tendency, the cognitive psychologists argue, makes you more likely to become depressed. theorizing about the difference is psychosocial in nature. As Another theory about the sex we will see, much psychology of depression suggests that it is a disorder of lack of power and control, and some scientists have onally have less control over the circumstances of their speculated that because women in so many societies traditi greater risk for depression. In support of this idea, some psychiatrists have produced lives than do men, they are at men decline to the levels seen in men in some traditional data suggesting that the elevated rates of depression in wo other theory suggests that men really do have as high a societies in which women don't have a subordinate role. Yet an ly more likely to mask it with substance abuse. rate of depression as do women, but they are simp e, although they run into trouble when one considers that women and men, as noted, All of these ideas are reasonabl have the same rate of bipolar depression; it is only un ipolar depression that is more common among women. These r failure to explain a major feature of female depressions, namely, that women theories seem particularly weak in thei at certain reproductive points: menstruation, menopause, and most of all, the are particularly at risk for depressions chers believe such increased risks are tied to the great weeks immediately after giving birth. A number of resear fluctuations that occur during ones: estrogen and progestero menstruation, menopause, and parturition in two main horm ne. As evidence, they cite trogen or progesterone levels (for the fact that women can get depressed when they artificially change their es mical events in the example, when taking birth-co ntrol pills). Critically, both of these hormon es can regulate neuroche brain, including the metabolism of neurotransmitters such as norepinephrine and serotonin. With massive changes in hormone levels (a thousandfold for progesterone at the time of giving birth, for exampl e), current speculation centers on the possibility that the ratio of estrogen to progesterone can change radically enough to trigger a major depression. is more and more confidence radictory findings, but there This is a new area of research with some seemingly cont among scientists that there is a hormonal contribution to the preponderance of female depressions. Obviously, the next subject in a section on hormones and de pression will have to look at glucocorticoids. But given how central this is to the whole venture of this book, the subject requires expansion. HOW DOES STRESS INTERACT WITH THE BIOLOGY Of DEPRESSION? and the Onset of Depression Stress, Glucocorticoids, The first stress-depression link is an obvious one, in that stress and depression tend to go together. This can run in two directions. First, studies of what is called "stress generatio the fact that people who are n" among depressives look at ressors at a higher than expected rate . This is even s prone to depression tend to experience st een when comparing them to individuals with other psychiatric disorders or health problems. Much of this appears to be stressors built to emerge. This is because if you interpret This raises the potential for a vicious cycle around lack of social support. the ambiguous social interactions around you as signs of re have been rejected, it can jection, and respond as if you increase the chances of winding up social ly isolated, thereby confirming your sense that you have been rejected... But the major way in which people think about a link between stress and depression, and the one that concerns us lly, people who are undergoing a lot of life stressors are direction. Specifica here, has causality running in the other more likely than average to succumb to a major depression, and people sunk in their first major depression are more undergone recent and significant likely than average to have stress. Obviously, not everyone who undergoes major stressors sinks into depression, and what those individual r as we proceed through this chapter. differences are about should be cleare As noted, some people have the grave misfortune of suffering from repeated depressive episodes, ones that can take ing the case histories of those on a rhythmic pattern stretching over years. When consider people, stressors emerge as triggers for only the first few depressions. In other words, have two, three major bouts of depression and, statistically, you are no more at risk for subsequent major depression than anyone else. But somewhere around the fourth depression or so, a mad clockwork takes over, and the depressive waves crash, regardless of whether the outside transition is about will be considered below. world pummels you with stressors. What that Laboratory studies also link stress and the symptoms of depression. Stress a lab rat, and it becomes anhedonic. Specifically, it takes a strong er electrical current th an normal in the rat's pleasure pathways to activate a sense of has been raised, just as in a depressive. pleasure. The threshold for perceiving pleasure 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

151 Pa g e 151 of 212 Critically, glucocorticoids can do the same. A key point in chapter 10 was how glucocorticoids and stress could disrupt memory. Part of the evidence fo th Cushing's syndrome (as a reminder, that is a r that came from people wi condition in which any of a number of different types of tumors wind up causing vast excesses of glucocorticoids in the bloodstream), as well as fr om people prescribed high doses of glucocorticoids to treat a number of ailments. It has ents prescribed synthetic Cushingoid patients and pati that a significant subset of also been known for decades of memory problems. This has been a bit tricky to glucocorticoids become clinically depressed, independent hetic glucocorticoids, the tendency is to get, if anything, demonstrate. First, when someone is initially treated with synt s in. You can immediately guess that we week or so before the depression kick euphoric and even manic, perhaps for a chotomies between short- and long-term stress physiology; chapter 16 will explore in are dealing with one of our di even more detail where that transien lication, does someone with Cushing's t euphoria comes from. As a second comp of synthetic glucocortico syndrome or someone taking high pharmacological doses ids get depressed because u show it is the depressing disease? Yo it because they recognize they have a glucocorticoids cause that state, or is glucocorticoids that are the culprits by demonstrating higher depression rates in this population than among people with, for example, the same disease a nd the same severity but not receiving s also not much of a predictive scien ce to this phenomenon. For example, no glucocorticoids. At this stage, there' clinician can reliably predict beforehand which patient is going to get depressed when put on high-dose glucocorticoids, let alone at what dose, an d whether it is when the dose is raised or lowered to that level. Nonetheless, have lots of glucocorticoids in the bloodstream and the risk of a depression increases. Stress and glucocorticoids tangle up with biology in predisposing a person toward depression in an additional, critical ing a genetic component to depression. Does this mean that if you have "the way. Back to that business about there be e? Obviously not, and the best evidence creek, it's inevitabl gene" (or genes) "for" depression, that's it, you're up the identical twins. One has depression and the ot for this is that factoid about her, sharing all the same genes, has about a general population. There, pretty solid well, a much higher rate than in the 50 percent chance of having the disease as r way. Share every single gene with someone who is evidence for genes being involved. But flip this the othe not having the disease. depressive and you still have a 50 percent chance of e brain, or behavior. They're about Genes are rarely about inevitability, es pecially when it comes to humans, th encies. In this case, genes increase the risk of depression only in certain environments: vulnerability, propensities, tend you guessed it, only in st ressful environments. This is shown in a number of ways, but most dramatically in a recent study by Avshalom Caspi at King's College, London. Scientis ts identified a certain gene in humans that increases the ions"—a few different different "allelic vers fically, it is a gene that comes in a few risk of depression. More speci types or flavors that differ slightly in function; have one of those versions, and you're at increased risk. What that gene as it is a doozy. But the key thing is that having version is I'm not telling yet; I'm saving it for the end of this chapter, X of this gene Z doesn't guarantee you get depression, it just increases your risk. And, in fact, knowing nothing more about someone than which version of gene Z she has doesn't increase your odds of predicting whether she gets en coupled with a history of repeated major stressors. depressed. Version X increases depression risk only wh Amazingly, the same has been shown w ith studies of some nonhuman primate species, who carry a close equivalent of that gene Z. It's not the gene that causes it. It's that environment. More specifically, the gene interacts with a certain a gene that makes you vulnerable in a stressful environment. Glucocorticoid profiles once a depression has been established Not surprisingly, glucocorticoid levels are typically abnormal in people who are clinically depressed. A relatively infrequent subtype of depression, called "atypical depression," is dominated by the psychomotor features of the ical and psychological exhaustion. Just as disease—an incapacitating phys nic fatigue syndrome, is the case with chro al glucocorticoid levels. However, the far more common acterized by lower than norm atypical depression is char feature of depression is one of an overactive stress-response—somewhat of an overly activated sympathetic nervous system and, even more dramatically, elev ated levels of glucocorticoids. This ad ds to the picture that depressed people, get up, are actually vigilant and aroused, with a hormonal sitting on the edge of their beds without the energy to profile to match—but the battle is inside them. s has explored why, on a nuts-and-bolts level, glucocorticoid levels are often Research stretching back some forty year elevated in depression. from the brain (back to The elevated levels appear to be due to too mu ch of a stress signal are commanded to by the ticoids only when they typically secrete glucocor chapter 2—remember that the adrenals brain, via the pituitary), rather than the adrenals just getting some depressive glucocorticoid hiccup all on their own ecretion of glucocorticoids is due to what is called feedback resistance—in now and then. Moreover, the excessive s other words, the brain is less effective than it should be at shutting down glucocorticoid secretion. Normally, the circulating glucocorticoid levels, and if they get higher levels of this hormone are tightly regulated—the brain senses than desired (the "desired" level shifts depending on whether events are calm or stressful), the brain stops secreting nk. In depressives, this feedback regulation fails— CRH. Just like the regulation of water in a toilet bowl ta concentrations of circulating glucocorticoids that should shut down the system fail to do so, as the brain does not sense the feedback signal.* 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

152 Pa g e 152 of 212 * Careful readers will recall a discussion on page 248 of the use organisms have of the dexamethasone suppression test to show that many aged obsessively careful reader will recall that The same test is used here. The truly trouble turning off glucocorticoid secretion. during aging, the resistance"—probably arises from damage to a part of the br problem of shutting off glucocorticoid secretion—the "dexamethasone ain that helps to ong-term we'll see, this might occur in some l Does similar damage occur in depression? As terminate the glucocorticoid stress-response. ticoid levels occur in depressives with no evidence of damage. Most likely sustained depressives. However, the elevated glucocor stress decreases he bloodstream. urons less effective at sensing the hormone in t rs in that part of the brain, making the ne the number of glucocorticoid recepto What are the consequences of elevated glucocorticoid levels before and during a depression? The first most critical question to as ids increase the risk of depression? A k is, how does an excess of glucocortico ion about whether depression is about serotonin or preceding section detailed, at great leng th, the considerable confus well, in that the hormones e, the glucocorticoid angle fits norepinephrine or dopamine. To the extent that this is the cas ransmitter systems—the amount of neurotransmitter synthesized, how fast it is can alter features of all three neurot broken down, how many recepto rs there are for each neurotransmitter, ho w well the receptors work, and so on. Moreover, stress has been shown to cause many of the same changes as well. Sustained stress will deplete dopamine from those "pleasure" pathways, and norepinephrine from that alerting locus ceruleus part of the brain. Moreover, stress alters all sorts of aspects of the synthesis, release, efficacy, and breakdown of serotonin. It is not clear which of it is not clear which neurotrans those stress effects are most im portant, simply because mitter or neurotransmitters are most important. However, it is probably safe to say th at whatever neurochemical abnormalities wind up being shown oids causing those same abnormalities. ere is precedent for stress and glucocortic definitively to underlie depression, th ppear to have some other consequences as well. They may play a role, for Those elevated glucocorticoid levels a example, in the fact that de pressive patients often are at least mildly immunosuppressed, and are more prone to t three- to fourfold, even the risk of heart disease abou osteoporosis. Moreover, prolonged major depression increases after controlling for smoking and alcohol consumption, and the glucocorticoid excess is likely to contribute to that as well. And there may be more consequences. Think back to chapter 10 and its discussion of the many ways in which ture emerged in the 1980s, it immediately suggested that glucocorticoids can damage the hippocampus. As that litera there may be problems with the hippocampus in people with major depression. This speculation was reinforced by the arative memory—is mediated by the fact that the type of memory most often impaired in depression—decl hippocampus. As was discussed in chapter 10, there is atrophy of the hippocampus in long-term depression. The longer the depressive history, the more precedes it), and the lt of the depression (rather than atrophy emerges as a resu atrophy and the more memory problems. While no one has explicitly shown yet that the atrophy occurs only in those depressives with the elevated glucocortico id levels, the atrophy is most common in the subtypes of depression in which the glucocorticoid excess is most common. Chroni c depression has also been ed volume in the frontal cortex. This was initially puzzling for those of us who associated in some studies with decreas orticoid-tinted glasses, but has recently been view the world through glucoc resolved. In the ra t, the hippocampus is y of receptors for the target in the brain for glucocorticoid action, as the overwhelmingly measured by the densit ate brain, the hippocampus and frontal co hormone; however, in the prim rtex seem to be equally and markedly sensitive to glucocorticoids. evidence suggests that the glucocor ticoid excess of depression may have So some pretty decent circumstantial . Chapter 10 noted an array of bad something to do with the decreased vol ume of the hippocampus and frontal cortex things that glucocorticoids could do to neurons. Some obsessively careful studies have shown loss of cells in the confusion, it is those supportive glial frontal cortex accompanying th e volume loss in depression—as one point of cells rather than neurons that are lost. But in the hippocampus, no one has a clue yet; it could be the killing or atrophying of neurons, the inhibition of the birth of new neurons, or all the above.* Whatever the explanation is at the ent; years to decades after these major cellular level, it appears to be perman depressions have been gotten under control (typically with medication), the volume loss is still there. Anti-glucocorticoids as antidepressants The glucocorticoid-depression link has some important implications. When I first introduced that link at the beginning of the chapter, it was ing that the adult brain, particularly the so showed that stress hippocampus, can make new neurons. It al * Chapter 10 detailed the revolutionary find esis. The finding also noted that and glucocorticoids are the strongest inhibitors of such neurogen se new neurons are good it is not clear yet what the for, although it wouldn't be crazy to think that new neurons in the hippocampus might have something good to do for memory. Thu s, it doesn't fore and during depression might contr of neurogenesis in the hippocampus be that an inhibition seem crazy, either, to speculate ibute to the memory d that the inhibition of problems that have been reviewed. This seem s plausible to me. But there is also the a dditional idea floating around in the fiel and that antidepressants neurogenesis gives rise to the emotional symptoms as well (that is to say, the anhedonia and grie f that define a depression), sible studies is. This theory has garnered a lot of attention, and there have been some highly vi work by jump-starting hippocampal neurogenes inks the functions of supporting it. Nonetheless, I don't find those studies or the ba sic idea to be too convincing—I can come up with a route that l the hippocampus to the emotional features of a depression, but it s disease. (You'll note feels way too convoluted to be at the core of what causes thi 't come and stab me.) that I bury this in a footnote, in the hope ect on the other side of this question won that some colleagues whom I like and resp 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

153 Pa g e 153 of 212 meant to give some insight into the flavor of what a depression is like—a person looks like an enervated sea sponge, sitting there motionless on the edge of his bed, but he's actua lly boiling, in the middle of an internal battle. Tacit in actually immensely stressful, that description was the idea that undergoing a depression is among other and, therefore, st the opposite scenario—stress and etion. The data just reviewed sugge things, stimulates glucocorticoid secr ession, rather than merely a consequence. glucocorticoid excess can be a cause of depr vel clinical intervention should work: take one of those depressives with high If that is really the case, then a no glucocorticoid levels, find some drug that works on the adre nals to lower glucocorticoid secretion, and the depression should lessen. And, very exciting, that has been shown. The approach, though, is filled with problems. You don't want to this book, it should ch because, umpteen pages in to suppress glucocorticoid levels too mu be apparent by now that rtant. Moreover, the "adrenal steroidogenesis inhibitors," as those drugs are called, can those hormones are pretty impo ports have shown them to have antidepressant effects in have some nasty side effects. Nonetheless, some solid re people with high-glucocorticoid depressions. id receptors in the brain. These exist to use a drug that blocks glucocortico Another version of the same approach is and are relatively safe, and there's no w decent evidence that they work as we ll.* A relatively obscure hormone called DHEA, which has some ability to block glucocorticoid acce ss to its receptor, has been reported to have some antidepressant qualities as well. Thus, these recent studies not only teach us so mething about the bases of depression, but may open the way for a whole new generation of medications for the disease. Some investigators have built on these observations with a fairly radical suggestion. For those biological psychiatrists concerned with the hormonal aspects of depression, the trad itional glucocorticoid scenario is outlined above. In it, en someone is treated with an the abnormal tidepressants, depressions are stressful and raise glucocorticoid levels; wh neurochemistry (related to serotonin, norepinephrine, etc.) is normalized, lessening the depression and, by the way, making life feel less stressful, with glucocorticoid levels returning to normal as a by-product. The new scenario is the logical extension of the inverted causality also just discussed. In this version, for any of a number of rtion drug." Not * Interestingly, the best glucocorticoid r eceptor out there is a drug already famous— no torious to some—namel y, RU486, the "abo fectively. nother steroid hormone, but it blocks glucocorticoid receptors ef only does it block receptors in the uterus for progesterone, a someone (because the person is under a lot of stress, because something about reasons, glucocorticoid levels rise in the regulatory control of glucocorticoids is awry in that person), causing changes in the chemistry of serotonin (or norepinephrine, etc.) and a depression. In this scenario, antidepressants work by normalizing glucocorticoid levels, try and alleviating the depression. thereby normalizing the brain chemis of the different classes of the primary mechanism of action For this view to be supported, it has to be shown that antidepressants is to work on the gluc levels precede the changes ocorticoid system, and that changes in glucocorticoid evidence that antidep toms. A few researchers have presented in brain chemistry or depressive symp ressants work to rapidly alter numbers of glucocorticoid r eceptors in the brain, altering regulato ry control of the system and lowering toms of depression; other researchers s precede changes in the traditional symp glucocorticoid levels, and these change have not observed this. As usual, more re search is needed. But even if it turns out that, in some patients, depression is driven by elevated glucocorticoid levels (and recovery from depression thus mediated by reduction of those levels), that can't be the general mechanism of the disease in all cases: only about half of depre ssives actually have elevated system seems to work perf glucocorticoid levels. In the other half, the glucocorticoid ectly normally. Perhaps this particular stress/depression link is relevant only during the first few rounds of someone's depression (before the endogenous rhythmicity kicks in), or only in a subset of individuals. We have now seen ways in which stress and glucocorticoids are intertwined with the biology of depression. That intertwining is made even ti g the psychological picture of the disease. ghter when considerin STRESS AND THE PSYCHODYNAMICS OF MAJOR DEPRESSIONS I have to begin with Freud. I know it is obligatory to dump on Freud, and some of it is deserved, but there is much that who, nearly a century after their major contributions, are still he still has to offer. I can think of few other scientists considered important and correct enough for anyone to want to bother pointing out their errors instead of just consigning them to th e library archives. cused on the issue that we began with—why is it that most of us can have Freud was fascinated with depression and fo occasional terrible experiences, feel depressed, and then r ecover, while a few of us coll apse into major depression (melancholia)? In his classic essay "Mourning and Melancholia" (1917), Freud began with what the two have in common. In both cases, he felt, there is the loss of a love object. (In Freudian term s, such an "object" is usually a person, bu t can also be a goal or an ideal.) In ambivalence, mixed feelings—elements of hatred as well as Freud's formulation, in every loving relationship there is depression—mourning—you are able to d eal with those mixed feelings in a love. In the case of a small, reactive 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

154 Pa g e 154 of 212 healthy manner: you lose, you grieve, and then you recover. In the case of a major melancholic depression, you have become obsessed with the ambivalence— ncilable nature of the intense love alongside the the simultaneity, the irreco eorized, is the internal conflict generated by this intense hatred. Melancholia—a major depression—Freud th ambivalence. obsessed with the ession. If you are of grief experienced in a major depr This can begin to explain the intensity intensely mixed feelings, you grieve doubly after a loss—for your loss of the loved individual and for the loss of any difficulties. "If only I had said the things I needed to, if only we could have worked chance now to ever resolve the rge yourself of the ambivalence. For the rest of your life, things out"—for all of time, you have lost the chance to pu pure, unsullied love, and y oor to let you into a place of you will be reaching for the d ou can never reach that door. It also explains the intensity of the guilt often experienced in major depression. If you truly harbored intense anger e aftermath of your loss there must be toward the person along with love, in th some facet of you that is celebrating, alongside the grieving. "He's gone; that's terrible but... thank god, I can finally live, I can finally grow up, no more of ere must come a paralyzing belief that you have become a this or that." Inevitably, a metaphorical instant later, th pleasure at a time like this. Incapacitating guilt. horrible monster to feel any sense of relief or This theory also explains the tendency of major depressives in such circumstances to, oddly, begin to take on some of the traits of the lost loved/hated one—and not just any traits, but invariably the ones that the survivor found most By taking on a trait, you are being loyal to your lost, irritating. Psychodynamically, this is wonderfully logical. beloved opponent. By picking an irritating trait, you are still trying to convince the world you were right to be e what it was like to have to put up with that for years? irritated—you see how you hate it when I do it; can you imagin And by picking a trait that, most of all, you find irritating, you are not only still trying to score points in your argument with the departed, but you are punishing yourself for arguing as well. Out of the Freudian school of thought has come one of the more apt descriptions of depression—"aggression turned inward." Suddenly homotor retardation, the impulse to suicide all make sense. As do the elevated the loss of pleasure, the psyc glucocorticoid levels. This does not describe someone too lethargic to function; it is more like the actual state of a patient in depression, exhausted from the most draining emotional conflict of his or her life—one going on entirely within. If that doesn't count as psychologically stressful, I don't know what does. Like other good parts of Freud, these ideas are empathic and fi t many clinical traits; they just feel "right." But they are ce, especially biologically oriented ps ychiatry. There is no way to study the hard to assimilate into modern scien the effects of on, for example, or nsity and internalization of aggressi correlation between serotonin receptor de estrogen-progesterone ratios on love-hate ratios. The branch of psychological theorizing about depression that seems mes from experimental psychology. Work in this field has most useful to me, and is most tightly linked to stress, co formative model of depression. generated an extraordinarily in STRESS, LEARNED HELPLESSNESS, AND DEPRESSION In order to appreciate the experiment eceding chapter on al studies underlying this model, r ecall that in the pr psychological stress, we saw that certain features dominated as psychologically stressful: a loss of control and of predictability within certain contexts, a loss of outlets for frus tration, a loss of sources of support, a perception of life ychologists Martin Seligman a worsening. In one style of experiment, pioneered by the ps nd Steven Maier, animals are exposed to pathological amounts of these psychological stressors. The result is a condition strikingly similar to a human depression. the general approach in these studies always emphasizes repeated stressors Although the actual stressors may differ, . For example, a rat may be subjected to a long series of ontrol on the part of the animal with a complete absence of c frequent, uncontrollable, and unpredictable shocks or noises, with no outlets. After awhile, something extraordinary happens to that rat. This can be shown with a test. Ta ke a fresh, unstressed rat, and give it something easy to learn. Put it in a room, for example, with the floor divided into two halves. Occasionally, electric ity that will cause a mild shock is delivered to one half, and just beforehand, there is a signal indicating which half of the floor is about to be electrified. Your run-of- readily and calmly shifts the side of the-mill rat can learn this "active avoida nce task" easily, and within a short time it to the signal. Simple. Except for a rat w the room it sits in according posed to repeated ho has recently been ex uncontrollable stressors. That rat cannot l earn the task. It does not rary, it has learned to be learn to cope. On the cont helpless. This phenomenon, called learned helplessness, is quite gene ralized; the animal has troubl e coping with all sorts of Such helplessness extends to tasks having to do with its varied tasks after its exposure to uncontrollable stressors. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

155 Pa g e 155 of 212 ordinary life, like competing with another animal for food, or avoiding social aggression. One might wonder whether the helplessness is induced by the physical stress of receivi e psychological stressor of ng the shocks or, instead, th is the latter. The clearest way to demonstrate this is to having no control over or capacity to predict the shocks. It "yoke" pairs of rats—one gets shocked under conditions marked by predictability and a certain degree of control, the the control or predictability. Only the latter rat becomes other rat gets the identical pattern of shocks, but without helpless. Seligman argues persuasively that animals suffering from learned helplessness share many psychological features ve a motivational problem—one of the r with depressed humans. Such animals ha easons that they are helpless is that ation. This is quite similar to the response when they are in a new situ they often do not even attempt a coping that would improve her life. "I'm too tired, it seems depressed person who doesn't even try the simplest task overwhelming to take on something like that, it's not going to work anyway..." have a cognitive problem, something awry with how they perceive the world Animals with learned helplessness also works or not. For example, and think about it. When they do make the rare coping respons e, they can't tell whether it l rat's response rate increases (in other if you tighten the associatio n between a coping response and a reward, a norma , linking rewards more closely words, if the coping response works for the rat, it persists in that response). In contrast to the rare coping responses of a helpless rat has little effect on its response rate. Seligman believes that this is not a , they have actually learned the task; instead, he thinks consequence of helpless animals somehow missing the rules of not to bother paying attention. By all logic, that rat sh ould have learned, "When I am getting shocked, there is absolutely nothing I can do, and that feels terrible, but it isn't the whole world; it isn't true for everything." Instead, it has learned, "There is nothing I can do. Ever." Even when control and mastery are potentially made available to it, the rat cannot perceive them. This is very similar to the depressed human who always sees glasses half empty. As Beck and other cognitive therap ists have emphasized, much of what constitutes a depression is centered around responding to one awful thing and overgeneralizing from it— cognitively distorting how the world works. The learned helplessness paradigm produces animals with other features strikingly similar to those in humans with he rat stops grooming itself and loses interest in sex and major depressions. There is a rat's equivalent of dysphoria—t food. The rat's failure even to attempt coping responses uivalent of suggests that it experiences an animal eq tilate themselves, biting at themselves. ls of learned helplessness, animals mu psychomotor retardation.* In some mode eep architecture, elevated Many of the vegetative symptoms appear as well—sleep loss and disorganization of sl glucocorticoid levels. Most critically, these animals tend to be depleted of norepinephrine in certain parts of the brain, while antidepressant drugs and ECT speed up their recovery from the learned helplessness state. Learned helplessness has been induced in rodents, cats, dogs , birds, fish, insects, and primates, including humans. It takes surprisingly little in terms of uncontrollable unpleas antness to make humans give up and become helpless in a er escapable or inescapable generalized way. In one study by Donald Hiroto, student volunteers were exposed to eith so that they were exposed to the same amount of noise). loud noises (as in all such studies, the two groups were paired loud noise; the "inescapable" Afterward, they were given a learning task in which a correct response turned off a of learning the task. Helplessness can even be generalized to group was significantly less capable ation. Perhaps the rat about psychomotor retard learned helplessness phenomenon is really just * One might wonder if the entire is so wiped out ft the emphasis away e avoidance coping tasks. This would shi doesn't have the energy to perform activ after the uncontrollable shocks that it simply from learned helplessness as a co gnitive state ("there is nothing I can do about this") or an an hedonic emotional state ("nothi ng feels pleasurable") y object to this ng that I'm just going to sit he to one of psychomotor inhibition ("everything seems so exhausti re"). Seligman and Maier strongl portant, are also interpretation and present data showing that rats with learned helplessne ss are not only as active as control rats but, more im ally ning situations where the coping response impaired in "passive avoidance tasks"— lear involves remaining s till, rather than actu doing help). retardation view is retardation should ere a little psychomotor something (in other words, situations wh Championing the psychomotor another major figure in this field, Jay Weiss, who presents an eq ual amount of data showing that "helpless" rats perform normal ly on passive een going on for ve or emotional one. This debate has b ssness is a motor phenomenon and not a cogniti avoidance tasks, indicating that the helple to resolve the conflicting views. decades and I sure don't know how nonaversive learning situations. Hiroto and Seligman did a follow-up study in which, again, there was either group was less capable of solving simple word puzzles. controllable or uncontrollable noise. Afterward the latter Giving up can also be induced by stressors far more subtle than uncontrollable loud noises. In another study, Hiroto and Seligman gave volunteers a learning ta sk in which they had to pick a card of a certain color according to rules that they had to discern along the way. In one group, these rules were learnable; in the other group, the rules were not (the card color was randomized). Afterward, the latter group was less capable of coping with a simple and easily solved duced helplessness afterward in social demonstrated that unsolvable tasks in task. Seligman and colleagues have also coping situations. Thus humans can be provoked into at leas t transient cases of learned helplessness, and with surprising ease. Naturally, there is tremendous individual variation in how readily this happens—some of us are more vulnerable than others (and you can bet that this is going to be important in considering stress management in the final chapter). In the experiment involving inescapable noise, Hiroto had given the students a personality inventory beforehand. Based on that, he was 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

156 Pa g e 156 of 212 able to identify the students who came in to the experiment with a strongly "int ernalized locus of control"—a belief l in their lives—and, in contrast, the n destiny and had a great deal of contro that they were the masters of their ow e outcomes to chance and luck . In the aftermath of the markedly "externalized" volunteers, who tended to attribut Transferring that to learned helplessness. rnalized students were far more vulnerable uncontrollable stressor, the exte me external stressors, the more to the real world, with the sa locus of control, the less the that someone has an internal likelihood of a depression. as extremely important in forming links among stress, personality, and Collectively, these studies strike me depression. Our lives are repl ete with incidents in which we become irrationally helpless. Some are silly and the zoologist whose hyenas figured in inconsequential. Once in the African cam p that I shared with Laurence Frank, er the campfire. Inspecting the mess, chapter 7, we managed to make a disa ster of preparing macaroni and cheese ov we ruefully admitted that it might have helped if we had bothered to read the instructions on the box. Yet we had both lt a formless dread about trying to ma ke sense of such instructions. Frank avoided doing that; in fact, we both fe summed it up: "Face it. We suffer from learned cooking helplessness." But life is full of more significant exampl es. If a teacher at a critical point of our education, or a loved one at a critical point of our emotional development, frequently exposes us to his or her own specialized uncontrollable stressors, we may grow up with distorted beliefs about what we cannot learn or ways in which we are unlikely to be loved. In one chilling demonstration of this, some psychologists studied inner-city school kids with severe reading problems. Were they the students' resistance to e psychologists circumvented intellectually incapable of reading? Apparently not. Th them Chinese characters. Within hours they were capable learning to read by, instead, teaching of reading more complex symbolic sentences than they could in English. The children had apparently been previously taught all too well that reading English was beyond their ability. A major depression, these findings suggest, can be the outcome of particularly severe lessons in uncontroUability for is may explain an array of findings that those of us who are already vulnerable. Th show that if a child is stressed in certain ways—loss of a parent to death, divorce of parents, being a victim of abusive parenting—the child is more at risk for depression years later. What could be a more severe lesson that awful things can happen that are beyond our control than a lesson at an age when we are first forming our impressions about the nature of the world? As an underpinning of this, Paul Plotsky and Charles Nemeroff of Emory University have shown that rats or monkeys elong increase in CRH levels in their brain. exposed to stressors early in life have a lif "According to our model," writes Seligman, "depression is t pessimism specific to the not generalized pessimism, bu we learn to be helpless—we lack the effects of one's own skilled actions." Su bjected to enough uncontrollable stress, when things are motivation to try to live because we assume the worst; we lack the cognitive clarity to perceive ing lack of pleasure in everything.* actually going fine, and we feel an ach wledge that these are brutal experiments to subject an animal * Before we leave the issue of learned helplessness, let me ackno to. Is there no r's growth, and with see if some drug slows the tumo tri dish—grow a tumor and then t. You can study cancer in a pe alternative? Painfully, I think no ith atherosclerotic plaque formation in a drug removes what other toxicity; you can experiment w dish—grow blood-vessel cells and see if your dosage. But you can't mimic depression in of us are going to cholesterol from their sides, and at what a petri dish, or with a computer. Millions succumb to this nightmarish diso rder, the treatments are still not very good, and an imal models remain the best methods for see king improvement. animal research, while sad, is acceptable, If you are of the school that believes that your goal is to do only good science on the smallest number of animals with the least pain. ATTEMPTING AN INTEGRATION Psychological approaches to depression give us some insight into the nature of the disease. According to one school, it is a state brought about by pathological overexposure to loss of control and outlets for frustration. In another one, it is the internalized battle of turned inward. These psychological view, the Freudian ambivalences, aggression views contrast with the more biological ones—that depression is a disorder of abnormal neurotransmitter levels, n parts of the brain, abnormal hormone ratios, genetic vulnerability. abnormal communication between certai oking at the world, and researchers and There are extremely different ways of lo clinicians from different orientations often don't have a word to say to one another about their mutual interest in depression. Sometimes they seem to be itter autoreceptors, cognitive bivalence versus neurotransm ent languages— psychodynamic am talking radically differ overgeneralization versus allelic variants of genes. ress is the unifying theme that pulls together these disparate What I view as the main point of this chapter is that st threads of biology and psychology. We have now seen some important links between stress an d depression: extremes of ps ychological stress can cause a depression. Moreover, stress is a predisposing factor in something in a laboratory animal that looks pretty close to ypical endocrine changes of depression. In addition, genes human depression as well, and brings about some of the t 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

157 Pa g e 157 of 212 that predispose to depression only do so in a stressful environment. Tightening the link further, glucocorticoids, as a central hormone of the stress-response, an animal, and can cause depression can bring about depression-like states in in humans. And finally, both stress and glucocorticoids can bring about neurochemical changes that have been implicated in depression. With these findings in hand, the pieces begin to fit together. rm of extremes of lack of Stress, particularly in the fo a person. Cognitively, this involves a distortive belief control and outlets, causes an array of deleterious changes in that there is no control or outlets in any circumstance-learned helple ssness. On the affective le vel, there is anhedonia; y disruptions of serotonin, ochemical level, there are likel behaviorally, there is psychomotor retardation. On the neur norepinephrine, and dopamine signaling—as will be shown in chapter 16, prolonged stress can deplete dopamine in the pleasure pathways. Physiologically, there are alterations in, among other things, appetite, sleep patterns, and sensitivity of the this array of changes, collectively, a major depression. glucocorticoid system to feedback regulation. We call our hands. But some critical questions remain to be asked. This is terrific. I believe we have a stress-related disease on One concerns why it is that after three or so bouts of major depression the stress-depression link uncouples. This is the business about depressive episodes taking on an internal rhythm of their own, independent of whether the outside such a transition occur? At present, there's a lot of world is actually pummeling you with stressors. Why should theorizing but very little in the way of actual data. But the most basic question remains, why do only some of us get depressed? An obvious answer is because some of us are exposed to a lot more stressors th an others. And, when factoring in deve lopment, that can be stated in a way to more stressors than others, but if we are exposed to that also includes history—not only are some of us exposed er subsequent stressors are be more vulnerable to whatev some awful stressors early in life, forever after we will static load, of wear and t ear, where exposure to severe stress produces rents of thrown at us. This is the essence of allo vulnerability. fferences in the amount of on can be explained by di So differential incidences of depressi stress, and/or in stress s and the same history of stress, some of us are more vulnerable than others. histories. But even for the same stressor Why should some of us succumb more readily? To begin to make sense of this, we have to invert that question, to state it in a more world-weary way. How is it that getting depressed? All things considered, this can be an awful world, and at times it must avoid any of us manage to seem miraculous that any of us resist despair. that provoke depression. As ring from the effects of stress The answer is that we have built into us a biology of recove we've seen, stress and glucocorticoids can bring about many of the same alterations in neurotransmitter systems that ress depletes norepinephrine. No one is of the best documented links is that st have been implicated in depression. One sure exactly why the depletion occurs, although it probably has something to do with norepinephrine being consumed faster than usual (rather than its being made more slowly than usual). t it simultaneously initiates the gradual synthesis of more Critically, not only does stress deplete norepinephrine, bu norepinephrine. At the same time that norepinephrine content is plummeting, shortly after the onset of stress, the brain is starting to make more of the key enzyme tyrosine hydroxylase, which synthesizes norepinephrine. Both glucocorticoids and, indirectly, the autonomic nervous system play a role in inducing the new tyrosine hydroxylase. The main point is that, in most of us, stress may 're about to see there are si milar mechanisms related to cause depletion of norepinephrine, but only transiently. We changes linked to depression along serotonin. Thus, while everyday stressors bring about some of the neurochemical "blue"—at the same time, we are alr with some of the symptoms—we feel eady building in the mechanisms of recovery. We get over it, we put things behind us, we get things in perspective, we move on with our lives ... we heal and we recover. depressed? There is increasing evidence So, given the same stressors and stress hi stories, why do only some of us get lnerability to depression is that you don't recover from for a reasonable answer, which is that the biology of vu creases your risk " where one version in g of the different versions of "gene Z, stressors very well. Back to that findin for depression, but only when coupled with a history of major stressors. The gene turns out to code for a protein called the serotonin transporter (also known as 5-HTT, derived from breviation for serotonin is the fact that the chemical ab "5-HT"). In other words, the pump that causes the reuptake of serotonin from the synapse. Whose actions are inhibited selective serotonin reuptake inhibitors . Aha. A whole bunch of pieces here by drugs like Prozac, which are SSRIs— HTT gene differ as to how good are teetering on the edge of falling into place. The diff erent allelic versions of the 5- they are at removing serotonin from the synapse. And where does stress fit in? Glucocorticoids help regulate how much 5-HTT is made from the gene. And, critically, glucocorticoids differ in how good they are at doing that, depending on which allelic version of the 5-HTT gene you have. This allows us to come up with a working model of 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

158 Pa g e 158 of 212 depression risk. It is a simplistic one, ood of scads more and a more realistic version must in corporate the likelih ocorticoids/5-HTT story* Nonetheless, d stressors than simply this stress/gluc examples of interactions among genes an maybe what occurs is something like this: a major stressor comes along and produces some of the neurochemical , especially early in life, the changes of depression. The more prior history of stress you have less of a stressor it takes to produce those neurochemical changes. But the same stress signal, namely glucocorticoids, alters norepinephrine synthesis, serotonin * For example, there is probably an equivalent story concerning stress, glucocorticoids, and the genetics of tyrosine hydroxyla se. trafficking, and so on, starting you on the road toward recovery. Unless your genetic makeup means that those recovery steps don't work very well. experience. Take a sufficien tly severe stressor and, as This is the essence of the interaction between biology and cal recovery mechanisms can studies suggest, virtually all of us will fall into desp air. No degree of neurochemi nightmares that life can produ maintain your equilibrium in the face of some of the ce. Conversely, have a life th a genetic predisposition, you may be safe—a car whose brakes are faulty sufficiently free of stress, and even wi presents no danger if it is never driven. But in between those two extremes, it is the interaction between the ambiguous experiences that life throws at us and the biol ogy of our vulnerabilities and resiliencies that determines which of us fall prey to this awful disease. 15 PERSONALITY, TEMPERAMENT, AND THEIR STRESS-RELATED CONSEQUENCES s can modulate stress-responses. Perceive yourself in a The main point of chapter 13 was that psychological factor given situation to have expressive outlets, control, and predictive information, for example, and you are less this chapter explores is the fact that people habitually differ in how they likely to have a stress-response. What modulate their stress-responses with psychological variable s. Your style, your temperament, your personality have ies for control or safety si much to do with whether you regularly perceive opportunit gnals when they are there, whether you consistently interpret am biguous circumstances as implying good news or bad, whether you typically support. Some folks are good at modulating stress in these ways, and others are seek out and take advantage of social egory of what Richard Davidson has called "affective style." And this turns out terrible. These fall within the larger cat to be a very important factor in understanding why some people are more prone toward stress-related diseases than others. We start with a study in contrasts. Co nsider Gary. In the prime of his life, he is, by most estimates, a success. He's done okay for himself materially, and he's never come close to going hungry He's also had more than his share of sexual partners. And he has done extremely well in the hierarchical world that dominates most of his waking hours. he does is compete—he's already Numb He's good at what he does, and what er 2 and breathing down the neck of Number 1, who's grown complacen t and a bit slack. Things are goo d and likely to get better. But you wouldn't call Gary satisfied. In fact, he never really has been. Everything is a battle to him. The mere appearance of a rival and he views every interaction with a potential comp etitor as an in-your-face rockets him into a tensely agitated state, personal provocation. He views virtually every interaction with a distrustful vigilance. Not surprisingly, Gary has no friends to speak of. His subordinates give him a wide, f earful berth because of his tenden cy to take any frustration out knows their daughter Caitland—this is the sort of guy who on them. He behaves the same toward Kathleen, and barely infants. And when he looks at all he's accomplished, all he can think of is that is completely indifferent to the cutest of he is still not Number 1. Gary's profile comes with some physiolo gical correlates. Elevated basal glucocorticoid levels—a constant low-grade wish on your worst stressor for him. An immune system that you wouldn't stress-response because life is one big "good" to "bad" cholesterol, enemy. Elevated resting blood pressure, an unhealthy ratio of and already the early stages a bit, a premature d eath in late middle-age. of serious atherosclerosis. And, looking ahead prime-aged and Number 2 in his world, but he got there through a different Contrast that with Kenneth. He's also route, one reflecting the differ ent approach to life that he's had ever si nce he was a kid. Someone caustic or jaded might dismiss him as merely being a politician, but he's basically a good guy—works well with others, comes to their 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

159 Pa g e 159 of 212 aid, and they in turn to frustrated about anything, and it isn't all his. Consensus builder, team play er, and if he's ever that certain he ever is, he certainly doesn't take it out on those around him. Number 1 spot, but he did something extraordinary—he A few years ago, Kenneth was poised for a move to the walked away from it all. Ti wasn't going to starve, and he had reached the realization mes were good enough that he that there were things in life more important than fighting your way up the hierarchy. So he's spending time with his kids, Sam and Allan, making sure they grow up safe and healthy. He has a best friend in their mother, Barbara, and never gives a thought to what he's turned his back on. Not surprisingly, Kenneth has a physiological profile quite different from Gary's, basically the opposite on every stress-related measure, and enjoys a robust good health. He is destined to live to a ripe old age, surrounded by kids, grandkids, and Barbara. Normally, with these sorts of profiles, you try to protect the privacy of the individuals involved, but I'm going to violate that by including pictures of Gary and Kenneth on the next page. Check them out. Isn't that something? Some baboons are driven sharks, avoid ulcers by giving them, see the world as full of water holes that are half empty. "Gary." "Kenneth" (with infant). And some baboons are the opposite in every way. Talk to any pet owner, and they will give ardent testimonials as to the indelible personality of their parakeet, turtle, or bunny. And they'd usually be at least somewhat right—people ncerned lab rats. Some rats have an aggressive proactive have published papers on animal personality. Some have co it in the bedding. These animals don't w object in their cage and they bury style for dealing with stressors—put a ne have much in the way of a glucocorticoid stress response. e animals who respond to a In contrast, there are reactiv menacing by avoiding it. They have a more marked glucocorticoid stress-response. And then there are studies about 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

160 Pa g e 160 of 212 stress-related personality differences in geese. There's even been a great st udy published about sunfish personalities rongly individualistic, and butterflies). Animals are st (some of whom are shy, and some of whom are outgoing social tonishing differences in their personal ities, temperaments, and coping styles. when it comes to primates, there are as physiological consequences and disease risks related to stress. This is not the These differences carry some distinctive impact on health of how an is, instead, the study of the study of what external stressors have to do with health. This individual perceives, responds to, and copes with those external stressors. The lessons learned from some of these animals can be strikingly relevant to humans. STRESS AND THE SUCCESSFUL PRIMATE lks cope with them better everyday lives and how some fo If you are interested in understanding the stressors in our than others, study a troop of baboons in the Serengeti—big, smart, long-lived, highly social animals who live in groups of from 50 to 1 50. The Serengeti is a great place for them to li lems with predators, ve, offering minimal prob hours a day, fora low infant-mortality rates, easy access to food. Baboons there work perhaps four ging through the ible grasses. This has a critical implication for me, which has made them the fields and trees for fruits, tubers, and ed i during the summers of the past two ay from my laboratory to the Serenget perfect study subjects when I've snuck aw decades. If baboons are spending only fo ur hours a day filling their stomachs, that leaves them with eight hours a day of sunlight to be vile to one another. Social competition, coalitions forming to gang up on other animals, big males in bad moods beating up on someone smaller, snid e gestures behind someone's back—just like us. I am not being facetious. Think about some of the themes of the first chapter—how few of us are getting our ulcers to eat, how few of us become because we have to walk ten miles a day looking for grubs hypertensive because we are about to punch it out with someone over the last gulp from the water hole. We are ecologically buffered and tters. Because the ecosystem of the ly over social and psychological ma privileged enough to be stressed main e same luxury to make each ot her sick with social and Serengeti is so ideal for savanna baboons, they have th psychological stressors. Of course, like ours tion, friendships, relatives who support , theirs is a world filled with affilia ly competitive society as well each other; but it is a vicious . If a baboon in the Serengeti is miserable, it is almost always because another baboon has worked hard and long to bring ab out that state. Individual styles of coping with the social stress appear to be critical . Thus, one of the things I set out to test was whether such styles predicted tailed behavioral data, and differences in stress-related physiology and disease. I watc hed the baboons, collected de then would anesthetize the animals u nder controlled conditions, using a blowgun. Once they were unconscious, I could measure their glucocorticoid levels, their ability to make antibodies, their cholesterol profiles, and so on, under basal conditions and a range of stressed conditions.* * The controls are daunting. You have to find an anesthetic that . You have to dart does not distort the levels of hormones that you are measuring every animal at the same time (continued) give us a sense of how different male baboons can be. Two males of similar The cases of Gary and Kenneth already ranks may differ dramatically as to how readily they form coalitional partnerships with other males, how much they like to groom females, whether they play with kids, whether they sulk after losing a fight or go beat up on someone data to try to formalize analyzed years of behavioral smaller. Two students, Justina Ray and Charles Virgin, and I and personality among these animals. We fo different elements of style und some fascinating correlations between personality styles and physiology. ter of behavioral traits erarchy, we observed a clus Among males who were in the higher-ranking half of the hi associated with low resting gluc of their specific ranks. Some of these traits were related ocorticoid levels independent one another. The first trait was whether a male could tell the difference between a to how males competed with threatening and a neutral inter action with a rival. How does one spot this in a baboon? Look at a particular male and next to him, and makes a threatening two different scenarios. First scenario: along comes his worst rival, sits down gesture. What does our male subject do next? Alternativ e scenario: our guy is sitting there, his worst rival comes along and ... wanders off to the next field to fall asleep. What does our guy do in this situation? ot away, they get agitated, vigilant, Some males can tell the difference between these situations. Threatened from a fo doing. They can tell prepared; when they instead s ee their rival is taking a nap, they keep do ing whatever they were t some males get agitated even when their rival is taking a that one situation is bad news, the other is meaningless. Bu situation that happens five times a day. nap across the field—the sort of If a male baboon can't tell the difference between the two e levels reflect basal, (continued) of day to control for daily fluc tuations in hormone levels. If you want to get a first blood sample in which hormon e who is sick or injured or who has had a nonstressed conditions, you can't dart someon fight or intercourse that day. For some of the cholesterol ls, you can't spend studies, I could not dart anyone who had eaten in the preceding twelve hours. If you are trying to measure resting hormone leve ee it coming. all morning making the same animal nervous as you repeatedly try to dart him; instead you get one shot, and you can't let him s dart. Quite a thing to ls change in response to the le rapidly, before hormone leve Finally, once you dart him, you have to obtain the first blood samp do with your college education. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

161 Pa g e 161 of 212 Why are these studies exclusively about male At any given time in s? Because of the difficulties inherent in trying to dart and anesthetize females. t to dart a female rcent of the adult females are either pregnant or nursing their young. You don't wan this baboon population, approximately 80 pe that the anesthesia will enda nger the pregnancy. And you don't want to dart a female who is pregnant, as there is a good chance who has a tized. of milk while Mom is anesthe nds a day badly endangered for lack youngster holding on to her in a panic as she goes down, or spe of the guy who can tell the are twice as high as those situations, on the average his resting glucocorticoid levels difference—after correcting for rank as a variable. If a rival napping across the field throws a male into turmoil, the ate of stress. No wonder his glucocorticoid levels are elevated. These stressed latter's going to be in a constant st has studied. As you will recall from baboons are similar to the hyperreact ive macaque monkeys that Jay Kaplan spond to every social provocation with an overactivation of their stress- chapter 3, these are individuals who re cardiovascular risk. response (the sympathetic nervous system) and carry the greater Next variable: if the situation really is threatening (the rival's a foot away and making menacing moves), does our male sit there passively and wait for the fight, or does he take control of the situation and strike first? Males who sit orticoid levels than the take -charge types, after rank is there passively, abdicating control, have much higher glucoc ranking as well as high-ranking males. eliminated as a factor in the analys is. We see the same pattern in low- won or lost? Some guys are gr A third variable: after a fight, can the baboon tell whether he eat at it; they win a fight, eat up someone smaller. Other baboons react the same lose a fight, and they b and they groom their best friend. They way regardless of outcome; they can't tell if life is improving or worsening. The baboon who can't tell the difference between winning and losing has much higher glucocorticoid levels, on average, than the guys who can, independent of rank. Final variable: if a male has lost a fight, what does he do next? Does he sulk by himself, groom someone, or beat someone up? Discourag-ingly, it turns out that the males who are most likely to go beat on someone—thus displaying coid levels, again after rank is elimin displaced aggression—have lower glucocorti ated as a variable. This is true for both subordinate baboons and the high-ranking ones. Thus, after factoring out rank, lower basal glucocorticoid levels are found in males who are best at telling the difference between threatening and neutral interactions; who ta ke the initiative if the situation clearly is threatening; who are best at telling whether they won or lost; and, in th e latter case, who are most likely to make someone else pay for the defeat. This echoes some of th e themes from the chapter on psychological stress. The males who were coping social control (initiating the fights), predictability (they best (at least by this endocrine measure) had high degrees of good news), and outlets for frustration can accurately assess whether a situation is threatening, whether an outcome is these individuals' lives, (a tendency to give rather than get ul cers). Remarkably, this style is stable over the years of and carries a ficantly longer big payoff—males with this cluster of low-glucocorticoid tr aits remain high ranking signi than average. Our subsequent studies have shown another set of traits that also predict low basal glucocorticoid levels. These traits Instead, they are related to patterns of social affiliation. have nothing to do with how males compete with one another. Males who spent the most time grooming females not in heat (not of immediate sexual interest—just good old platonic friends), who are groomed by them the most frequently, who spend the most time playing with the young— id guys. Put most basically (and not at y), these are male all anthropomor-phicall these are the low-glucocortico baboons who are most capable of developing friendships. This finding is remarkably similar to those discussed in previous chapters regarding the protectiv e effects of social affili ation against stress-related disease in humans. And as will be discussed in the final chapter of this book, this clus ter of personality traits is also stable over time and comes with a distinctive payoff as well—a male baboon's equivalent of a successful old age. for winding up with elevated basal glucocorticoid Thus, among some male baboons, there are at least two routes competition in perspective an levels, independent of social rank—an inability to keep d social isolation. Stephen tified another personality style that th has studied rhesus monkeys and iden Suomi at the National Institutes of Heal should seem familiar, which carries some About 20 percent of rhesus are what he calls "high- physiological correlates. reactors." Just like the baboons who find a rival napping to be an arousing threat, these individual monkeys see , the response to the perceived threat is a shrinking timidity. Put them into a challenges everywhere. But in their case s would find to be a stimulating place novel environment that other rhesus monkey to explore, and they react with fear, y and withdrawn, and again pouring out glucocorticoids. Place them with new peers, an d they freeze with anxiety—sh releasing vast amounts of glucocorticoids. Separate them fro m a loved one, and they are at ypi-cally likely to collapse ds, overactivation of the symp into a depression, complete with excessive glucocorticoi athetic nervous system, and immunosuppression. These appear to be lifelong styles of dealing with the world, beginning early in infancy. rsonalities arise? When it comes to the baboons, I'll never know. Male From where do these various primate pe baboons change troops at puberty, often moving dozens of miles before finding an adult troop to join. It is virtually impossible to track the same individuals from birth to adulthood, so I have no idea what their childhoods were like, stern, whether they were forced to whether their mothers were permissive or 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

162 Pa g e 162 of 212 take piano lessons, and so on. But Suomi has done eleg ant work that indicates both genetic and environmental s shown that an infant ences. For example, he ha components to these personality differ monkey has a significant chance of sharing a personality trait with its father, despite the formation of social groups in which the father is not contrast, the high-reactivity personality in these monkeys present—a sure hint at a heritable, genetic component. In ly nurturing mothers—a powerful vote g such animals early in life to atypical can be completely prevented by fosterin lt around mothering style. for environmental factors bui Broadly, these various studies suggest two ways that a primat e's personality style might lead down the path to stress- they are conf magnitude of the stressors e's a mismatch between the related disease. In the first way, ther ronted with and the magnitude of their stress-response—the most neutral of circumstances is perceived as a threat, demanding either a hostile, confrontational response (as with some of my baboons and Kaplan's macaques) or an anxious situation that most certainly Suomi's monkeys). At the most withdrawal (as with some of extreme they even react to a ple, winning a fight) the same way as if it were a stressful misery (losing one). does not constitute a stressor (for exam In their second style of dysfunction, th e animal does not take advantage of th e coping responses that might make a stressor more manageable—they don't grab the minimal control available in a tough situation, they don't make use of effective outlets when the going gets tough, and they lack social support. It would seem relatively straightforward to pull together some sound psychotherapeutic advice for these unhappy beasts. But in reality, it's hopeless. Baboons and macaque s get distracted during therapy sessions, habitually pulling of the week and thus consta books off the shelves, for example; they don't know the days ntly miss appointments; they eat the plants in the waiting room, and so on. Thus, it might be more useful to apply those same insights to making an overactive stress-response and incr sense of some humans who are prone toward eased risk of stress-related disease. THE HUMAN REALM: A CAUTIONARY NOTE There are, by now, some fairly impressive and convincing studies linking human personality types with stress-related diseases. Probably the best place to start, t some reported links that, I suspect, however, is with a bit of caution abou should be taken with a grain of salt. I've already noted some skepticism about early psychoanalytic theorizing that linked certain personality types with colitis (see chapter 5). Another example concerns miscarri ages and abortions. Chapter 7 reviewed the mechanisms by which stress can cause the loss of a pregnancy, and one hardly needs to have experienced that personally to have an o miscarry repeatedly, and inkling of the trauma involved. Thus, you can imagine the particular agony for women wh the special state of misery for those wh o never get a medical explanation for the problem—no expert has a clue what's wrong. Into that breach have charge d people who have attempted to uncove r personality traits common to women labeled as "psychogenic aborters." Some researchers have identified one subgroup of women with repeated "psychogenic " abortions (accounting for characterized as emotionally gical development." They are about half the cases) as being "retarded in their psycholo immature women, highly dependent on their husbands, who on some unconscious level view the impending arrival of the child as a threat to their own childlike relationship with their spouse. Another personality type identified, at the are characterized as being assertive and inde opposite extreme, are women who pendent, who really don't want to have o supposed profiles is an unconscious desire not to have the child—either a child. Thus, a common theme in the tw cramp their independent lifestyles. attention or because of reluctance to because of competition for the spouse's Many experts are skeptical about the studies behind these ch aracterizations, however. The fi rst reason harks back to a caveat I aired early in the book: a diag nosis of "psychogenic" anything (impotency, amenorrhea, abortion, and so on) is usually a diagnosis by exclusion. In other words, the ph ysician can't find any disease or organic cause, and until one c bucket. This may mean that, is discovered, the disorder gets tossed into the psychogeni legitimately, it is heavily that the relevant hormone, neurotransmitter, or genetic explained by psychological variables, or it may simply mean abnormality has not yet been discovered. Once it is discover magically transformed into ed, the psychogenic disease is seems to be one that is an organic problem—"Oh, it wasn't your personality after all. " The area of repeated aborting rife with recent biological in sights—in other words, if so many of last decade's psychogenic aborters now have an rrent "psychogenic" skeptical of any cu trend is likely to continue. So be organic explanation for their malady, that label. Another difficulty is that these studies are all retrospectiv examine the personalities of e in design: the researchers women after they have had repeated abortio ns. A study may thus cite the case of a woman who has had three miscarriages in a row, noting that she is emotionally withdrawn and dependent on her ture of the research design husband. But because of the na e traits are a cause of the , one can't tell whether thes miscarriages or a response to them—thr ee successive miscarriages could well ex act a heavy emotional price, perhaps making the subject withdrawn and more dependent on her husband. In order to study the phenomenon properly, one would need to look at personality profiles of women before they become pregnant, to see if these traits predict who is going to have repeated miscarriages. To my knowledge, this kind of study has not yet been carried out. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

163 Pa g e 163 of 212 As a final problem, none of the studies provides any reas onable speculation as to how a particular personality type anisms? What siological mech . What are the mediating phy may lead to a tendency not to carry fetuses to term ed? The absence of any science in that hormones and organ functions are disrupt area makes me pretty suspicious of precedent in the but although there is increase the risk of a miscarriage, the claims. Psychological stressors can with an increased risk for of personality is associated medical literature for thinking that having a certain type miscarriages, scientists are far from being able to agr ee on what personality is associated, let alone whether the equence of the miscarriages. personality is a cause or cons PSYCHIATRIC DISORDERS AND ABNORMAL STRESS-RESPONSES associated with distinctive A number of psychiatric disorders involve personalities, role s, and temperaments that are stress-responses. We have seen an example of this in th e previous chapter on depression— about half of depressives fficiently elevated to cause than in other people, often su have resting glucocorticoid levels that are dramatically higher problems with metabolism or immunity. Or in some cases, depressives are unable to turn off glucocorticoid secretion, their brains being less sensitive to a shut-off signal. A theme in the previous section on some troubled nonhuman pr imates is that there is a discrepancy between the sorts of stressors they are exposed to and the coping responses th ey come up with. Learned helplessness, which we saw to challenge occurs, and what is be an underpinning of depression, appears to be another ex ample of such discrepancy. A the response of a depressive individual? "I can't, it's too much, why bother doing anything, it isn't going to work anyway, nothing I do ever works..." The discrepancy here is that in the face of stressful challenges, depressives don't even attempt to mount a coping response. A different type of discrepancy is seen with people who are anxiety-prone. Anxiety Disorders What is anxiety? A sense of disquiet, of disease, of the sands constantly shifting menacingly beneath your feet— where constant vigilance is the only ho pe of effectively protecting yourself. Anxiety disorders come in a number of flavors. To na me just a few: generalized an xiety disorder is just that— ecific things. In people with panic attacks, the anxiety boils over with a generalized—whereas phobias focus on sp paralyzing, hyperventilating sense of crisis that causes massive activation of the sympathetic nervous system. In self in endless patterns of cal ming, distracting ritual. In obsessive-compulsive disorder, the anxiety buries and busies it post-traumatic stress disord er, the anxiety can be tr aced to a specific trauma. e need to escape from something real. out fear. Fear is the vigilance and th In none of these cases is the anxiety ab Anxiety is about dread and foreboding and your imagination running away with you. Much as with depression, anxiety is rooted in a cognitive distortion. In this case, people prone toward anxiety overestimate risks and the likelihood of a bad outcome. Unlike depressives, the anxiety-prone person is still attempting to mobilize coping responses. But the discrepancy is the distorted belief that stressors are everywhere and perpetual, and that the only hope for safety is constant mobilization of coping responses. Life consists of the concrete, agitated present of solving a problem that someone else might not even consider to exist.* are associated with chro risingly, anxiety disorders Awful. And immensely stressful. Not surp nically overactive stress- responses, and with increased risk of ma ny of the diseases that fill the pages of this book (anxiety-prone rats, for example, have a shortened life span). However, glucocortico id excess is not the usual response. Instead, it's too much dance of circulating catecholamines (epinephrine and norepinephrine). sympathetic activation, an overabun We have now seen some interesting contrasts between glucocorticoids and the catech olamines (epinephrine and norepinephrine). Chapter 2 emphasized how the former defend you against stressors by pes out the space wherein t he symbol is * Emphasizing the concrete nature of anxiet y, the psychoanalyst Anna Ar agno has written, "Anxiety wi born." handing out guns from the gun locker within seconds, in contrast to glucocorticoids, which defend you by constructing new weapons over the course of minutes to hours. Or there can be an elaboratio n of this time course, in which catecholamines mediate the respon orticoids mediate preparation for the se to a current stressor while glucoc ric disorders, it seems that increases in the catecholamines have something to next stressor. When it comes to psychiat es, where overabundance of gluc ocorticoids seems more of a do with still trying to cope and the effort that involv signal of having given up on attempting to cope. You can show this with a lab rat. Rats, being nocturnal creatures, don't like bright li ghts, are made anxious by them. Pu t a rat in a cage whose edges are dark, just the place a rat likes to hunker down. But the rat is really hungry and there's some wonderful food in the middle of the cage, under a bright 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

164 Pa g e 164 of 212 light. Massive anxiety—the rat starts toward the food, pulls b ack, again and again, frantically tries to figure ways to attempt to cope, and this phase is dominated by is anxiety, a disorganized the food that avoid the light. This ed perimeter. And that is , just lies there, in the shad catecholamines. If it goes on for too long, the animal gives up depression, and it is dominated by glucocorticoids. The Biology of Anxiety The main point of this chapter is to explore how different psychiatric disorders and personality styles involve dealing bill. But it is worth looking at the biology of the disease a poorly with stress, and we've just seen how anxiety fits the bit. anxious about that are innate. Bright lights for a rat. Being dangled up in the There are some things that mammals get ng your breathing obstructed for most air if you are a terrestrial creature. Havi any animal. But most things that make they are associated with some trauma , or maybe because we've generalized us anxious are learned. Maybe because th a trauma. Organisms are pr them based on their similarity to something associated wi edisposed to learn some of others—humans and spiders, for example, those associations more readily than or monkeys and snakes. But we can learn to be anxious about utterly novel things—as we speed up to get across a suspension bridge quickly, wondering if the guy in that panel truck is from Al-Qaeda. 10, which concerned the hippocampus and than what we focused on in chapter This is a different type of learning earning, where a certain autonomic respons e in your body has been conditioned. declarative learning. This is implicit l assault, where her brain has become conditioned Thus, consider a woman who has suffered a traumatic ees a similar-looking man. Pavlovian learning—ring the bell associated with to speed up her heart every time she s ate salivary glands; see a certain type food, and the brain has learned to activ of face, and the brain has learned to activate the sympathetic nervous system . The conditioned memory can be elicite d without you even being conscious a fine time, when suddenly the anxiety is there, she's of it. That woman finds herself in a crowded party, having til a few seconds later that she realizes that the man talking gasping, heart racing, and she hasn't a clue why. It is not un consciousness of the similarity. man. The body responds before there is just behind her has an accent just like the As we saw in chapter 10, while mild transient stress enhances declarative learning, prolonged or severe stress disrupts it. But in the case of this pre-consciou s, implicit, autonomic learning, any type of stress enhances it. For example, make a loud sound and a lab rat will have a startle respon se—in a few milliseconds, its muscles tense. Stress the rat beforehand with any type of stressor and the startle response is exaggerated and more likely to become a habitual, conditioned response. Same in us. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

165 Pa g e 165 of 212 As mentioned, this is outside the realm of the hippocampus , that wonderfully rational conduit of declarative memory, of a related structure, the ear conditioning are the province helping us recall someone's birthday. Instead, anxiety and f to look at brain areas that amygdala.* To begin to make sense of its function, you have project to the amygdala, and in turn. One route to the amygdala is from pain pathways. Which brings us back to where the amygdala projects to, The amygdala is about the latter. The there's subjective pain interpretation. chapter 9 and how there's pain and then Remarkably, the amygdala gets sensory information before that information structure also gets sensory information. reaches the cortex and causes conscious heart races before she is even aware awareness of the sensation—the woman's the autonomic nervous syst ts information from of the accent of the man. The amygdala ge em. What's the significance " whether this is a time to of this? Suppose some ambiguous information is filtering in, and your amygdala is "deciding get anxious. If your heart is pounding and your stomach is in your throat, that input will bias the amygdala to vote for cture, the amygdala is immensely se anxiety+ And, to complete the pi nsitive to glucocorticoid signals. The outputs from the amygdala make perfect sense—mostly projections to the hypothalamus and related outposts, tivate the sympathetic nervous system.++ And how does the which initiate the cascade of glucocorticoid release and ac CRH as a neurotransmitter. amygdala communicate?—by using Some of the most convincing work implicating the amygdala in anxiety comes from brain-imaging studies. Put people what parts of the brain are activated in response to each. Show a scary face, in a scanner, flash various pictures, see and the amygdala lights up. Make * The amygdala is also all about aggression. It is hard to unde rstand why organisms are aggressive outside of the context of un derstanding that they are anxious or fearful. + ort that if you can be found in the recent work of Larry Ca An exciting clinical implication of this hill and Roger Pitman of Harvard. They rep ffered a major trauma (with a drug from chapter 3 called a beta- block the sympathetic nervous system in someone who has just su blocker), you ? Decrease the sympathetic signa ss disorder. What's the rationale decrease the odds of the person developing post-traumatic stre l to the amygdala, and the amygdala is less likely to deci de that this is an even t that should provoke w ild arousal forever after. etic nervous athetic nervous system and, as ++ So an aroused amygdala activates the symp we saw in the previous pa ragraph, an aroused sympath system increases the odds of the amygdala activating. Anxiety can feed on itself. the pictures subliminal—flash them for thousandths of a second, too fast to be consciously seen (and too fast to cortex), and the am activate the visual ygdala lights up.* How does the functioning of the amygdala relate to anxiety? People with anxiety disorders have exaggerated startle responses, see menace that others don't. Give people some reading task, where they are flashed a series of nonsense slows down slightly for a menacing word, but people with words and have to quickly detect the real ones. Everyone even more. Commensurate with anxiety disorders slow down these findings, the amygdala in such a person shows the gdala in a control subject, esn't quite activate the amy rt of frightening, that do same hyperreactivity. A picture that is so does so in an anxious person. A frightening picture that is flashed up too briefly to be even noted subliminally in a gdala in someone who is anxious. No control subject does the trick to the amy wonder the sympathetic nervous system going off in the amygdala. then races—alarms are always Why does the amygdala work differently in someone who is anxious? Some am azing research in recent years shows how this might work. As we saw in chapter 10, major stressors and glucocorticoids disrupt hippocampal function— do that long-term potentiation business, a nd the dendritic processes in neurons shrink. the synapses aren't able to Remarkably, stress and glucocorticoids do just the opposite in the amygdala—synapses become more excitable, the amygdala of a neurons grow more of the cables that co nnect the cells to each other. And if you artificially make rat more excitable, the animal shows an anxiety-like disorder afterward. Joseph LeDoux of New York University, who pretty much put the amygdala on the map when it comes to anxiety, has these findings. Suppose a major trauma constructed a remarkable model out of tic stressor occurs, of a sufficient magnitude to disrupt hippocampal function while enhancing amygdaloid function. At some later point, in a similar setting, you have an anxious, autonomic state, agitated and fearful, and yo u haven't a clue why—this is because you ent via your hippocampus while your amygdala-mediated autonomic pathways never consolidated memories of the ev sure as hell remember. This is a version of free-floating anxiety. * Some recent studies that I find truly un the amygdala tends to settling show that if you flas h a picture of a face of someone from a different race, in the meantime, just rt of face is flashed and what sort of person is observing it. But eed to be done looking at what so light up. Endless studies n tions of that finding. think about the implica TYPE A AND THE ROLE OF UPHOLSTERY IN CARDIOVASCULAR PHYSIOLOGY A number of proposed links between personality and cardiovasc ular disease have been repo rted. Amid these, there is one proposed connection between personal so well-known that it has suffered the ity and heart disease that has become ultimate accolade—namely, being distorte 's minds (usually winding up being d beyond recognition in many people 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

166 Pa g e 166 of 212 ascribed to the most irritating behavioral trait that you want to complain about in someone else, or indirectly brag about in yourself). I'm talking being "Type A." in the early 1960s to describe a Two cardiologists, Meyer Friedman an d Ray Rosenman, coined the term Type A they found in some individuals. They didn't descri be these traits in terms related to stress (for collection of traits that utral or ambiguous situations as if they were stressful), example, defining Type-A people as those who responded to ne stead, they characterized Type-A people as immensely although I will attempt to do that reframing below. In competitive, overachiev-ing, time-pressured , impatient, and hostile. People with that profile, they reported, had an increased risk of cardiovascular disease. some 1950s Ozzie-and-Harriet cardiologist and you think This was met with enormous skepticism in the field. You're at the supermarket. Thus, about heart valves and circulating lipids, not about how so meone deals with a slow line the behavior and the disease as the there was an initial tendency among many in the field to view the link between reverse of what Friedman and Rosenman proposed—getting heart disease might make some people act in a more studies that showed that th e Type A-ness preceded the Type-A manner. But Friedman and Rosenman did prospective heart disease. This finding made a splash, and by the 1980s, some of the biggest guns in cardiology convened, luded that being Type A carries at least as much cardiac risk as does smoking or checked the evidence, and conc having high cholesterol levels. rlance. The trouble was, so Everyone was delighted, and "Type A" entered common pa on thereafter some careful studies failed to replicate the basic findings of Friedman and Rosenman. Suddenly, Type A wasn't looking good after t disease, being Type A was at once you had coronary hear all. Then, to add insult to injury, two studies showed th associated with better survival rates (in the notes at the end of the book, I discuss subtle ways to explain this finding). jor modifications. One was the recognition that personality By the late 1980s, the Type-A concept underwent some ma factors are more predictive of heart disease when considering people who get their first of a first heart attack is by later years, the occurrence heart attack at an early age— more about fats and smoking. inced most in the field that the key factor in the list of Moreover, work by Red-ford Williams of Duke University conv the original Type-A studies ientists reanalyzed some of Type A-ish symptoms is the hostility. For example, when sc and broke the constellation of traits into individual ones, hostility popped out as the only significant predictor of heart disease. The same result was found in studies of middle-aged doctors who had taken personality inventory tests twenty-five years earlier as an exercise in medical school. And the same thing was found when looking at American lawyers, Finnish twins, Western Elect ric employees—a range of populations . As another example, there is a can cities and the mortality rates due to cardiovascular correlation between how hostile people are in ten Ameri gh degree of hostility predicts disease.* These various studies have suggested that a hi coronary heart disease, . Many of these studies, atherosclerosis, hemorrhagic stroke, and higher rates of mortality with these diseases s like age, weight, blood pressure, cholesterol levels, and smoking. Thus, it moreover, controlled for important variable eart disease connection could be due to some other factor (for example, that hostile is unlikely that the hostility-h hostility). More recent studies es from the smoking, not the people are more likely to smoke, and the heart disease aris rall increase in mortality across all diseases, not just those have shown that hostility is associated with a significant ove + of the heart. the hostility is a sense of ith an alternative view. They Friedman and colleagues stuck w suggested that at the core of "time-pressured-ness"—"Can you believe that teller, how slowly he's working. I'm going to be here all day. I can't waste my life on some bank line. How did that kid know I was in a rush? I could kill him"—and that the core of being let alone enjoy anything There's no time to savor time-pressured is rampant insecurity. anything you've accomplished, y to hide from the world that anyone else has done, because you mu st rush off to prove yourse lf all over again, and tr for another day what a fraud you are. Their work suggested th at a persistent sense of ins ecurity is, in fact, a better predictor of cardi ovascular profiles * The hostility measures were self-rated in a Gallup poll. What was the rank order of ghest to lowest: the cities in terms of hostility? From hi Philadelphia, New York, Cl eveland, Des Moines, Chicago, Detr oit, Denver, Minneapolis , Seattle, Honolulu. This mostly makes sens e to me, except what's up with Des Moines? + or my health by making me hate him." Perhaps modifying a wonder ful aphorism to "I will le t no man degrade my soul 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

167 Pa g e 167 of 212 Type A's in action. The photo on the left shows the early-morning parking pattern of a patient support group for Type- A individuals with cardiovascular disease taway that doesn't waste a second. everyone positioned for that quick ge — On the right, the same scene later in the day. than is hostility, although theirs appears to be a minority view in the field. as a surrogate variable), it ther as a primary factor or Insofar as hostility has something to do with your heart (whe r example, the study of lawyers suggested that overt remains unclear which aspects of hostility are bad news. Fo re critical—in other words, frequent open expression of the anger you feel aggressiveness and cynical mistrust we pport of that, experimental studies show that the full expression of anger is a powerful predicts heart disease. In su original Type-A data a particularly contrast, in the reanalysis of the stimulant of the cardiovascular system. By s of hostility, but also the tendency not to express it when powerful predictor of heart disease was not only high degree angry. This latter view is supported by some fascinating work by James Gross of Stanford University. Show a gory view of someone's leg sgust, for example (thanks to volunteers a film clip that ev okes some strong emotion. Di and, no surprise, show the physiological markers of having being amputated). They writhe in discomfort and distaste turned on their sympathetic nervous systems. Now, show so me other volunteers the same film clip but, beforehand, instruct them to try not to express their emotions ("so that if someone were watching, they'd have no idea what you were feeling"). Run them through the blood and guts, and, with them gripping the arms of their chairs and trying to c activation becomes even gr remain stoic, and still, the sympatheti eater. Repressing the expression of strong emotions e physiology that go appears to exaggerate the intensity of th es along with them. Why would great hostility (of whatever variant) be bad for your h eart? Some of it is likely to be that roundabout realm of risk factors, in that hostile individuals are more likely to smoke, eat poorly, drink to variables, in that hostile people lack excess. Moreover, there are psychosocial social support because they tend to drive people away. But there ar e direct biological consequen ces to hostility as well. Su bjectively, we can describe hostile persons as those who get all worked up and angry over incidents that the rest of us would find only mildly circumstances that fail to all. Similarly, their stress-res provocative, if provocative at ponses switch into high gear in perturb everyone else's. Give both hostile and non-hostile people a nonsocial stressor (like some math problems) and nothing exciting happens; everyone has roughly the same degree of mild cardiovascu lar activation. But if you e, norepinephrine, and generate a situation with a social pr ovocation, the hostile pe ople dump more epinephrin glucocorticoids into their bloodstreams and wind up with higher blood pressures and a host of other undesirable provocations have been used in studies: the subjects may features of their cardiovascula r systems. All sorts of social be requested to take a test and, during it, be repeatedly interrupted; or they may play a video game in which the other cases, the cardiovascular ing smart aleck. In these and opponent not only is rigged to win but acts like a disparag stress-responses of the non-hostile are relatively mild. But blood pressure goes through the roof in the hostile people. milar these folks are to Jay Kaplan's hy (Isn't it remarkable how si perreactive monkeys, with their exaggerated my baboons, the ones who of cardiovascular disease? Or to sympathetic responses to stressors and their increased risk can't differentiate between th events in their world? Th ere are card-carrying Type-A reatening and nonthreatening individuals out there with tails.) Here is that discrepancy ag ain. For anxious people, life is full of menacing stressors that demand vigilant coping responses. For the Type A, life is full of menacing stressors that demand vigilant coping tive of the rest of their lives. If each day is filled This is probably representa responses of a particularly hostile nature. with cardiovascular provocations that ev eryone else responds to as no big deal , life will slowly ha mmer away at the of cardiovascular disease is no surprise. hearts of the hostile. An increased risk A pleasing thing is that Type A-ness is not forever. If you reduce the hostility component in Type-A people through therapy (using some of the approaches that will be outlined in the final chapter), you reduce the risk for further heart disease. This is great news. I've noticed that many health professionals who treat Type-A people are mostly trying to reform these folks. Basically, many Type -A people are abusive pains in the keister to lots of folks around them. When tone between the lines that Type A-ness (of which many of you talk to some of the Type-A experts, there is an odd them are admittedly pe rfect examples) is a kind of ethical failing, and that the term is a fancied-up medical way of describing people who just aren't nice to others. Added to this is a tendency I've noticed for a lot of the Type-A experts to be lay preachers, or descendants of the field, one an clergy. That religious linkage will even sneak in the back door. I once talked wi th two leaders in 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

168 Pa g e 168 of 212 atheist and the other agnostic, and when they tried to give me a sense of how they try to get through to Type-A subjects about their bad ways, they made use of a religi ous sermon.* I finally asked these two M.D.s an obvious Was the work that they do question—were they in the business of blood vessels or souls? about heart disease or about ethics? And without a beat they both chos for getting at the bigger issues. I e ethics. Heart disease was just a wedge thought this was wonderful. If it takes turning our coronary vessels into our ledgers of sin and reducing circulating to be more decent to each other, more power to them. lipids as an act of redemption in order to get people Interior Decorating as Scientific Method A final question about this field: How was Type-A behavi how scientists make their or discovered? We all know discernment of the di splacement of water), scoveries in the bathtub (Archimedes and his discoveries. There are the di discoveries in one's sleep (Kekule and his dream of carbons dancing in a ring to form benzene), discoveries at the symphony (our scientist, strained by overwork, is forced to the concert by a significant other; during a quiet woodwind section, there's the sud- s youth. His * I listened to a tape of this sermon, calle d "Back in the Box," by the Reverend John Ort-berg. It concerns an incident from hi and skillful Monopoly visits to her were player, and his summer happened to be a viciously competitive grandmother, saintly, kind, nurturant, also ere he practiced like mad, honed his Machiavellian instinct, dev littered with his defeats at the game. He described one year wh eloped a ruthless mopped up the board with her. After which, jugular-gripping style, and finally way. his grandmother rose and calmly put the pieces a the box." Ama "You know," she said offhandedly, "this is a great game, but when it is all over with, the pieces just go back in ss your property, your ually it will all be over lth, your accomplishments, your awards, your what-evers, and event hotels . . . [the sermon takes off from there] . . . your wea ll you are left with is how you lived your life. with and those pieces go back in the box. And a I listened to this tape while racing to beat eady so as not to m er train, Powerbook r red lights on my way to a 5:00 A.M. commut iss a moment of his chapter. And this while driving, using the tim e to listen to this sermon work on the train, eating breakfast one-handed on tape as research for t things I do not subscribe to, reduced me to tears. was filled with Jesus and other ous from the first sentence and sermon, whose trajectory was obvi den realization, the scribbled equation on the program notes, the rushed "Darling, I must leave this instant for the with the rest being history). But every now and Masterpiece Theater]," ond syllable, like in laboratory [accent on sec then someone else makes the discovery and comes and tells the scientist about it. And who is that someone? Very s could be summed up by often someone whose role in the proces will probably never end an imaginary proverb that up embroidered on someone's pot holder: "If you want to know if the elephant at the zoo has a stomachache, don't ask messes become attuned to circumstances that change the the veterinarian, ask the cage cleaner." People who clean up changing the course of medical history. 950s that fact caused a guy to just miss amount of mess there is. Back in the 1 I had the privilege of hearing the story from the horse's mouth, Dr. Meyer Friedman. It was the mid-1950s, Friedman and Rosenman had their successful cardi ology practice, and they were having an unexpected problem. They were spending a fortune having to reup-holster the chairs in their waiting rooms. This is not the sort of issue that would demand a cardiologist's attention. Nonethel ess, there seemed to be no end of chai rs that had to be fixed. One day, a ok at the chairs, and discover new upholsterer came in to see to the problem, took one lo ed the Type A-cardiovascular your patients? People don't wear out chairs this way." It was only the front- disease link. "What the hell is wrong with shreds, as if some very short beavers most few inches of the seat cushion and of the padded armrests that were torn to spent each night in the office craning thei r necks to savage the fronts of the ch airs. The patients in the waiting rooms ay at the armrests. s, fidgeting, clawing aw all habitually sat on the edges of their seat The rest should have been history: up-swelling of music as the upholsterer is seized by the arms and held in a penetrating gaze— "Good heavens, man, do you realize what you've just sa id?" Hurried conferences between the zied sleepless nights as teams of idea ers spread across listic young upholster upholsterer and other cardiologists. Fren the land, carrying the news of their discovery back to Upholstery/Cardiology Headquarters—"Nope, you don't see that or the oncologists, or the podiatrists, just wear pattern in the waiting-room chairs of the urologists, or the neurologists, the cardiologists. There's something diff erent about people who wind up with h eart disease"—and the field of Type-A therapy takes off. Instead, none of that happened. Dr. Friedman sighs. A confession. "I didn't pay any attention to the man. I was too busy; it went in one ear and out the other." It wasn't until four or five years later that 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

169 Pa g e 169 of 212 How it all began . .. almost. Dr. Friedman's formal research with hi s patients began to yield some hints, at which point there was the thunderclap of memory—Oh, my god, the upholsterer, remember that guy going on about the wear pattern? And to this day, no one remembers his name.* r figure to me, passed n into the past tense. Friedman * Since the last edition, it has been necessary to edit this sectio , who was somewhat of a fathe ng toxic clock, and he , had so little time left, yet he had somehow beaten that ticki away recently at age ninety-one. He was a man who, statistically til his last days, he was seeing patients, running an institute at had all the time in the world. But he hadn 't turned into a con-tentless geezer—up un e on the subject. his work, anticipating his next data, arguin g with competitors w UCSF Medical Center, cranky about delays in ith a different tak idea that it might not be fulfilled. And ing its own reward and no rancor at the Full of appetites, but with an appetite be (continued) There have been a host of other studies concerning personalit y, temperament, and stress-rel ated physiology. Scientists have reported differences in stress-related immune function between optimists and pessimists. Others have shown higher glucocorticoid levels in shyer individuals in social settings. Others have considered neurosis as a factor. But let's consider one more subject, one that is particularly interesting because it concerns the last people on earth who you'd think were stressed. WHEN LIFE CONSISTS OF NOTHING BUT SQUEEZING TIGHTLY ith overactive stress-responses, and argued that a common This chapter has discussed personality types associated w what sort of stressors life throws at these folks and what sort of coping theme among them is a discrepancy between a newly recognized version of an overactive stress-response. responses they come up with. This final section is about And it's puzzling. These are not people who are dealing with their stressors too passively, too persistently, too vigilantly, or with too much hostility. They don't appear to have all that many stre ssors. They claim they're not depressed or anxious, and the describe themselves as pretty happy, successful, and psychological tests they are given show th ey're right. In fact, they ising approximately 5 accomplished (and, according to personality tests, they really are). Yet, these people (compr tivated stress-responses. What's their problem? percent of the population) have chronically ac 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

170 Pa g e 170 of 212 Their problem, I think, is one that offers insight into an unexpected vulnerability of our human psyche. The people in question are said to about those Type-A p at the world would be a more decent place if (continued) deeply engaged with the idea th eople— something was done Friedman was one of the two people I described a few paragraphs ba he was in the ck (along with his medical director, Bart Sparagon) who said ad been a driven, g and confessional with this. He was a gentle, courtly man who h business of ethics. Friedman would do some thing very interestin steamrolling son of a bitch before a heart a EO Type-A barracudas with ont of a group of his patients, ruthless C ttack in his fifties. He'd stand up in fr heart, but look at me, I their first heart attacks at age forty-two, and say, "Look at me—n ot look at me, I used to be so Type A that I developed a bad ticed, whose prove it—tales of people he was cu used to be so Type A that I was a bad person," and then he'd rt to, whose efforts he never no s at age ninety, metaphorically the ex-alcoh olic preacher who has been there. Cardiolo gy as accomplishments he envied. And here he wa e world a healthier place or a kinder place. Here was a man who did both. I miss redemption. It would be hard to make a choice between making th him. Clifford Goodenough, Figure Walking in a Landscape, goldleaf tempera, oil on masonite, 1991. y regard these folks with a have "repressive" personalities, and we all have met someone like them. In fact, we usuall tinge of envy—"I wish I had their discipline; everything seems to come so easily to them. How do they do it?" t's i's. They describe themselves as planners who These are the archetypal people who cross all their and dot all their don't like surprises, who li ve structured, rule-bound lives —walking to work the same way each day, always wearing the same style of clothes—the sort of people who can tell you what they're having for lunch two weeks from black and white, filled with ve to set up their world in Wednesday. Not surprisingly, they don't like ambiguity and stri good or bad people, behaviors that are permitted or strictly forbidden. They keep a tight lid on their emotions. Stoic, regimented, hardworking, productive, solid folks who never stand out in a crowd (unless you begin to wonder at the eir extreme conventionality). unconventional nature of th tify repressive individuals. For starters, as noted, the Some personality tests, pioneered by Richard Davidson, iden anxious. Instead, the tests re personality tests show that these people aren't depressed or veal their need for social cial disapproval, and their discomfort with ambiguity, as shown by the extremely high conformity, their dread of so illed with "never" and "always." No gray ts framed as absolutes, statements f rates at which they agree with statemen tones here. Intertwined with those character of emotional expression. The tests reveal how repressive istics is a peculiar lack messy, complicated emotions fo people "inhibit negative affect"—no expressing of those r them, and little recognition of those complications in others. For ex- rs to recall an experience associated with a specific stro ample, ask repressors and non-represso ng emotion. Both groups report that particular emotion with equal intensity. However, when asked what else they were feeling, non- repressors typically report an array of additional, nondominant feelings: "Well, it mostly made me angry, but also a stly report no secondary emotions. Black-and-white feelings, little sad, and a little disgusted too..." Repressors steadfa with little tolerance for subtle blends. Are these people for real? Maybe not. Maybe beneath their tranqu il exteriors, they're actually anxious messes who won't admit to their frailties. Careful study indicates that some repressors are indeed mo stly concerned about keeping swers on personality questionnaires when they that they tend to give less "repressed" an up appearances. (One clue is can be anonymous.) And so their physiological symptoms of stress are easy to explain. We can cross those folks off the list. anxiety, but not even aware ving themselves—roiling with What about the rest of the repressors? Could they be decei of it? Even careful questionnaires cannot ferret it out, psychol ogists traditionally detect that sort of self-deception; to rely on less structured, more open-ended tests (of the "What do you see in this picture?" variety). Those tests show logical stress is also readily explained. anxious than they realize; their physio that, yes, some repressors are far more 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

171 Pa g e 171 of 212 Yet even after you cross the anxious self -deceivers off the list, there remains a gr oup of people with tight, constrained ppy, productive, socially interactive. But they have personalities who are truly just fine: mentally healthy, ha elevated as among highly overactive stress-responses. The levels of glucocorticoids in their bloodstream are as sympathetic tone as well. When expose d to a cognitive challenge, repressors depressed people, and they have elevated t rate, blood pressure, sweating, and muscle tension. And these overaroused show unusually large increases in hear example, repressive individuals have relatively poor immune function. stress-responses exact a price. For Furthermore, coronary disease patients who have repr re vulnerable to cardiac essive personalities are mo complications than are non-repressors. yet the people harboring them are not stressed, depressed, or anxious. Overactive, endangering stress-responses— Back to our envious thought—"I wish 1 had their discipline. How do they do it?" The way they do it, I suspect, is by surprises. And this comes d world with no ambiguity or working like maniacs to generate their structured, represse with a physiological bill. have used electroencephalogr aphic (EEG) techniques to Davidson and Andrew Tomarken of Vanderbilt University show unusually enhanced activity in a portion of the frontal co rtex of repressors. As will be covered at length in the next chapter, this is a region of the brain involved in inhibiting impulsive emotion and cognition (for example, It's the nearest anatomical metabolic activity in this area has been reported to be decr eased in violent sociopaths). equivalent we have to a superego; makes you say you love the appalling dinner, compliment the new hairdo, keeps rk showed with emotional you toilet trained. It keeps those emotions tightly under control, and as Gross's wo repression, it takes a lot of work lly tight squeeze on those emotional sphincters. to keep an especia It can be a frightening world out ther e, and the body may well reflect the effort of threading our way through those dark, menacing forests. How much better it would be to be able to sit, relaxed, on the sun-drenched porch of a villa, far, far from the wild things baying. Yet, what looks like relaxation could well be exhaustion—exhaustion from the labor of having built a wall around that villa, the effort of keeping out that unsettling, challenging, vibrant world. A lesson of repressive personality types and their invisible burdens is that, sometimes, it can be enormously stressful to construct a world without stressors. 16 NKIES, AND PLEASURE JUNKIES, ADRENALINE JU derstand how stress works and how to live healthier lives and make the world Okay, it's great that we're trying to un e we devoted a little space to a really a better place and all that, but it's tim important issue—why can't we tickle ourselves? Before tackling this profound question, we first need to consider why not all people can make you feel ticklish. It probably requires that it be a person that you feel positive about. Thus, you're five and there's no one who can evoke you around the room first. Or you're twelve and it's the ticklish feelings in you like your nutty uncle who chases person in junior high school who's making your stomach feel like it's full of butterflies and making other parts of your body feel all mysterious and weird. It's why most of us probably wouldn't get the giggles if we were tickled by, say, Slobodan Milosovic. Most of us feel fairly positive about ourselves. So why can't we tickle ourselves? Philosophers have ruminated on this one through the ages, and have come up with some speculati ons. But theories ab out self-tickling ar e a dime a dozen. Finally, a scientist has tackled this mystery by doing an experiment. tickle yourself because you rst theorized that you can't Sarah-Jayne Blackmore of the University College of London fi know exactly when and where you're going to be tickled. There's no element of surprise. So she set out to test this by ed to a foam pad where, thanks to various pulleys and inventing a tickling machine. It consists of a lever attach fulcrums run by a computer, when you mo ve the lever with one hand, the foam pad almost instantaneously strokes the palm of the other hand, moving in the same direction as the movement of the lever. antified the whole thing, coming up w Being a hard-nosed scientist, Blackmore qu ith a Tickle Index. Then reinvent the you do, nope. No element of surprise. You can't tickle wheel—if someone else operates the lever, it tickles you; if yourself, even with a tickle machine. Then Blackmore tested her theory by removing the sense of predictability from the self-tickling process. First, remove e lever and, unexpectedly, there's a the sense of predictability about when the tickling occurs—the person moves th 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

172 Pa g e 172 of 212 time lag until the foam pad moves. Anything more than three-tenths of a second delay and it scores as high of a Tickle Index as if someone else had done it. Now, the tickling occurs—the where remove the sense of predictability about xpectedly, the foam pad moves person moves the lever, say, forward and back, and, une in a different direction. it feels as ticklish as if pected the pad to move, and Anything more than a 90-degree deviation from where you ex someone else had done it.* kled doesn't feel ticklish until ther e is an element of surprise. Of Now we've gotten somewhere. Being tic unpredictability. Of lack of control. And suddenly, our beautiful world of tickle science is shattered around us. We the cornerstones of psyc back learning about how spent a whole bunch of time some pages hological stress are built being tickled by the right around a lack of control and predictability. Those were bad things, yet most of us like person.+ lines to see movies that to crumble—we stand in long of our grand edifice begin Hey, wait a second—more pieces surprise and terrify us, we bungee jump and go on roller coasters that most definitely deprive us of a sense of control and predictability. We pay good money * An experiment this elegant and clever and eccentric makes me proud to be a scientist. + ling political correctness. I once read some weir d screed about how no one actually likes being ti A brief digression into tick ckled, that it is all pleasurable but is about power and control on the part of th e tickler, particularly when children are in volved, and how the laughing isn't really , and soon terms like ance and loving of their chains eir acquiescence to their subordin reflexive, and the requesting to be tickled is some sign of th "phallocentric" and "dead white male" and fake ist, one of the f about. As a biolog quotes from Chief Seattle were being bandied irst things you do pecies do this? is is to go for the Phylogenetic Precedent to when confronting a puzzle like th gain insight into a human phenomenon— do other s Because if other, closely related species do the same thing, th at weakens arguments about how th e whole phenomenon is embedded in human e first words they get trained in American Sign Language—one of th imps love to be tickled. All those chimps who culture. I can report here that ch master is "tickle" and one of the first sentences is "tickle me." In college, I worked with one of those chimps. He'd do the "t ickle me" sequence correctly, and you'd tickle him like mad—chimps curl up and cover their ribs and make this fast, soundless, breathy giggle when they're being in his eye and it's, use of how it's all just too much. Then he gets a gleamy look tickled. Stop, he sits up, catches his breath, mops his brow beca "Tickle me," all over again. to be stressed sometimes. And, as long as we're at it, as on the sympathetic nervous we've seen already, we turn at? Chapter 9 oriented orticoids during sex, what's up with th system and secrete ample amounts of glucoc us to the role starting point of this chapter, if you stress. But, as the king us feel less awful during of stress-induced analgesia in ma get the right amount of stress, if you get doesn't just feel less awful; it can feel allostatically challenged just right, it great. and risk-taking to feel so gr eat that they get addicted? So how does that work? And why do some people find stress addictive qualities of various substances of abuse? And how does stress interact with the pleasures and THE NEUROCHEMISTRY OF PLEASURE e brain contains a pleasure pathway that makes heavy use of the neurotransmitter As we saw in chapter 14, th dopamine. As we also saw in that chapter, if that pathway becomes depleted of dopamine, anhedo-nia or dysphoria a region deep in the brain called the ventral tegmentum. can be an outcome. This "dopaminergic" projection begins in nucleus accumbens and then, in rts of other places. These It then projects to something called the turn, goes on to all so include the frontal cortex whic h, as we saw in chapters 10 and 12, plays a key role in executive function, decision e cortex which, as we saw in chapter so projections to the anterior cingulat making, and impulse control. There are al 14, seems to play a role in having a sense of sadness (leading to the idea that the dopaminergic projection normally eavy projection into the amygdala which, as we saw in the last chapter, plays a inhibits the cingulate). There's also a h key role in anxiety and fear. The relationship between dopamine and rst pass, one might predict that the pleasure is subtle and critical. On fi bout reward. For example, take a monke y who has been trained in a task: a neurotransmitter is about pleasure, a sses a lever ten times; this leads, ten seconds later, to a distinctive bell sounds, which means that the monkey now pre desirable food reward. You might initially guess that activation of the dopamine pathway causes neurons in the frontal response to the reward. Some brilliant studies by Wolfram Schultz of the cortex to become their most active in re interesting. Yes, frontal neurons become excited in University in Fribourg in Switzerland showed something mo response to reward. But the biggest response comes earlier, around the time of the bell sounding and the task commencing. This isn't a signal 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

173 Pa g e 173 of 212 Philip Guston, Bad Habits, oil on canvas, 1970. know what that lig y and expectation and confidence. It's "I of, "This feels great." It's about master ht means. I know food. I'm all over this. This is going to be great." The the rules: IF I press the lever, THEN I'm going to get some pleasure is in the anticipation of a reward; from the standpoint of dopamine, the reward is almost an afterthought. the "appetitive" stage, one tion, of working for reward as Psychologists refer to the period of anticipation, of expecta reward the "consummately" stage. What Schultz's findings filled with appetite, and call the stage that commences with ted, pleasure is more about the appetite than about the sating.* show is that if you know your appetite is going to be sa would have made * A college friend, who had a seemingly endless string of disastr ous relationships, summed up this concept with a cynicism that p is the price you pay for the anticipation of it." (It was Shaw who once wrote, "Love is the gross George Bernard Shaw proud: "A relationshi exaggeration of the differences between one person and everybody else.") pleasurable anticipation fuels the work The next key thing to learn is that the dopamine and its associated sense of needed to get that reward. Paul Phillips from the University of North Carolina has used some immensely fancy techniques to measure millisecond bursts of dopamine in rats a nd has showed with the best time resolution to date that cher, he artificially stimul ated dopamine release and, the burst comes just before the behavior. Then, in the clin e dopamine does indeed fuel the behavior. suddenly, the rat would start lever pressing. Th her part of the brain. There's can change, just like in any ot The next critical point is that the strength of these pathways the burst of dopaminergic pleasure once that light comes on, and all that is required is to train for longer and longer -increasing amounts of lever ts of dopamine to fuel ever intervals between light and reward, for those anticipatory burs pressing. This is how gratification postponement works—the co re of goal-directed behavior is expectation. Soon we're forgoing immediate pleasure in order to get good grades in order to get into a good college in order to get a good job in order to get into the nursing home of our choice. a signal, does a task, and then gets . Suppose in one setup, the subject gets Recent work by Schultz adds a twist to this n, there's the signal, the task, and then, rather than a certain a reward. In the second situatio ty of reward, there's simply benevolent context (that is, the outcome is still likely to be a high probability of it. In other words, within a generally there is even greater release of dopamine. Right after the Under those conditions, good), there's an element of surprise. task is completed, dopamine rel ease starts to rise far higher than usual, peaking right around the time that the reward, if it's going to happen, should be arriving. Introduce, "This is going to be great... maybe ... probably ..." and your in anticipation. This is the essence of why, as we learned in Intro Psych, neurons spritz dopamine all over the place ndings show is that if you think there's a reasonably good intermittent reinforcement is so reinforcing. What these fi about the appetite more chance that your appetite is going to be sated, but you're not positive, pleasure becomes even than about the sating. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

174 Pa g e 174 of 212 So dopamine plays an important role in the anticipation of pleasure and in energizing you in order to respond to incentives. However, it can't be the whole story of pleasur For example, rats can still e, reward, and anticipation. when artificially deplet ed of dopamine in those pathways. Opioids probably respond to reward to some extent even play a role in the other pathways involved. Moreover, the dopamine pathway might be most relevant to spiky, intense versions udents (either gender) who are in what g study shows this. Get some college st of anticipation. A recent and fascinatin they believe to be their "one true love" relationship. Put them in a scanner and flash up various familiar but neutral a picture of the student's beloved. faces. Somewhere along the way, flash up For people who were in the first few . For people whose relationship was more on the order of months of the relationship, the dopamine pathways lit up there was activation of the anterior cin-gul years, that's not what happened. Instead, ate, that part of the brain discussed to be about edgy, make-you-crazy- in the chapter on depression. The tegm entum/accumbens dopamine system seems ter, it's the cingulate weighing in, mediating something akin, perhaps, to with-anticipation passion. Two years la comfort and warmth ... or maybe even a nonhyperventilating version of love. STRESS AND REWARD led is the anticipation of being tickled. The element of surp rise and lack of So the really good thing about being tick control. In other words, we're back to where we started—when does a lack of control and predictability fuel dopamine release and a sense of anticip atory pleasure, and when is it the core of what makes psychological stress stressful? The key seems to be whether the uncertainty occurs in a benign or malevolent context. If it's the right person tickling you in that adolescent stage of being on the cusp of sexuality, maybe, just maybe, that tickling is going to be followed good, like hand-holding. In contrast, if it's Slobodan Milosovic who is tickling you, maybe, just really by something maybe, it will be followed up by his trying to ethnically cleanse you. If the context is one of you being at risk for getting shocked, the lack of predictability adds to the stress. If the context is one in which that special someone is likely to eventually say yes, he a fifty-year courtship. Part at's needed to start you off on r running hot and cold is all th of what makes the Las Vegas world of gambling so addictive is the brilliant ways in which people are manipulated into thinking that the environment is a benign, rather than malevolent, one—the belief that the outcome is likely to be ... so long as you keep putting in those coins and you a good one, especially for some one as lucky and special as pressing that lever. What makes for the benign sort of environment in which uncertainty is pleasurable, ra ther than stressful? One key element is how long the experience goes on. Pleasurable lack of control is a ll about transience—it's not for nothing biases toward uncertainty s long. Another thing that tes rather than three week that roller-coaster rides are three minu being pleasurable is if it comes bound wi control and predictability. No matter how real and thin a larger package of at Anthony Perkins is stalking Janet Leigh, not you. No viscer-ally gripping the scary movie may be, you still know th the bungee jumping is, it's still in the context of having matter how wild and scary and unpredictable and exhilarating mping Safety Police. This is the essence of play. a license from the Bungee Ju assured yourself that these folks have You surrender some degree of control—think of how a dog initiates play with another dog by crouching down, making himself smaller, more vulnerable and less in control. But it has to be within a larger context of safety. You don't roll over and expose your throat in play to someone you haven't sniffed over carefully. Time now to introduce some really unexpected neurochemistry that ties this all together. Glucocorticoids, those the scene of the crime for virtually all the stress-related pathology we've hormones which have been discovered at s ... will trigger the release of dopamine from pleasure been learning about, those same villainous glucocorticoid pathways. It's not some generic effect upon all the dopamine pathways in the brain. Just the pleasure pathway. Most rdeaux in France have shown that lab el Le Moal of the University of Bo remarkably, Pier Vincenzo Piazza and Mich coids, will lever-press the exact rats will even work in order to get infused with glucocorti amount needed to maximize the amount of dopamine released by the hormone. And what is the pattern of glucocorticoid exposure that maximized dopamine release? You can probably guess re and prolonged stress, and As we've seen, experience seve already. A moderate rise that doesn't go on for too long. learning, synaptic plasticity, and immune defenses are impa ired. As we saw, experience moderate and transient stress, and memory, synaptic plasticity, and immunity are enhanced. Same thing here. Experience severe and prolonged rned to chapter 14—dopamine depletion, dysphoria, and depression. But with glucocorticoid exposure, and we've retu moderate and transient glucocorticoid elevation you rel activation of the amygdala ease dopamine. And transient releases dopamine as well. Couple th e glucocorticoid rise with the accompan ying activation of the sympathetic nervous system, and you're also enhancing glucose and oxygen delivery to the brain. You feel focused, alert, alive, motivate d, anticipatory. You feel great. We have a name for such transient stress. We call it "stimulation."* ADRENALINE JUNKIES 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

175 Pa g e 175 of 212 What does this tell us about the subset of people who thrive on stress and risk-taking, who are most alive under + circumstances that woul d ulcerate anyone else? y envelope. They spend every last These are the folks who push ever important dinner guests, dollar in Monopoly, have furtive sex in complicated recipe on public places, try out a new, Soldier of Fortune. answer the ad in What's up with them? We can make some pretty informed gues ses. Maybe they release atypically low amounts of dopamine. Or, as another atypically unresponsive to a dopamine receptors that are version of the same problem, maybe they have versions of dopamine signal. In that scenario, it's hard to "just say no" to some thrilling possibility when there's not a whole lot of buse). Supporting this idea are pleasurable yes's in one's life (a point that we'll return to when considering substance a addictive personalities.++ eceptors in people with some reports of atypical versions of dopamine r ng is fine, but those transients of stimulation cause As another possibility, maybe the baseline of dopamine signali whopping great rises of dopamine, bigger anticipatory pleasure signals than in most other people. That would certainly encourage one to try the stuff again. There's yet another possibility. Experience something thrillin g with the right intensity and duration, and dopamine is y. End of experience, dopamine levels go back down to baseline. What if someone's released in the pleasure pathwa brain happens not to be great at keeping up with dopamine reserves in the pleasure pathway? As a result, at een when people are administered ntrol an autoimmune * This explains a pattern, noted in chapter 14, that is often s synthetic glucocorticoids to co euphoric. or inflammatory disease. Eventu ally, people typically feel depressed. But th e first few days, it's the opposite— energized and + What should be obvious is that "epinephrine junkies," more proper would be " transiently and instead of the term "adrenaline junkies" or even moderately increased levels of glucocorticoids junkies." at are addictive across the board in a wide r n research believe that there are personalities th ++ Many in the field of addictio ange of areas—with drugs of abuse, with alcohol, with gambling, with being financ ially or sexually imprudent. Th is is controversial, however. the end of a stimulating increase in dopamine release, dopamine levels not only drop back to baseline, but to a you started. What's the only solution then to smidgen below baseline. In other words, a little lower than where se that's thrilling and, of ipate pleasure? Find something el counteract this mild dysphoria, this mild inability to antic necessity, a bit riskier, in order to achieve the same dopamin e peak of the prior time. Afte rward, your baseline drops a bigger, in the s other stimulant, each one having to be bit lower. Necessitating another, and an earch for the giddy heights of dopamine that you reached that first time. This is the essence of the downward ratcheting of addiction. sixteen-year-old Evel Knievel, Once, a long time ago, the behind the steering wheel with his brand-new driver's permit, sped up to beat a red light, and got a bit of a buzz from this. He then discovered, the next time doing it, that it didn't feel quite as exciting. ADDICTION nces that different cultur es have come up with that can cause you to be There's an astonishing number of substa field of addiction research ruinously addicted, to compulsively take the substance desp ite negative consequences. The has long had to grapple with the sheer variety of these compounds, from the standpoint of understanding their effects on brain chemistry. Alcohol is very different from tobacco or cocaine. Let alone trying to make sense of how things like gambling or shopping wind up being addictive. Amid this variety, though, there's a cr itical commonality, which is that th ese compounds all cause the release of eus accumbens pathway. Not all to the same extent. Cocaine, which directly dopamine in the ventral tegmentum-nucl causes the release of dopamine from those neurons, is extremely good at doing it. Other drugs which do so through lcohol, for example. But they all do to intervening steps are much less potent—a at least some extent, and in brain- imaging studies of humans taking addictive drugs, the more subjectively pleasurable a person finds a particular exposure to a drug to have been, the more activation of that pathway. This certainly makes sense and defines an e it will be and thus come back for more. addictive substance—you anticipate how pleasurabl But addictive substances are not only addictive, but also typically have th e property of causing tolerance, or habituation. In other words, 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

176 Pa g e 176 of 212 Toland Grinnell, Rodent Addiction System (White), detail, mixed media, 2003. you need increasing amounts of the stuff to get the same anticipatory oomph as before. The explanation lies, in part, with the magnitude of dopamine released by these compounds. Consider some of the sources of pleasure we have— promotion at work, beautiful sunset, great sex, getting a park ing spot where there's still time on the meter. They all release dopamine for most people. Same thing for a rat. Food for a hungry rat, sex for a horny one, and dopamine ve the rat some cocaine a nd there is a THOUSAND-FOLD levels rise 50 to 100 percent in this pathway. But gi increase in dopamine release. this tidal wave of dopamine? We consid ered a related version in chapter 14. What's the neurochemical consequence of If someone always yells at you, you stop listening. If you flood a synapse with a gazillion times more of a the recipient neuron has to compensate neurotransmitter than is usually the case, by becoming less sensitive. No one is sure what the mechanism is fo r what's termed an "opponent ybe fewer of whatever the process" that counteracts the dopamine blast. Maybe fewer dopamine receptors, ma rdless of the mechanism, the next dopamine receptors connect to. But rega time, it is going to take even more addictive cycle of escalating drug use. pact on that neuron. This is the dopamine release to have the same im addiction. Early on, addiction is about "wanting" the drug, Around this point, there is a transition in the process of anticipating its effects, and about how high those dopamine levels are when they're pouring out in a drug-induced state (in addition, the release of endogenous opiates around th is time fuels that sense of "wanting"). It's about the motivation to get the reward of a drug. With time there's the transition to "needing" the drug, which is about how low addiction is when it is no longer the issue of how good the dopamine lows are without the drug. The stranglehold of eels. It's about the motivation to avoid the punishment of not having the drug. the drug feels, but how bad its absence f when rats are deprived of a drug they are addicted to, George Koob of the Scripps Research Institute has shown that CRH in the brain, particularly in pathwa ys mediating fear and anxiety, such as there is a tenfold increase in levels of in the amygdala. No wonder you feel so awful. Brain-imaging studies of drug us ers at that stage sh ow that viewing a film of actors pretending to use drugs activates dopamine pathways in the brain more than does watching porn films. forcement that we discussed earlier. You're ntext of the uncertainty and intermittent rein This process emerges in the co pretty sure you've scraped together enough money, you're pretty sure you can find a dealer, you're pretty sure you but still, there's that element of uncertainty amid the won't get caught, you're pretty sure it will be good stuff— anticipation, and that stokes the addictiveness like crazy. So this tells us something about the acquisition of addiction, the downward spiral of tolerance to the drug, and the ocesses can occur. There's a last basic psychological contexts in which those pr feature of addiction that needs to be discussed. Consider the rare individual who has beaten his addiction, left his demons behind, rebooted and started a 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

177 Pa g e 177 of 212 new life. It's been months, years, even decades since he's gone near the dr ug. But uncontrollable circumstances put rner, in that same music studio, back back when—back on that same street co him back where he always used the drug the bar in the country club—and the cr aving comes roaring back like it was in the same overstuffed armchair near yesterday. The capacity to induce that cr time; as many drug abusers in that aving doesn't necessarily decline with situation will say, it is as if they had never stopped using. ndent relapse—the itch is stronger in so me places than others, specifically in This is the phenomenon of context-depe places that you associate a lab rat. Get them addicted ow the identical phenomenon in with prior drug use. You can sh fused with the stuff. Stick them in a novel to some substance, where they are willing to lever-press like mad to get in them. But put them back in cage with a lever and you may get some lever pressing out of the cage that they associate And, as with humans, the potential for relapse doesn't with the drug exposure, and they lever-press like mad. necessarily decrease over time. This process of associating drug use with a particular se tting is a type of learning, an d a lot of current addiction research explores the neurobiology of such learning. This work focuses not so much on those dopamine neurons, but on the neurons that project to them. Many of them come from cortical and hippocampal regions that carry information about setting. If you repeatedly use a drug in the same setting, those projections onto those dopamine neurons are the same ways as the hippocampal synapses repeatedly activated and eventu ally become potentiated, strengthened, in we learned about in chapter 10. When those projections get strong enough, if you return to that setting, the dopamine situation, you don't even need to place rely by the context. In a lab rat in this anticipation of the drug gets triggered me Just electrically stimulate those path the animal back into the same setting. ways that project onto the dopamine really no such thing as an cliches of addiction, there's ug craving. As goes one of the neurons, and you reinstate the dr ex-addict—it is simply an addict who is not in the context that triggers use. STRESS AND SUBSTANCE ABUSE We are finally in a position to consider the interactions between stress and drug abuse. We begin by considering what taking any of various psychostimulant drugs does to the stress-response. And everyone knows the answer to that one—"I'm not feeling any pain." Drugs of abuse make you feel less stressed. ecent for this, given a few provisos. Peopl e do generally report themselves as In general, the evidence is pretty d feeling less stressed, less anxious, if a st ressor occurs after some psychoactive drug 's effects have kicked in. Alcohol is sintegrates anxiety. You can best known for this, and is formally termed an anxiolytic, a drug that "lyses," or di put into a brightly lit cage. rats hug the dark corners when show this with a lab rat. As discussed in the last chapter, Put a hungry rat in a cage with some food in the brightly lit center, and how long does it take to overcome its anxious conflict and go for the food? Alcoho do many other addictive compounds. l decreases the time to do this, as orticoid levels when they are first taken. But with How does this work? Many drugs, including alcohol, raise glucoc s of the stress-response. Alc more sustained use, various drugs can blunt the nuts and bolt ohol, for example, has been arousal and to dampen CRH-mediated e extent of sympathetic nervous system reported in some cases to decrease th sal of the stressor. What does that jargon mean? Basically, anxiety. In addition, drugs may change the cognitive apprai state that you can barely remember what species you are, you may not pick up on if you're in such a mess of an altered the subtle fact that someth ing stressful has occurred. wnside of the anxiety-reducing consequences of getting wasted. As the blood Intrinsic in that explanation is the do levels of the drug drop, as the effect s wear off, the cognition a nd reality sneak back in an d, if anything, the drugs become just the opposite, become anxiety-generating. The dyna mics of many of these drugs in the body is such that the amount of time that blood levels are rising, with their stress-reducing effects, is sh orter than the amount of time that they are dropping. So what's the solution? Drink, ingest, inhale, shoot up, snort all over again. to blunting the machinery of the stress- So various psychostimulants can decrease stress-responses, secondary response, plus making you such a disoriented mess that you don't even notice that there's been a stressor. How about the flip side of this relationship: What does stress have to do with the likelihood of taking (and abusing) drugs? The relapse, although it's not clear punch line is that stress pushes you toward more dr ug use and a greater chance of completely clear how stress does this. initially becoming addicted. Set up a rat in a situation where if it presses a lever The first issue is the effect of stress on X number of times, it gets infused with some potentially addictive drug—alcohol, amphetamines, cocaine. Remarkably, only some rats get into this "self-administration" paradigm enough to get addicted (and we'll see shortly which rats are more likely). If you stress a rat just before the start of this session of drug exposure, it is now more as you'd expect from chapter 13, unpredictable stress drives likely to self-administer to the point of addiction. And just a rat toward addiction more 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

178 Pa g e 178 of 212 effectively than does predicta ble stress. Similarly, put a rat or a monkey in a position of being socially subordinate, cohol consumption in humans as well. no surprise, stress clearly increases al and the same increased risk occurs. And, e potential of a drug only if the stressor comes right before the drug exposure. Importantly, stress increases the addictiv In other words, short-term stress. The type that boosts dop es stress have this effect? amine levels transiently. Why do Imagine that you go into a bout of exposure to a novel, potentially addictive drug, and you just happen to be the type of rat or human for whom the drug doesn't do a whole lot—you're not releasing much dopamine or the other neurotransmitters involved, you're not getting this anticipator y sense afterward of wanting to do it again. But couple that same ho-hum dopamine rise with a rise due to stress and, whoa, you erroneously decide that something cosmic te stress increases the reinforcing potential of a drug. has just happened—where can you get some more? Thus, acu licated. Stress increases the li All that makes sense. But, naturally, things get more comp kelihood of self-administering even as a fetus. Stress a a drug to an addictive extent, but this time we're talking about stress during childhood. Or pregnant rat and her offspring will have an increased propens ity for drug self-administration as adults. Give a rat an experimentally induced birth complication by briefly depriving it of oxygen at birth, and you produce the same. Ditto nkey from its mother during onhuman primates—separate a mo if stressing a rat in its infancy. The same works in n development, and that animal is more likely to self-adminis ter drugs as an adult. The same has been shown in humans. In these instances, the stressor during development can't be working merely by causing a transient rise in dopamine release. Something long term has to be occurring. We're back in chapter 6 and perinatal experiences causing lifelong "programming" of the brain and body. It's not clear how this works in terms of addictive substances, other than that there obviously has to be a permanent change in the sensitivity of the reward pathways. What about once the addiction has occurre d—what does ongoing stress do to the extent of abuse? No surprise, it levels and giving increases it. How does this work? Mayb e because of transient stressors briefl y boosting dopamine the drug more oomph. But by now, the main point for the addict may not be about wanting the high as much as needing to avoid the low of drug withdrawal. As noted, during this time, levels of anxiety-mediating CRH are way up in the amygdala. Moreover, glucocorticoid secretion is consistently elevated during withdrawal, into the range wher e it depletes dopamine. And what happens if you add additional stress on top of that? in this scenario is make the dopamine depletion even worse. Thus increasing All that the extra glucocorticoids can do the craving for that drug-induced boost of dopamine. ed to and successfully goes g whatever drug she's addict What about that rare individual who manages to stop abusin on the wagon? Stress increases the odds of her relapsing into drug use. As usual, the same is true in rats. Get a rat who is self-administering a drug by lever pressing to the point of addiction. Now, switch the rat to being infused with saline instead of with the drug. Soon the lever pressing "extinguishes"—the rat gives up on it, won't bother with the lever anymore. Some time later, return the rat to that cag e with the drug-associated le ver and there's an increased ain. Infuse the rat with a bit of the drug just before likelihood that the rat will try lever pressing for the drug ag it's even more likely to start self-adm returning it to that familiar locale and inistering again—you' ve reawakened the rn it to the cage, it's even more likely to restart the drug taste for that drug. If you stress the rat right before you retu e drug use. And, as usual, use. As usual, unpredictable and uncontrollable stressors are th e ones that really revive th the human studies show basically the same thing. How does stress do this? It's not entirely clear. The effects of glucocorticoids on dopamine release may be relevant, the stress-induced increase in sympathetic del built around their interaction. Maybe it's but I have not seen a clear mo arousal, mediated by CRH in the am ygdala. There's also some evidence su will increase the ggesting that stress strength of those associative projections into the pleasure pathway. Perhaps it has something to do with stress impairing the functioning of the frontal cortex, which normally has that sensible, restraining role of gratification postponement and decision making— shut down your frontal cortex and suddenly you have what seems like an know, why don't I start taking that drug again which nearly destroyed my life." irresistibly clever idea: "I So stress can increase the odds of abusin the first place, make withdrawal harder, g a drug to the point of addiction in le than others? Immensely and make relapse more likely. Why do all the above happen more readily to some peop azza and Le Moal has started to answer this. interesting work by Pi the individuals who are more prone toward putting on fat Remember those apples and pears in chapter 5? Who are healthy version of fat deposition? We saw that they are likely to be people around their gut, becoming apples, the less with more of a tendency to secrete glucocorticoids in response to stressors, and to have a slow ss-response. Same thing here. er recovery from such a stre Which rats are most likely to self-administer when given a chance and, once self-administering, to do so to the point of escalating addiction? The ones who orally disrupted by being placed in a are "high reactors," who are most behavi onger than the other rats in response novel environment, who are more reactive to stress. They secr ete glucocorticoids l e first exposed to the drug. So if you're the kind of more dopamine when they ar to a stressor, causing them to pour out 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

179 Pa g e 179 of 212 rat who is particularly thrown out of kilter by stress, you're atypically likely to try something that temporarily promises to make things right. THE REALM OF SYNTHETIC PLEASURE at positive and negative affect are not Chapter 13 raised the important point th mere opposites of each other, and that they can independently influence one's risk of depression. Addiction maps onto this point well, in that an addiction can broadly serve two dissociable functions. One involves positive affect—drugs can generate pleasure (albeit with an ultimate cost that offsets the transient rewards). The other function concerns negative affect—drugs can be used to try ear, anxiety, and stress. This dual purp ose transitions us to the next chapter to self-medicate away pain, depression, f with its theme that society do es not evenly distribute healthy opportunities fo r pleasure, or sources of fear and anxiety. It is hard to "just say no" when life demands a constant vigilance and when there are few other things to which to say "yes." come up with some pretty we westernized humans, have The premise of this book is that we humans, especially strange sources of negative emotions—worrying about and being saddened by purely psychological events that are sternized humans have also come up with displaced over space and time. But we we some strange sources of positive emotions. ami of sound getting gooseflesh, I was Once, during a concert of cathedral orga n music, as I sat there amid that tsun for a medieval peasant, this must have been the loudest human-made sound struck with a thought—way back when, can no longer im at would be awe-inspiring in ways we they would ever experience, something th agine. No wonder they signed up for the religion being proffered. And now Leroy Almon, Mr. and Mrs. Satan Fishing, 1994. rers might chance we are constantly pummeled with sou nds that dwarf quaint cathedral organs . Once, hunter-gathe upon a gold mine— honey from a wild bee hive—and thus would briefly satisfy one of our most hard-wired food eted commercial cravings. Now we have hundreds of car efully engineered, designed, and mark foods filled with rapidly absorbed processed sugars that cause a burst of sensation that can't be matched by some lowly natural food. Once, we had lives that, amid considerable privation and negatives, also offered a huge array of subtle and often hard- won pleasures. And now we have drugs that cause spasms of pleasure and dopamine a thousand-fold higher than anything stimulated in our drug-free world. Peter Sterling, of allostasis fame, has written brilliantly about how our sources of pleasure have become so narrowed and artificially strong. His thinking cent ers around the fact that ou r anticipatory pleasure pa thway is stimulated by many different things. For this to work, the pathway must rapidly habituate, must desensitize to any given source that has stimulated it, so that it is prepared to respond to the next stimulant. But unnaturally strong explosions of synthetic e unnaturally strong degrees of hab ituation. This has two consequences. experience and sensation and pleasure evok autumn, or by the As the first, soon we hardly notice an ymore the fleeting whispers of pleasure cau sed by leaves in lingering glance of the right person, or by the promise of reward that will come after a long, difficult, and worthy task. The other consequence is that, afte tificial deluges of intensity and moment r awhile, we even habituate to those ar -ness. If we were nothing but machines of local homeosta tic regulation, as we consume more, we would desire less. But instead, our tragedy is that we just become hungrier. More and faster and stronger. "Now" isn't as good as it used to be, and won't suffice tomorrow. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

180 Pa g e 180 of 212 17 THE VIEW FROM THE BOTTOM in which stress can make you sick, I voiced a caveat— when I discuss a way Toward the end of the first chapter, you more likely to get diseases that make you sick. that is merely shorthand for discussing how stress can make ss at a reconciliation between That was basically a first pa ream medical crowd that is e extreme, you have the mainst two very different camps that think about poor health. At on concerned with reductive biology. For them, poor health revolves around issues of bacteria, viruses, genetic eme are the folks anchored mutations, and so on. At the other extr in mind-body issues, for whom poor health is about of its goals, tried to develop lot of this book has, as one ontrol and efficacy, and so on. A psychological stress, lack of c further links between those two viewpoints. This has come in the form of showing how sensitive reductive biology factors, and exploring the mechanisms that account for this. And it has come in can be to some of those psychological the form of criticizing the extremes of both camps: on the on e hand, trying to make clear how limiting it is to believe to indicate the damaging idiocy of DNA sequence, and on the other, trying that humans can ever be reduced to a denying the realities of human physiology and disease. The ideal resolution harks back to the wisdom of Herbert Weiner, as discussed in chapter 8, that disease, even th e most reductive of diseases, cannot be appreciated without considering the person who is ill. Terrific; we're finally getting somewhere. But this analysis, and most pages of this book up until now, have left out a third leg in this stool—the idea that poor health also has something to do with poor jobs in a shrinking economy, or a diet funded by food stamps with too a crummy overcrowded apartm many meals consisting of Coke and Cheetos, or living in ent close to a toxic waste dump or without enough heat in winter. Let alone living on the streets or in a refugee camp or a war zone. If we can't person who is ill, we also can't consid consider disease outside the context of the er it outside the context of the society in which that person has gotten ill, an d that person's place in that society. ections between I recently found support fo r this view in an unexpected corner. Neuroanatomy is the st udy of the conn form of stamp collecting— s system, and it can sometime different areas of the nervou s seem like a mind-numbing some multisyllabically named part of the brain sends its axons in a projection with another multisyllabic name to eighteen multisyllabic target sites, whereas in the next county over in the brain... During a period of my errant youth I took particular pleasure in knowing as much neuroanatomy as possible, the more obscu re, the better. One of my favorite names was that given to a tiny space that exists between two layers of the meninges, the tough fibrous s called the "Virchow-Robin space," and my ability to toss off that name won wrapping found around the brain. It wa me the esteem of my fellow neuroanatomy dorks. I never figured out who Robin was, but Virchow was Rudolph Virchow, a nineteenth-cen tury German pathologist and anatomist. Man, to be honored by having your name attached een the king of reductive n wrap—this guy must have b to some microscopic space between two layers of Saran brai re a monocle, which he'd remove before peering down a nuts-and-bolts science to merit that. I'd bet he even wo microscope. And then I found out a bit about Rudolph Virchow. As a young physician, he came of age with two shattering nd and the doomed European ttempted to combat firstha events—a massive typhus outbreak in 1847 that he a revolutions of 1848. Th e first was the perfect case for teaching that di about appalling living sease can be as much ught just how effectively the machinery of power can conditions as it is about microorganisms. The second ta ath, he emerged not just as someone who was a scientist subjugate those in appalling living conditions. In its afterm plus a physician plus a public health pioneer plus a progressive politician—that would be plenty unique. But in saw all those roles as manifestations of addition, through a creative synthesis, he a single whole. "Medicine is a social he wrote. And, "Physicians are the natural attorneys of science, and politics nothing but medicine on a large scale," med for him. And unless one the poor." This is an extraordinarily large vision for a man getting microscopic spaces na ian these days, this vision must also happens to be a very atypical physic as sadly quaint as Picasso thinking he could throw some paint on a canvas, call it seem extraordinarily quaint, and do something to halt Fascism. Guernica, ease of a supposedly enlarged The history of status thymicolymphaticus, the imaginary dis thymus gland in infants, 8, taught us that your place in society can leave its imprint you eventually detailed at the end of chapter on the corpse ciety it is, can leave an become. The purpose of this chapter is to show how your place in so ciety, and the sort of so int incorporates the erstanding this impr are alive, and to show that part of und imprint on patterns of disease while you 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

181 Pa g e 181 of 212 notion of stress. This will be preparatory for an important notion to be discussed in the final chapter on stress management—that certain techniques for reducing stress work differently depending on where you dwell in your society's hierarchy. er of chapters is to introduce some A strategy that I've employed in a numb ontext of animals, phenomenon in the c often social primates. This has been in order to show so me principle in a simplified form before turning to the complexity of humans. I do the same in this chapter, beginning with a discussion of what social rank has to do with animals. But this time, there is a paradoxical twist that, by the end of this health and stress-related diseases among chapter, should seem depressing as hell—this time, it is we humans who provide a brutally simple version and our the nuance and subtlety. nonhuman primate cousins PECKING ORDERS AMONG BEASTS WITH TAILS d among hens, they exist in all sorts of hierarchies—might have first been discerne While pecking orders—dominance enly. Instead of every contested item being fought species. Resources, no matter how plentiful, are rarely divvied up ev . As formalized systems of inequities, these are great for with bloodied tooth and claw, dominance hierarchies emerge animals smart enough to know their place. substitutes for continual aggression between to heights of animal complexity by primates. Consider baboons, the kind Hierarchical competition has been taken so beasts. In some cases, the hierarchy can be fluid, with running around savannas in big social groups of a hundred or ranks changing all the time; in other cases, rank is heredi tary and lifelong. In some cas es, rank can depend on the situation—A outranks B when it comes to a contested food item, but the order is reversed if it is competition for someone of the opposite sex. There can be circularit ies in hierarchies—A defeats B defeat s C defeats A. Ranking can involve unced by A, unless receiving some well-timed help from C, in which case A is sent coalitional support—B gets tro packing. The actual confrontat ion between two animals can include anything ranging from a near fatal brawl to a highly dominant individual doing nothing more than shifting menacingly and giving subordinates the willies. Regardless of the particulars, if you're going to be a savanna baboon, you probably don't want to be a low-ranking one. You sit there for two minutes digging some root out of the ground to eat, clean it off and ... anyone higher spend hours sweet-talking someone into grooming you, getting rid of those ranking can rip it off from you. You bothersome thorns and nettles and parasites in your hair, and the grooming session can be broken up by someone dominant just for the sheer pleasure of hassling you. Or you could be sitting there, minding your own business, bird- watching, and some high-ranking guy having a bad day decides to make you pay for it by slashing you with his olence. A middle- canines. (Such third-party "displacement aggression" accounts for a huge percen tage of baboon vi unges at an adult female, who bites a turns and chases a subadult male, who l ranking male gets trounced in a fight, juvenile, who slaps an infant.) For a subordinate animal, life is filled with a dispro portionate share not only of physical stressors but of psychological stressors as well—lack of control, of predictability, of outlets for frustration. It's not surprising, then, that among subordinate male baboons, resting levels of glucocorticoids are significantly everyday basal circumstances are stressful. And that's higher than among dominant individuals—for a subordinate, ids. When a real st ressor comes along, their glucocorticoid just the start of subordinates' problems with glucocortico s. And when it's all passed, th eir recovery appears to be response is smaller and slower than in dominant individual unt as an inefficient stress-response.* delayed. All these are features that co More problems for subordinate individuals: elevated resting blood pressure; sluggish cardiovascular response to real stressors; a sluggish * I spent about a dozen summers with my baboons figuring out the neuroendocrine mechanisms that give rise to the inefficient gl ucocorticoid the pituitary, and the adrena ls in the regulation system in the subordinate animals. "Neuro endocrine mechanisms" means the steps linking the brain, lem. There turn out of glucocorticoid release. The question becomes which of the step s—brain, pituitary, adrenals—is the spot where there is a prob differently in subordinate and dominant ba to be a number of sites where things work ive rise to the boons. Interestingly, the mechanisms that g pattern in subordinate baboons are virtually identical with those that give rise to th ur in many humans with e elevated glucocorticoid levels that occ major depression. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

182 Pa g e 182 of 212 Grooming, a wonderful means of social cohesion and stre ss reduction, in a society where everyone's back is not scratched equally. ong male subordinates, testosterone levels that are more recovery; suppressed levels of the good HDL cholesterol; am rculating white blood cells; and lower circulating levels of easily suppressed by stress than in dominant males; fewer ci insulin-like growth factor-I, something called which helps heal wounds. As should be clear umpteen pages into this e indices of bodies that book, all these ar are chronically stressed. A chronically activated stress-response (elevated glucocorticoid levels, or resting blood pressure that is too high, or an lots of other animal species as well. s to be a marker of being low ranking in enhanced risk of atherosclerosis) appear standard-issue monkeys like rhesus to b easts called prosimians (such as mouse This occurs in primates ranging from lemurs). Same for rats, mice, hamsters, guinea pigs, wolves, rabbits, pigs. Even fish. Ev en sugar gliders, whatever they might be. A critical question: I'm writing as if being low ranking and subject to all those physical and psychological stressors e. Could it be the other way around? Could having a second-rate stress- chronically activates the stress-respons response set you up for being low ranking? You can answer this question with stud ies of captive animals, wher e you can artificially form a social group. Monitor glucocorticoid levels, blood pressure, and so on when the group is first formed, and again once rankings have rection the causality works—do physiological differences emerged, and the comparison will tell you in which di 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

183 Pa g e 183 of 212 A middle-ranking baboon, who has spent all morning stalking an impala, has the kill stolen from him by a high- ranking male. predict who is going to wind up with which rank, or is it the other way around? The answer, overwhelmingly, is that rank emerges first, and drives the distinctive stress profile. So we've developed a pretty clear pictur ronically stressed equals an overactive e. Social subordination equals being ch elated disease. Now it's time to see why that's simplistic and wrong. stress-response equals more stress-r The first hint is hardly a subtle one. When you stand up at some scientific meeting and tell about the health-related miseries of your subordinate baboons or tree shrews or sugar gliders, invariably some other endocrinologist who subordinate animals don't have high blood studies the subject in some other species gets up and says, "Well, my social subordination is not associated ." There are lots of species in which pressure or elevated glucocorticoid levels with an overactive stress-response. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

184 Pa g e 184 of 212 Why should that be? Why should being subordinate not be so bad in that species? The answer is that in that species, it's not so bad being subordinate, or possibly it's actually a drag being dominant. a South American monkey called the ma An example of the first is seen with rmoset. Being subordinate among them does not involve the misery of physical and psychological stressors; it isn't a case of subjugation being forcibly imposed on you by big, mean, dominant animals. Instead, it is a relaxed waiting strategy—marmosets live in small helping out your cally means you are social groups of related "cooperative breeders," where being subordinate typi more dominant older sibling or cousin and waiting your turn to graduate into that role. Commensurate with this picture, David Abbott at the Wisconsin Regional Primate that subordinate marmosets Research Center has shown don't have overactive stress-responses. Wild dogs and dwarf mongooses provide examples of the s econd situation in which subordination isn't so bad. Being a life of luxury, effortle ssly getting the best of the pickings and occasionally dominant in those species doesn't mean endowing an art museum. None of that status quo stuff. Instead, being dominant requires the constant reasser-tion of high rank through overt aggression—one is tested again and again. As Scott and Nancy Creel at Montana State have the elevated basal als among those species who University have shown, it's not the subordinate anim glucocorticoid levels, it's the dominant ones. Recently, Abbott and I drew on the collaborative efforts of a large numbe r of colleagues who have studied rank/stress features of a primate soci ety predict whether it is the physiology issues in nonhuman primates. We formalized what rdinate animals who dominant or the subo have the elevated stress-responses. To the experts on each primate species, we posed the same questions: in the does aggression play in species that you study, what are the rewards of being dominant? How much of a role take? What sources of coping and does a subordinate individual have to maintaining dominance? How much grief of that species have ava ilable to them? What covert support (including the presence of relatives) do subordinates alternatives to competition are are they to get caught and how eat at the rules, how likely available? If subordinates ch bad is the punishment? How often does the hierarchy change? Amid seventeen questions asked concerning the dozen different species for which ther e are decent amounts of data av ailable, the best predictors of elevated glucocorticoid levels among subordinate animals turn out to be if they are frequently harassed by dominant individuals and if they lack the opportunities for social support. rns out that rank can also mean different things in different things in different species. It tu So rank means different Primatologists these days talk about primate "culture," and this is not an social groups within the same species. have a very different culture from the in one part of the rain forest can anthropomorphic term. For example, chimps folks four valleys over—different frequencies of social behaviors, use of similar vocalizations but with different meanings (in other words, something ap pes of tool use. And a "dialect"), different ty proaching the concept of intergroup differences influence the rank-stress relationship. us monkeys, where subordinates normally take a lot of grief and have One example is found among female rhes cept in one social group that was studied, which, for some reason, had high elevated basal glucocorticoid levels—ex rates of reconciliatory behaviors among animals after fights. The same is found in a baboon troop that just happened to be a relatively benign place to be a low-ranking individual. Another exampl e concerns male baboons where, as noted, subordinates normally have the elevated glucocorticoid levels—except during a severe drought, when the dominant males were so busy looking for food that they didn't have the time or energy to hassle everyone else ate animal, an environmenta l stressor can be a blessing, (implying, ironically, that for a subordin insofar as it saves you from a more severe social stressor). A critical intergroup difference in the stress-response concer ns the stability of the dominance hierarchy. Consider an individual is getting trounced 95 percent of in the hierarchy. In a stable system, that animal who is, say, Number 10 percent of the time. In contra the time by Number 9 but, in turn, thrashes Number 11 95 st, if Number 10 were winning only 51 percent of interactions with Number 11, that suggests that the two may be close to switching positions. In a stable hierarchy, 95 percent of the interactions up and down the entrenched and have all the nant individuals are stably ranks reinforce the status quo. Under those conditions, domi psychological perks of their position— control, predicta bility, and so on. And under those conditions, among the various primate species discussed above, it is the dominant individuals who have the healthiest stress-responses. s unstable—some key individual has died, someone when the hierarchy become In contrast, there are rare periods influential has transferred into the group, some pivotal rmed or come apart—and a coalitional partnership has fo revolution results, with animals changing ranks left and right. Under those conditions, it is typically the dominant ing, the most challenges, individuals who are in the very center of the hurricane of instability , subject to the most fight l politics.* During such unstable periods among those same and who are most affected by the see-sawing of coalitiona nger have the healthie st stress-responses. primate species, the dominant individuals no lo 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

185 Pa g e 185 of 212 So while rank is an important predictor of individual differ ences in the stress-response, the meaning of that rank, the itical variable is important. Another cr a particular society, is at least as psychological baggage that accompanies it in its rank and society. For example, an animal's personal experience of both consider a period when an immensely aggressive male has joined a troop of baboons and is raising hell, attacking animals unprovoked left and right. One instead, the pattern reflects this destabilizing brute. But, might predict stress-responses throughout the troop thanks to acked by this character, there were no r those lucky enough never to be att the individual experience of animals—fo changes in immune function. In contrast, ular baboon suffered at re frequently that partic among those attacked, the mo us, you ask the question, "W this guy's teeth, the more immunosuppressed she was. Th hat are the effects of an , "It depends—it's not the aggressive, stressful individual on immune function in a social group?" The answer is abstract state of living in a stressful so ciety which is immunosuppressive. Instead, it is the concrete state of how often + your own nose is being rubbed in that instability." stful to have been the czar of Russia in 1917? * After all, do you think it would have been re + All you have to do to appreciate that bad times for a group as a whole do not necessarily tran slate into bad times for every individual is to fortunes black-marketing penicillin or ho arding critical food su consider all the people who have made pplies during wartime. As a final variable, it is not just rank that is an important predictor of the stress-response, not just the society in which society experiences both; it's also pers the rank occurs, or how a member of the onality— the topic of chapter 15. As of provocations, and they half empty and life as full we saw, some primates see glasses as can't take advantage of outlets or social support—those are the individuals with overactive stress-responses. For them, their rank, their lly salutary, but if their personality keeps them from society, their personal experiences might all be wonderfu one levels and arteries and immune perceiving those advantages, their horm systems are going to pay a price. All things considered, this presents a pretty subtle picture of what social rank has to do with stress-related disease when considering complicated and subtle among primates. It's reasonable to exp ect the picture to be that much more humans. Time for a surprise. DO HUMANS HAVE RANKS? I personally was always picked last fo r the whiffleball team as a kid, bein g short, uncoordinated, and typically preoccupied with some book I was lugging around. Thus, having been perpetually ensconced at the bottom of that tical about the notion of ranking systems for humans. pecking order, I am skep studies of human "dominance" Part of the problem is definitional, in that some supposed are actually examining Type- contents to their stile, competitive are ones who, in interviews, have ho A features—people defined as "dominant" answers, or who speak quickly and interrupt the interviewer. This is not dominance in a way that any zoologist would endorse. humans who are competing ndividual differences in logical correlates of i Other studies have examined the physio directly against one another in a way that looks like dom for example, the hormonal inance. Some have examined, ng on whether they won or lost thei r match. Others have examined the responses in college wrestlers dependi in the military. One of the most fruitful areas has been to examine ranks in endocrine correlates of rank competition the corporate world. Chapter 13 showed how the "executive stress syndrome" is mostly a myth—people at the top give ulcers, rather than get them. Most studies have shown that it is middle management that succumbs to the stress- related diseases. This is thought to reflect the killer combination that these folks are often burdened with, namely, high work demands but little autonomy—responsibility without control. Collectively, these studies have produced some experimentally a bit dubious as to what reliable correlations. I'm just they mean. For starters, I'm not sure what a couple of minutes of competitive wrestling between two highly ogged arteries. At the other end, I wonder eaches us about which sixty-year-old gets cl conditioned twenty-year-olds t what the larger meaning is of rankings among business execu tives— while primate hierarch ies can ultimately indicate how hard you have to work for your calories, corporate hierarchies are ultimately about how hard you have to work history, societies were most for, say, a plasma TV. Another reason for my skepticism is that for 99 percent of human probably strikingly unhierarchical. This is based on the fact that contemporary hunter-gatherer bands are remarkably egalitarian. But my skepticism is most strongly anchored in two reasons having to do with the complexity of the human psyche. in at least systems simultaneously, and idea First, humans can belong to a number of different ranking lly are excelling one of them (and thus, may be giving the greatest psychological weight to that one). So, the lowly subordinate in the ving tremendous prestige and self-esteem from being the mailroom of the big corporation may, after hours, be deri her weekend softball team, or may be at the top of the class at the adult- deacon of his church, or the captain of 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

186 Pa g e 186 of 212 extension school. One person's highly empowering dominance hierarchy may be a mere 9-to-5 irrelevancy to the person in the next cubicle, and this will greatly skew results. And most important, people put all sorts of spin inside their heads about ranks. Consider a marathon being observed by a Martian scientist studying physiology and rank in humans. The obvious thing to do is keep track of the order in ly dominates 5,000. But what Runner 1 dominates 5, who clear which people finish the race. if runner 5,000 is a couch potato who took up running just a few months ago, who half expected to keel over from a coronary by mile 13 and instead finished— sure, hours after the crowds wandered off—but finished, exhausted and glowing. And what if eading in the sports section that someone of their world-class quality should runner 5 had spent the previous week r ree, maybe even blow away the field. No Ma rtian on earth could predict correctly who is certainly finish in the top th going to feel exultantly dominant afterward. against some external yardstick. This lves, their own previous best time, as People are as likely to race against themse the kid in the mailroom can be seen in the corporate world as well. An artificial example: is doing a fabulous job and is rewarded, implausibly, with a $50,000 a year salary. A senior vice president screws up pective of that Martian, or big-time and is punished, even more implausibly, with a $50, 001 a year salary. By the pers ed wildebeest, it's obvious that the vice president is in bette r shape to acquire the nuts even by a hierarchically mind and berries needed for survival. But you can guess who is going to be going to work contentedly and who is going to be making angry phone calls to a headhunter from the cell phone in the BMW. Humans can play internal, ider the following rationalizing games with rank based on their knowledge of what determined their placement. Cons sort of competitive interaction typically show at least a small rise in their fascinating example: guys who win at some ider the win to have come from sheer luck. circulating testosterone levels—unless they cons When you put all those qualifiers together, I think the net result is some pretty shaky ground when it comes to considering human rank and its relevance to the stress-response. Except in one realm. If you want to figure out the human equivalent of being a low-ranking ries with it atypically high rates of social animal, an equivalent that car physical and psychological stressors, which is ecologically meaningful in that it's not just about how many hours you have to work to buy an iPod, which is likely to overwhelm most of the rationalizations and alternative hierarchies that one can muster—check out a poor human. SOCIOECONOMIC STATUS, STRESS, AND DISEASE If you want to see an example of chronic stress, study poverty. Being poor involves lots of physical stressors. Manual even two or three exhausting jobs, complete with chronic work-related accidents. Maybe labor and a greater risk of sleep deprivation. Maybe walking to work, walking to the laundromat, walking back from the market with the heavy y to afford a new mattress that might air-conditioned car. Maybe too little mone bag of groceries, instead of driving an help that aching back, or some more hot water in the show er for that arthritic throb; and, of course, maybe some hunger thrown in as well... The list goes on and on. Naturally, being poor brings disproportionate amounts of psychological stressors as well. Lack of control, lack of predictability: numbing work on an assembly line, an occupational career spent taking orders or going from one temporary stint to the next. The first mes are bad—and studies show that the dele one laid off when economic ti terious effects of unemployment on health re threat of it first occurs. Wondering if the money will begin not at the time the person is laid off, but when the me stretch to the end of the month. Wondering if the rickety car will get you to tomorrow's job interview on time. How's this for an implication of lack of control: one study of the working poor showed that they were less likely to comply with their doctors' orders to take antihypertensive diuretics (drugs that lower blood pressure by making you urinate) the bathroom at work as often as th ey needed to when taking the drugs. because they weren't allowed to go to As a next factor, being poor means that you often can't cope with stressors very efficiently. Because you have no for the future, and can only respond to the present crisis. And when you do, resources in reserve, you can never plan your solutions in the present come with a whopping great price later on—metaphorically, or maybe not so metaphorically, you're always paying the rent with money fr om a loan shark. Everything has to be reactive, in the ou'll be in even worse shape to deal with the next stressor— growing strong moment. Which increases the odds that y from adversity is mostly a luxury for those who are better off. a marked lack of outlets. Feeling a means of coping, poverty brings with it Along with all of that stress and reduced g a relaxing vacation, buying an exercy little stressed with life and considerin cle, or taking some classical guitar obably not. Or how about qu itting that stressful job a nd taking some time off at lessons to get a little peace of mind? Pr home to figure out what you're doing with your life? Not when there's an extended family counting on your paycheck and no money in the bank. Feeling like at least jogging re gularly to get some exercise and let off some steam? a crime-riddled neighborhood, and jogging may wind up being Statistically, a poor person is far more likely to live in a hair-raising stressor. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

187 Pa g e 187 of 212 Finally, along with long hours of work and kids to take care of comes a serious lack of social support—if everyone you know is working two or three jobs, you and your loved ones, despite the best of intentions, aren't going to be having much time to sit around being supportive. Thus, poverty generally equals more stressors—and though the studies are mixed as to whether or not the poor have more major catastrophic stressors, they have plenty more chronic daily stressors. socioeconomic status (SES All these hardships suggest that low — typically measured by a combination of income, occupation, housing ation of the stress-response. Only a few studies ssociated with chronic activ conditions, and education) should be a have looked at this, but they support this view. One concerned school kids in Montreal, a city with fairly stable eight-year-old children, there was alr communities and low crime. In six- and eady a tendency for lower-SES kids to , with low-SES kids averaging almost age ten, there was a step-wise gradient have elevated glucocorticoid levels. By double the circulating glucocorticoids as the highest SES kids. Another example concerns people in Lithuania. In 1978, men in Lithuania, then part of the USSR, had the same mortality rates for coronary heart disease as did men in nearby Sweden. By 1994, following the disintegration of the Soviet Union, Lithuanians had four times the Swedish rate. In 1994 Sweden, SES was not related to glucocorticoid levels, whereas in 1994 Lithuania, it was strongly related. Findings like these suggest that being poor is associated with more stress-related diseases. As a first pass, let's just ask whether low SES is associated with mo re diseases, period. And is it ever. The health risk of poverty turns out to be a huge effect, the biggest risk factor there is in all of behavioral medicine— me gender, age, and ethnicity and you want to make some in other words, if you have a bunch of people of the sa most useful fact to know is going to live how long, the single predictions about who is each person's SES. If you want be poor. Poverty is associat ed with increased risks of to increase the odds of living a long and healthy life, don't cardiovascular disease, respiratory diseas e, ulcers, rheumatoid diso rders, psychiatric diseases, and a number of types ssociated with higher rates of people judging themselves to be of poor health, of of cancer, just to name a few.* It is a er, lower SES predicts lower birth weight, after controlling infant mortality, and of mortality due to all causes. Moreov for body size—and we know from chapter 6 the lifelong effects of low birth weight. In other words, be born poor but hit the lottery when you're three weeks ts a stroke. s of Europe, socioeconomic status accounts for 68 percent of the variance as to who ge * As but one example, across the countrie elanoma is an are even more common t among the poor, and, fascinatingly, some However, not all diseases are more prevalen among the wealthy. M d physical labor (or ure in a lounge chair may have different diseas e risks than getting your example, suggesting that sun expos neck red from stoope mean). Or multiple have a fair amount of melanin in their skin, if you know what I that a huge percentage of poor people laboring away in the sun sclerosis, and a few other autoimmune diseases and, during its heyday, polio. Or "hospitalism," a pediatric disease of the 1930 s in which infants sociality—and kids who would wind up in poorer would waste away in hospitals. It is now u nderstood that it was mostly due to lack of contact and actually hold them. -art incubators, necessitating that staff the hospitals couldn't afford state-of-the hospitals were less subject to this, since old, spend the rest of your life double-dating with Donald Tr ump, and you're still going to have a statistical increase in for the rest of your life. some realms of disease risk Is the relationship between SES and health just some little statistical hiccup in the dat a? No—it can be a huge effect. nsitive to SES, if you cling to the lowest rungs of the socioeconomic ladder, it In the case of some of those diseases se with those perched on top.* Or stated another way, this translates into a can mean ten times the prevalence compared five- to ten-year difference in life ex aring the poorest and wealthiest, and pectancy in some countries when comp erences when comparing subgroups of the poorest and wealthiest. decades' worth of diff ies. For example, one study of men in England and Wales demonstrated a steep Findings such as these go back centur a critical implication that has been SES gradient in mortality in every d ecade of the twentieth century. This has pointed out by Robert Evans of the University of British Columbia: the diseases that people were dying of most now. Different causes of death, but ly different from the most common ones frequently a century ago are dramatical th. Which tells you that the gradient arises less from same SES gradient, same relationship between SES and heal disease than from social class. Thus, writes Evans, the "roots [of the SES h ealth gradient] lie beyond the reach of medical therapy." lity? Maybe being poor sets you up for poor health. So SES and health are tightly linked. What direction is the causa But maybe it's the other way around, where being sickly sets you up for spiraling down into poverty. The latter certainly happens, but most of the relationship is due to the former. This is demonstrated by showing that your SES at lth later on. For example, pove rty early in life has adverse one point in life predicts important features of your hea ack to chapter 6 and the fetal origins of adult disease. On effects on health forever after—harking b e remarkable study involved a group of elderly nuns. They took their vows as young adults, and spent the rest of their lives sharing the same diet, same health care, same housing, and so on. De spite controlling for all these variables, in old age their they had when they became till predicted by the SES status patterns of disease, of dementia, and of longevity were s nuns more than half a century before. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

188 Pa g e 188 of 212 Thus, SES influences health, and the gr eater cumulative percentage of your life you've spent poor, the more of an adverse impact on e (even pre-DiCaprio) that there was a stri * A number of writers in the field have noted ct SES gradient as to who survived on th Titanic. or today in a developing country, the ? A century ago in the United States, health.* Why should SES influence health getting more infectious diseases, less food, and having an answer would be obvious. It would be about poor people astronomically higher infant mortality rate. But with our shift toward the modern prevalence of slow, degenerative diseases, the answers have shifted as well. THE PUZZLE OF HEALTH CARE ACCESS ed States, poor people (with or without health insurance) Let's start with the most plausible explanation. In the Unit don't have the same access to medical care r preventive check-u ps with doctors, as do the wealthy. This includes fewe has been noted, and less adequa a longer lag time for testing when something bothersome te care when something has actually been discovered, especi echnique. As one example of ally if the medical care invo lves an expensive, fancy t this, a 1967 study showed that the poorer you are judged to be (based on the neighborhood you live in, your home, the hospital. In more recent studies, are to try to revive you on the way to your appearance), the less likely paramedics S influenced your likelih ood of receiving physical , occupational, or speech for the same severity of a stroke, SE therapy, and how long you waited until undergoing surgery to repair the damaged blood vessel that caused the stroke. n the SES gradient. Make the health car e system equitable, socialize that This sure seems like it should explai medicine, and away would go th at gradient. But it can't be only about differential health care access, or even mostly about it. alence of disease: Australia, associated with increased prev For starters, consider countries in which poverty is robustly ance, Italy, Japan, the Netherlands, New Z Belgium, Denmark, Finland, Fr ealand, the former So viet Union, Spain, em, socialize the whole ize the medical care syst gdom, and, of course, the U.S. of A. Social Sweden, the United Kin country, turn it into a worker's paradi place like England, the SES gradient has se, and you still get the gradient. In a universal health car e allowing everyone equal health care gotten worse over this century, despite the imposition of access. helps to some extent. * What that means is that you're not completely sunk if you're born poor; social mobility You could cynically and care access are probably lly egalitarian health correctly point out that systems of wonderfu egalitarian in theory only—even be at least a smidgen more attentive to the the Swedish health care system is likely to wealthy industrialist, sick doc tor, or famous jock than to some no-accoun t poor person cluttering up a clinic. Some equality than others. But in at least one study of people enrolled in a prepaid people always get more of their share of ilities were available to all participants, poo health plan, where medical fac rer people had more car diovascular disease, despite making more use of the medical resources. ip forms the term I've A second vote against the importance of differential health care access is because the relationsh gradient. an everyone else. Instead, for been using, namely, a or people are less healthy th It's not the case that only po every step lower in the SES ladder, ther t in the SES hierarchy, the bigger is e is worse health (and the lower you ge This was a point made screamingly clear in each step of worsening health). the most celebrated study in the field, the llege of London. Marmot co nsidered a system where Whitehall studies of Michael Marmot of University Co gradations in SES status ar e so clear that occupational rank practically comes stam ped on people's foreheads—the -powered executives. Compare blue-collar workers to high British civil service system, which ranges from unskilled lity. Remember, this is a fourfold difference in ra the highest and lowest rungs and there's tes of cardiac disease morta important in the in a system where everyone has roughly equal health care access, is paid a liv ing wage, and, very context of the effects of unpredictability, is highly likely to continue to be able to earn that living wage. seases that have nothing to do with A final vote against the health care acces s argument: the gradient exists for di give her a good medical exam access. Take a young person and, each day, scrupulously, ination, check her vitals, ecture about good health habits, and then, for g ood measure, peruse her blood, run her on a treadmill, give her a stern l much at risk for some diseases as if she hadn't gotten all that attention. Poor centrifuge her a bit, and she is still just as n-derbilt Univers ity has carefully people are still more likely to get thos e access-proof diseases. Theodo re Pincus of Va documented the existence of an SES grad ile diabetes and rheumatoid arthritis. ient for two of those diseases, juven seem to rule out health care access as a ma Thus, the leading figures in this field all jor part of the story. This is not to rule it out completely (let alone suggest that we not bother trying to establish universal 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

189 Pa g e 189 of 212 The Whitehall Study, Mo rtality by Professional Level of Follow-up. , while the sociali italist America has the worst gradient health care access). As evidence, sweaty cap zed Scandinavian ients, despite their socialism. countries have the weakest. But they still have hefty grad The main cause has to be somewhere else. Thus, we move on to the next most plausible explanation. RISK FACTORS AND PROTECTIVE FACTORS ly (sufficiently so that it's been e more likely to drink and smoke excessive Poorer people in westernized societies ar be almost exclusively a low-SES activity) remarked that smoking is soon going to . These excesses take us back to the last chapter and having trouble "just saying no" when there are few yes's. Moreover, the poor are more likely to have an unhealthy diet—in the developing world, being poor means having trouble affording food, while in the westernized food. Thanks to industrialization, fewer jobs in our society involve world, it means having trouble affording healthy when combined with the costs of membership in some tony health club, the poor get less physical exertion and, exercise. They're more likely to be obe se, and in an apple-ish way. They are less likely to use a seat belt, wear a They are more likely to motorcycle helmet, own a car with air bags. live near a toxic dump, be mugged, have inadequate heat in the winter, live in crowded conditions (thereby increasing exposure to infectious diseases). The list seems endles s, and they all adversely impact health. Being poor is statistically likely to come with another risk factor-being poorly educated. Thus, maybe poor people don't understand, don't know about the risk factors they are being exposed to, or the health-promoting factors they are lacking—even if it is within their power to do somethin one example that boggles me, g, they aren't informed. As substantial numbers of people are apparently not aware that cigarettes do bad things to you, and the studies show that ations to note some public health trivia. Other studies these aren't folks too busy working on their doctoral dissert indicate that, for example, poor women are the least likely to know of th e need for Pap smears, thus increasing their risk for cervical cancer.* The intertwining of poverty and poor education probably explains the high rates of poor eat belts or crash helmets, people who, despite their poverty, could still be eating some what more healthfully, using s and so on, but don't. And it probably helps to explain why poor people are less likely to comply with some treatment regime prescribed for them that they can actually afford—they are less likely to have understood the instructions or to degree of education generalizes to better problem-solving think that following them is important. Moreover, a high ing better educated predicts that your community of friends and relatives is skills across the board. Statistically, be better educated as well, with those attendant advantages. However, the SES gradient isn't much a bout risk factors and protective factors. To show this requires some powerful statistical techniques in which you see if an effect still exis ts after you control for one or more of these factors. For example, the lower your SES, the greater your risk of lung cancer. But the lower your SES, the greater the likelihood le who smoke—does the inci dence of lung cancer still of smoking. So control for smoking—comparing only peop of smoking, does l ung cancer incidence increase with declining SES? Take it one step further—for the same amount still increase? For the drinking, does... and so on. Thes e types of analyses show that same amount of smoking and these risk factors matter—as Robert Evans has written, "Drinking sewage is probably unwise even for Bill Gates." They just 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

190 Pa g e 190 of 212 tes new advances in * In a subtle but striking complication to As medical research genera this story, education actua lly worsens health inequality. eciate it, and adopt it, and thus differen the educated who first hear about it, appr health care and preventive medicine, it is tially benefit from it, amplifying the health gradient even more. ies, smoking, cholesterol levels, blood pressure, and level don't matter that much. For example, in the Whitehall stud sk factors and same lack of protective ird of the SES gradient. For the same ri of exercise explain away only about a th factors, throw in poverty and you're more likely to get sick. So differential exposure to risk factors or protective factors does not explain a whole lot. This point is brought home in another way. Compare a wealthier country gives you . One can assume that being in countries that differ in wealth factors. For example, you fi more opportunities to buy protective factors and to avoid risk nd the least pollution in very because they are nonindustrial and th poor and very w ealthy countries; the former e latter because they either do it the wealthiest quarter or so countries on earth, there is cleanly or farm it out to someone else. Yet, when you consider citizens.* This is a poin t heavily emphasized by th and the health of its no relationship between a country's weal Stephen Bezruchka of the University of Washington, in considering the United States—despite the most expensive and sophisticated health care system in the world, there's an unconscionable number of less wealthy nations whose + ier lives than our own. citizens live longer, health e things get tense at the scientific access, and risk factors. This is wher So out go major roles for health care conferences. Much of this book has been about how a certain style of "mainstream" medicine, overly focused on how disease is exclusively about viruses, bacteria, and mutations, has grudgingly had to make room for the relevance of psychological factors, includ ing stress. In a similar way, among the "social epidemiologists" who think about the and risk factors. And thus, they too ew has long focused on health care access SES/health gradients, the mainstream vi have had to make room for psychological factors. Including stress. Big-time. central a point as any in this book. Once you get past the 25 percent poorest countrie s on earth, there's no * This may seem like an aside, but is as many countries wer e on the list whose are happy. (How tage of its citizens who say they relationship between the wealth of a country and the percen citizens are at least as happy, if not happ ier, than Americans, despite being in less wealthy countries? Ten, most with social welfare systems. And tes of the Soviet Union, or of Eastern Europe.) unhappiness? The dozen most unhappy are all ex-sta was 25th. As one example, and of itself. By 1997, it e expectancy, pretty lousy in + In 1960, the United States was 13th in lif Greeks, who have Americans, have a longer life expectancy. approximately half the average income of STRESS AND THE SES GRADIENT As discussed, the poor certainly have a hugely disproportionate share of both daily and major stressors. If you've gotten this far into this book and aren't wondering whether stress has something to do with the SES health gradient, you should get your money back. Does it? In the last edition of this book, I argued for a major role for stress based on three points. First, the poor have all those dual diseases, the strongest gradients e examines the SES gradient for indivi chronic daily stressors. Second, when on occur for diseases with the greatest sens ease, diabetes, Metabolic syndrome, and itivity to stress, such as heart dis you've rounded up the usual suspects psychiatric disorders. Finally, once —health care access and risk factors—and ruled them out as being of prime importance, what else is there to pin the SES gradient on? Sunspots? Kinda flimsy. With that sort of evidence, the social epidem iologists were willing to let in some of those psychologists if you kitchen, and stress physiologists, but through the back door, and—Cook, find them something to eat in the please. make the stress argument So that was the stress argument a half decade back. But sin ce then, striking new findings very solid. BEING POOR VERSUS FEELING POOR stress is heavily rooted in psychology once you are dealing with organisms who A central concept of this book is that aren't being chased by predators, and who have adequate shelter and sufficient calories to sustain good health. Once I mean everyone, then no one is. In order able fact that if everyone is poor, and those basic needs are met, it is an inevit to understand why stress and psychological factors have so much to do with the SES/health gradient, we have to begin with the obvious fact that it is never the case that everyone is poor thereby making no one poor. This brings us to a critical point in this field—the SES/health gradient is not r eally about a distribution that bottoms out at being poor. It's poorer than others around you. not about being poor. It's about feeling poor, which is to say, it's about feeling ornia at San Francisco. of the University of Calif carried out by Nancy Adler Beautiful work regarding this has been Instead of just looking at the relationship between SES and health, Adler looks at what health 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

191 Pa g e 191 of 212 has to do with what someone " Show someone a ladder with ten thinks and feels their SES is—their "subjective SES. rungs on it and ask them, "In society, where on this ladder would you rank yourself in terms of how well you're doing?" Simple. should average out to the middle of First off, if people were purely accurate and rational, the answers across a group the ladder's rungs. But cultural distortions come in—expansive, self-congratulatory European-Americans average out at higher than the middle rung (what Adler calls her Lake Wobegon Effect, where all th e children are above average); s, from a culture with less chest-thumpi age out to below the ng individualism, aver in contrast, Chinese-American middle rung. So you have to correct for those biases. In addition, given that you're asking how people feel about something, you need to control for people who have an illness of feeling, namely depression. at health measures have to do with one's subjective SES. Amazingly , it is at least as Once you've done that, look at wh Cardiovascular it is even better. l SES, and, in some cases, th measures as is one's actua good a predictor of these heal Feeling poor in our socioeconomic world measures, metabolism measures, glucocorticoid levels, obesity in kids. predicts poor health. This really isn't all that surprising . We can be an immensely competitive, covetous, invidious species, and not re's an example from a real particularly rational in how we make those comparisons. He m unrelated to this subject— show a bunch of women volunteers a series of pictures of attractive female models and, afterward, they feel in a worse seeing the pictures (and even more de mood, with lower self-esteem, than before pressingly, show those same pictures to men and afterward what declines is th eir stated satisfaction with their wives). So it's not about being poor. It's abou t feeling poor. What's th e difference? Adler shows th at subjective SES is built her words, the building blocks of subjective SES), plus around education, income, and occupational position (in ot Those last two measures are l security about the future. satisfaction with standard of living and feeling of financia critical. Income may tell you something (but certainly not everything) about SES; satisfaction with standard of living is the world of people who are poor and happy and zillionaires who are still grasping for more. All that messy stuff that dominates this book. And what is "feelings about fina ncial security" tapping into? A nxiety. So SES reality plus predictable your SES is are collectively better your confidence about how your satisfaction with that SES plus predictors of health than SES alone. This is not a hard and fast rule, and Ad necessarily that great of that subjective SES is not ler's most recent work shows , no doubt. But overall, this strikes me as immensely a predictor in certain ethnic groups—stay tuned for more impressive—when you're past the realm of worrying about ha ving adequate shelter and food, being poor is not as bad for you as feeling poor. POVERTY VERSUS POVERTY AMID PLENTY for this whole phenomenon is, It's about being to feel poor. This In many ways, an even more accurate tag line made nsidering the second body of re point is made clearer when co oned by Richard Wilkinson of search in this area, champi a top-down approach, looking at the "How are you doing?" the University of Nottingham in England. Wilkinson took ladder from the societal level. Let's consider how answers to "How are you doing?" can be distributed along the ladder. Suppose there is a business with ten employees. Each earns $5.50 an hour. Thus the company is paying out a total of $55/hour in salary, and the average income is $5.50/hour. With that distribution, the wealthiest employee is making $5.50/hour, or 10 percent of the total income ($5.50/$55). Meanwhile, in the next business, there are also ten employees. One earns $l/hour, the next $2/hour, the next $3, and so is again $5.50/hour. But now lary, and the average salary on. Once again, the company pays a total of $55/hour in sa the wealthiest employee, earning $10/ hour, takes home 18 percent of the total income ($10/$55). Now, in the third company, nine of the employees earn $l/hour, and the tenth earns $46/hour. Again, the company pays a total of $55/ hour, and the average salary is $5.50/hour. And here, the wealthiest employee takes home 84 percent of the total income ($46/$55). incomes. What Wilkinson and others have shown is that What we have here are businesses of increasingly unequal poverty is not only a predictor of poor health but, independent of absolute income, so is poverty amid plenty—the more income inequality there is in a societ y, the worse the health and mortality rates. This has been shown repeatedly, and at multiple levels. For example, income inequality predicts higher infant inequality predicts mortality rates across all ages (except mortality rates across a bunch of European countries. Income the United States, the elderly) in 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

192 Pa g e 192 of 212 whether you consider this at the level of states or cities. In a world of science often filled with wishy-washy data, the states is a really strong predictor of mortality rates effect is extremely reliable—income inequality across American shire, with the least egalitarian, the most egalitarian state, New Hamp among working men. When you compare Louisiana, the latter has about a 60 perc ent higher mortality rate.* Finally, Canada is both markedly more egalitarian —despite being a "poorer" country. and healthier than the United States income inequality and poor health doesn't seem to be Amid extraordinary findings like that, the relationship between e curve is for Canada—moreover, you don't find it when considering adults throughout universal. Note how flat th systems like Denmark. In other words, s with well-established social welfare Western Europe, particularly in countrie you probably can't pick up this effect when comparing individual parishes in Copenhagen because the overall pattern is so egalitarian in a place like that. Bu t it's a reasonably robust relationship while the flagship in the United Kingdom, 1 percent of the SES ladder controls for the health/income inequality relationship is the United St ates, where the top wealth, and it's a huge effect (and pe nearly 40 percent of the rsists even after co ntrolling for race). es to when they comparing themselv These studies of nations, states, and ci ties raise the issue of whom someone is u-doing ladder. Adler tries to get at this think of where they are on a how-are-yo by asking her question twice. First, r with respect to "society as a whol e," and second, with respect to "your you're asked to place yourself on the ladde immediate community." The top-down Wilkinson types get at this by comparing the predictive power of data at the national, state, and city levels. Neither l iterature has given a clear answer yet, bu t both seem to suggest that it is one's immediate community that is most important. As Tip O'Neil , the consummate politician, used to say, "All politics is local." l people know about is the immediate community of their This is obviously the case in traditional settings where al has, I'm he such village—look at how many chickens a loser. But thanks to urbanization, mobility, and the media that absolutely unprecedented can now occur—we makes for a global village, something can now be made to feel poor, or we don't even know. You can feel impoverished by the clothes of someone you pass poorly about ourselves, by people in a midtown crowd, by the unseen dr iver of a new car on the freeway, by kotas or Iowa, and Utah; the least egalitari * The most egalitarian states tend to be in New England, prairie states like the Da an are in the Deep South, plus Nevada. a fictional character in a Bill Gates on the evening news, even by movie. Our perceived SES may arise mostly out of our local community, but our modern world makes it possible to have our noses rubbed in it by a local community that stretches around the globe. e of the SES/health gradient. But maybe it isn't that Income inequality seems really important for making sens quality business is just a red herring built ar important. Maybe the ine ound the fact that places with big inequalities "poverty," instead her words, back to the key thing being tend to be poor places as well (in ot of "poverty amid plenty"). But, control for absolute income, and the inequality data still stand. graph if you're math-phobic—as a synopsis of the plot, the There's a second potential problem (warning: skip this para a cliffhanger finish). Moving up the SES is menaced by math villains but is saved in income inequality hypothesis ladder is associated with better health , as noted, each incremental step gets (by whatever measure you are using) but this is that the SES/health relationsh smaller. A mathematical way of stating ip forms an asymptote—going from very poor to lower middle class involves a steep rise in health that then tends to flatten out as you go into the upper SES ere SES averages out range. So if you examine w ealthy nations, you are examining countries wh to somewhere in the flat part of the curve. Therefore, co mpare two equally wealthy nations (that is to say, which have the same average differ in income inequality. By definition, the nation with the greater inequality SES on the flat part of the curve) that must have a lower average ng part of the curve, and thus will have more data points coming from the steeply declini nomenon doesn't really reflect some feature of society as a level of health. In this scenario, the income inequality phe atical inevitability, from individual data points. However, some fairly fancy whole, but merely emerges, as a mathem n all of the health-income inequality relationship in this artifact can't explai mathematical modeling studies show that the United States. But, alas, there might be a third problem. Suppose in some society the poor health of the poor was more sensitive to socioeconomic factors than th e good health of the rich. Now suppose you make income distribution in that society more equitable by transferring some wealth from the wealthy to the poor.* Maybe by doing that, you make the health d the health of the poor a lot of the wealthy a little worse, an transferred in order to make for completely equal income i * Appropriately, the proportion of the society's wealth that must be s termed the Robin Hood index. in the numerous poor and, overall, you've got a healthier better. A little worse in the few wealthy plus a lot better society. That wouldn't be very interesting in the context of stress and psychological factors. But Wilkinson makes an are healthier than extraordinary point—in socie ties that have more income equality, both the poor and the wealthy 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

193 Pa g e 193 of 212 their counterparts in a less equal soci ety with the same average income. There is something more profound happening here. ITY AND FEELING POOR TRANSLATE INTO BAD HEALTH? HOW DOES INCOME INEQUAL Income inequality and feeling poor could give rise to bad health through a number of routes. One, pioneered by Ichiro Kawachi of Harvard University, focuses on how income inequality makes for a psychologically crappier, more stressful life for everyone. He draws d "social capital." While "financial heavily upon a concept in sociology calle capital" says something about the depth and range of financial resources you can draw on in troubled times, social realm. By definition, social capital o ccurs at the level of a community, rather capital refers to the same in the social than at the level of individuals or individual social networks. A community in which there is a lot of volunteerism and numerous organizations that What makes for social capital? themselves. Where like they're part of something bigger than people can join which make them feel people don't lock ds from vandalizing a car ev their doors. Where people in the community would stop ki en if they don't know whose more income inequality in a society, ze cars. What Kawachi shows is that the car it is. Where kids don't try to vandali and the lower the social cap ital, the worse the health. the lower the social capital, ys and is still evolving as a hard-nosed measure, but, Obviously, "social capital" can be measured in a lot of wa ack of hostility, heavy participation in organizations for a broadly, it incorporates elements of trust, reciprocity, l common good (ranging from achieving fun—a bowling league—to more serious things—tenant organizations or a shing something. Most studies get easures: how people union) and those organizations accompli at it with two m answer a question like, "Do you think most people would try to take advantage of you if they got a chance, or would they try to be fair?" and how many organizations people belong to. Measures like those tell you that on the levels of ghborhoods, low social capital tends states, provinces, cities, and nei to mean poor health, poor self-reported health, and high mortality rates.* nse to Wilkinson. In his writing, he em phasizes that trust requires reciprocity, Findings such as these make perfect se ntrast, hierarchy is about domination, no t symmetry and equality. By definition, and reciprocity requires equality. In co ic income inequality and lots of soci you can't have a society with both dramat al capital. These findings would also have made sense to the late Aaron Antonovsky, who was one of the first to study the SES/health gradient. He stressed how damaging it is to health and psyche to be an invisibl e member of society. To rec ognize the extent to which the poor exist without feedback, just consider the varied ways that most of us have developed for looking through homeless people as we walk past them. s which, and which is most So income inequality, minimal trust, lack of social cohesi on all go together. Which cause predictive of poor health? To figure this out, you need so me fancy statistical techniques called path analysis. An om earlier chapters: chronic stress make example we're comfortable with by now fr s for more heart disease. Stress can so makes lots of people eat do this by directly increasing blood pressure. But stress al less healthfully. How much is rectly via blood pressure, and how much by the indirect route of changing diet? the path from stress to heart disease di That's the sort of thing that a path analysis can tell you. And Kawachi's work shows that the strongest route from income inequality (after controlling for absolute income) to poor health is via the social capital measures. How does lots of social capital turn into better health throughout a community? Less social isolation. More rapid diffusion of health information. Potentially, social constraints on publicly unhealthy behaviors. Less psychological stress. Better organized groups demanding better public services (and, related to that, another great measure of social capital is how many people in a community bother to vote). So it sounds like a solution to life's ills, including some stress-related ills, is to get into a community with lots of social capital. However, as will be touched on times, communities a great thing. Some in the next chapter, this isn't always get tremendous amounts of social capital by having all of their members goose-step to the same thoughts and beliefs and behaviors, and don't cotton much to anyone different. , the less binge drinking. * Even at the level of college campuses —the more social capital on a campus, by these measures that translates into more physical and shows another feature of income inequality Research by Kawachi and others psychological stress: the more economica lly unequal a society, the more crime— assault, robbery, and, particularly, equality is consistently a better predictor of crime than homicide—and the more gun ownership. Critically, income in poverty per se. This has been demonstrated on the level of states, provinces, cities, neighborhoods, even individual city blocks. And just as we saw in chapter 13 when we splacement aggression, poverty looked at the prevalence of di but not against the wealthy. The have-nots turn upon the have-nots. amid plenty predicts more crime— Meanwhile, Robert Evans (University of British Columbia), John Lynch, and George Kaplan (the latter two both of the University of Michigan) offer another route linking income inequality to poor health, once again via stress. This 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

194 Pa g e 194 of 212 pathway is one that, once you grasp it, is so demoralizing that you immediately want to man the barricades and sing revolutionary songs from It goes as follows: Les Miz. person in a society, you do ease the stress, for the average If you want to improve health and quality of life, and decr sit, safer streets, cleaner water, better public schools, so by spending money on public goods—better public tran financial distance between the in a society, the greater the universal health care. The bigger the income inequality is wealthy and the average. The bigger the distance between the wealthy and the av erage, the less benefit the wealthy will feel from expenditures on the public good. Instead, they would derive much more benefit by spending the same ttled water, private schools, private tter chauffeur, a gated community, bo (taxed) money on their private good—a be e incomes in a society, the health insurance. As Evans writes, "The more unequal ar more pronounced will be the disadvantages to its better-off members from public expenditure, and the more resources will those members have tes how this "secession of the wealthy" pushes [available to them] to mount effectiv e political opposition." He no toward "private affluence and public squalor." And more public squalor means more of the daily stressors and allostatic load that drives down health for everyone. For the wealth y, this is because of the costs of walling themselves for the rest of society, this is off from the rest of society, and because they have to live in it. more stressful reality. But this route certainly makes for So this is a route by which an unequal society makes for a ases the increasingly wealthy more psychological stress as well—if the skew in society bi toward wanting to avoid the public expenditures that would improve everyone else's quality of life... well, that might have some bad effects on trust, hostility, crime, and so on. So we've got income inequality, low soci al cohesion and social capital, class tens ions, and lots of crime all forming an unhealthy cluster. Let's see a grim exam together. By the late 1980s, life expectancy in ple of how these pieces come yzed by Evans, these were societies every Western European country. As anal Eastern Bloc countries was less than in in which there was a fair equity of income distribution, but a highly unequal distribution of freedoms of movement, d to Russia since the dissolutio n of the Soviet Union? A speech, practice of beliefs, and so on. And what has happene absolute wealth—and an and crime, a decline in massive increase in income inequality overall decline in life in an industri alized society. expectancy that is unprecedented One more grim example of how this works. America: enor mous wealth, enormous income inequality, high crime, the most heavily armed nation on earth. And markedly low levels of social capital— it is virtually the constitutional right of an American to be mobile and anonymous. Show your independence. Move across the country for any job opportunity. (He lives across th tle, er, stunted?) Get a new accent, get a new e street from his parents? Isn't that a lit culture, get a new name, unlist your phone number, reboot your life. All of which are the antitheses of developing explain something subtle about the health-income inequality relationship. Compare the social capital. This helps to United States and Canada. As shown, th e former has more income inequality and worse health. But restrict your inequality of Canada—and those U.S. ican systems chosen to match the low analysis to a subset of atypical Amer yses show what this is about: it's cities health gradient. Some detailed anal still have worse health and a steeper SES/ 's that even for the same degree of qual society when it comes to income. It not just that America is a markedly une rther in the United States. cial capital is driven down fu worsening income inequality, so Our American credo is that people are willing to tolerate a so ciety with miserably low levels of social capital, so long as there can be massive income inequality ... with the hope that they will soon be sitting at the top of this steep inequality have steadily ri pyramid. Over the last quarter-century, poverty and income sen, and every social capital measure of trust, community participation, and voter part icipation has declined.* And what about Amer ican health? We have disparity anomie: "bowling alon * The political scientist Robert Pu tnam of Harvard coined his famous metaphor fo r this spreading American e." In recent ipating in that quintessential American socia Americans bowl, but there are fewer people partic decades, an increasing number of l phenomenon, bowling leagues. between the wealth of our nation and the health of our citizens that is also unprecedented. And getting worse. en universal health insurance ler, writing around the time wh This is pretty depressing stuff, given its implications. Ad first became a frontpage issue (as was th e question of whethe r Hillary's hairstyle made her a more or less effective would "have a minor impact on SES-related inequalities in advocate for it), concluded that such universal coverage health." Her conclusion is anything but reactionary. Instead, it says that if you want to change the SES gradient, it's going to take something a whole lot bigger than rigging up insurance so that everyone can drop in regularly on a friendly small-town doc out of Norman Rockwell. Poverty, and the poor health of the poor, is about much more than simply not having enough money* It's about the stressors caused in a society that tolerates leaving so many of its members so far behind. This is relevant to an even larger depressing thought. I initially reviewed what social rank has to do with health in rtionate share of disease, more stress-related disease? nonhuman primates. Do low-ranking monkeys have a dispropo And the answer was, "Well, it e animal lives in, its 's actually not that simple." It depends on the sort of society th rsonality, the availability of social support. Change some of personal experience of that society, its coping skills, its pe 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

195 Pa g e 195 of 212 those variables and the rank/health gradient can shift in the exact opposite direction. This is the sort of finding that licated and subtle my animals are. primatologists revel in—look how comp The second half of this chapter looked at humans. Do poor humans have a disproportionate share of disease? The rdless of gender or age or race. In societies with answer was "Yes, yes, over and over." Rega universal health care and those without. In societies that are ethnically homogenous and those rife with ethnic tensions. In societies in which illiteracy is widespread and those in which it has been virtually banished. In those in which infant mortality has been plummeting and in some wealthy, industrialized societies in which rates have inexcusably been climbing. And in a capitalist credo of "Living well is the best revenge" and those in which it societies in which the central mythology is his ability, to each a ccording to his needs." is a socialist anthem of "From each according to ship is nuanced and filled What does this dichotomy between our animal cousins and us signify? The primate relation with qualifiers; erty. They are very ence of having very little money, but not of pov * Evans makes this point by noti ng, "Most graduate students have had the experi different things." the human relationship is a sledgehammer that obliterates every societal difference. Ar e we humans actually less complicated and sophisticated than nonhuman primates? Not ev en the most chauvinistic primatologists holding out re is a fairly recent human for their beasts would vote for that conclusion. I think it s uggests something else. Agricultu invention, and in many ways it was one of the great stupid moves of all time. Hunter-gatherers have thousands of wild sources of food to subsist on. Agriculture changed all that, generating an overwhelming reliance on a few dozen domesticated food sources, making you extremely vulnerable to the next famine, the next locust infestation, the next potato blight. Agriculture allowed for the stockpiling of surplus resources and thus, inevitably the unequal stockpiling of them—stratification of society and the invention of classes. Thus, it allowed for the invention of poverty. I think imate-human difference is that when humans invented poverty, they came up with a way that the punch line of the pr of subjugating the low-ranking like nothing ever before seen in the primate world. 18 MANAGING STRESS only been skim- By now, if you are not depressed by a ll the bad news in the preceding chapters , you probably have ming. Stress can wreak havoc with your metabolism, raise your blood pressure, burst your white blood cells, make you flatulent, ruin your sex life, and if that's not enough, possibly damage your brain.* Why don't we throw in the towel right now? there. This frequently hits me at e scene in a quiet, subtle way, it is There is hope. Although it may sneak onto th gerontology conferences. I' m sitting there, listening to the umpteenth lecture with the same general tone—the kidney expert speaking about how that organ di pert on how immunity declines, and sintegrates with age, the immunology ex so on. There is always a bar graph set to 100 percent of Something Or Other for young subjects, with a bar showing that the elderly have only 75 percent of the kidney-related Something Or Other of young subjects, 63 percent of the muscle-related Something Or Other, and so on. lves the study of populations, rather than Now, there's a critical featur e to those bar graphs. Research typically invo single individuals one at a time. All those individuals never have the exact same level of Something Or Other— instead, the bars in a graph represen t the average for each age (see the gra ph on page 386). Suppose one group of pecia areata." This is the * An additional pathology, for those who are really trivia fans when it comes to stre ss-related disease, is "stress-related alo and terrified by something that y over the course of days. technical term for that extraordinary state of getting so stressed your hair turns white or gra eata with law, history, surprisingly frequent intersection of alopecia ar This really does occur. The a nnotated notes at the end of the book detail the and geopolitics. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

196 Pa g e 196 of 212 Henri Matisse, The Dance, oil on canvas, 1910. 21, for an average of 20. Another group may have scores of 10, 20, and 30. three subjects has scores of 19,20, and They also have an average sc ore of 20, but the variability of those scores would be much larger. By the convention of e of how much variability oup: the size of the "T" there is within each age gr science, the bars also contain a measur es within X distance of the average. of the subjects in the group had scor above the bar indicates what percentage riability increases with age—the conditions of the elderly are One thing that is utterly reliable is that the amount of va always much more variable than those of the young subjects. What a drag, you say as a res earcher, because with that as neat and you have to include more subjects in your aged population to get a reliable variance your statistics are not the young and old subjects, look about that fact for a minute. Lo average. But really think ok at the size of the bars for and suddenly the extr variance symbols, do some quick calculations, at the size of the T-shaped aordinary realization hits you—to generate a bar with that large of a variance term, amid the population of, say, fifty subjects, there have to better, their be six subjects where Something Or Other is improving with age. Their kidney filtration rates have gotten better they do decreased, blood pressures have on memory tests. Suddenly you're not sitting there semi-bored in the conference, waiting for the break to grab some of those unhealthy cinnamon buns. You're on the edge of your seat. those six? What are they are Who Schematic presentation of the fact that individuals may receive the same average score on a a group of young and old given test, yet the variability in the scores is typically greater among the older populations. doing right? And with all scientific det achment abandoned, how can I do that, too? ect in the field: "successful ists. Now it's the trendiest subj This pattern used to be a statistical irritant to gerontolog aging." Not everyone falls apart miserabl y with age, not every organ system poops out, not everything is bad news. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

197 Pa g e 197 of 212 The same pattern occurs in many other realms in which life tests us. Ten men are released from years spent as friends and family, with nightmares, difficulties readapting political hostages. Nine come out troubled, estranged from to everyday life; some of those nine will never function well again. Yet invariably there is one guy who comes out the times they put a gun to my head an d cocked the trigger were the worst in saying, "Yeah, the beatings were awful, wasn't until I was in captivity that I realized what is really my life, of course I would never want to do it again, but it he do it? What explains the I'm almost grateful." How did important, that I decided to devote the rest of my life to X. st survivor who came out nearly as me extraordinarily rare Holocau ntally healthy as when she went in? Consider the physiological studies of people carrying out dangerous, stressful tasks—parachuting, learning to land on g out underwater demolition. The studies an aircraft carrier in choppy seas, carryin ve massive stress-responses and a subset are physiologically unflustered. show the same pattern: most people ha And then there's that hair-raising, push the envelope, unpredictable world of supermarket lines. You've picked the slow one, and your simmering irritation is made worse by the person behind you who looks perfectly happy standing there, daydreaming. of stress-related disease and Despite the endless ways in which stress can disrupt, we do not all collapse into puddles e not all exposed to identical external st ressors; but given the same stressors, psychiatric dysfunction. Of course, we ar even the same major stressors, we vary tremendously in how our bodies and psyches cope. This final chapter asks the can cope? How do they do it? And how can we? Chapter 15 questions born of hope. Who makes up that subset that suggested that some personalities and temperaments aren't well suited to dealing with stress, and it is easy to imagine the opposite case that some are. That's true, but this chap ter shows that having the "right" personality doesn't explain all successful coping—there's even hope for the rest of us. We begin by more systematically examining cases of individuals who just happen to be fabulous at dealing with stress. O ARE AMAZING AT DEALING WITH STRESS TALES FROM THE TRENCHES: SOME FOLKS WH Successful Aging successful aging, a subject that was cove red at length in chapter 12. Amid a lot Probably the best place to start is with ularly bleak set of findings had to do with glucocorticoids. Old rats, recall, of good news in that chapter, one partic have elevated levels during basal, non-stressful situations and difficulty secrete too much of these hormones—they the evidence that this could arise from damage to the shutting off secretion at the end of stress. I discussed hippocampus, the part of the brain that (in addition to playing a role in learning and memory) helps inhibit glucocorticoid secretion. Then, to complete the distressing st ory, it was revealed that gl ucocorticoids could hasten the of glucocorticoids to damage the hippocampus increases death of hippocampal neurons. Furthermore, the tendency the oversecretion of glucocorticoids, which in turn leads to more hippocampal damage, more glucocorticoids, spiraling downward. d cascade" model around twenty years ago. It I proposed that "feed forwar seemed to describe a basic and inevitable feature of aging ective, having just spent eighty hours a week important (at least from my provincial persp in the rat, one that seemed studying it in graduate school). I was pretty proud of myself. Then an old friend, Michael Meaney of McGill at deflated that grandiosity. University, did an experiment th mething clever first. that cascade in old rats. But they did so Meaney and colleagues studied Before starting the ry capacity of the rats. As is usual, on th e average these old rats had memory problems, studies, they tested the memo l, a subset were doing just fine, with no memory impairment whatsoever. compared with young controls. But as usua up of old rats into the impaired and the unimpaired. The latter turned out to show no Meaney and crew split the gro evidence at all of that degenerative f eed forward cascade. They had normal glucocorticoid levels basally and after stress. Their hippocampi had not lost neurons or lost receptors for glucocorticoids. All those awful degenerative had to do was age successfully. features turned out not to be an inevitable part of the aging process. All those rats have had something to do with their childhoods. If a rat is What was this subset of rats doing right? Oddly, it might handled during the first few weeks of its life, it secretes less glucocorticoids as an adult. This generated a syllogism: if of glucocorticoids secreted as an ad neonatal handling decreases the amount ult, and such secretion in an adult en handling a rat in the first few weeks of its life should influences the rate of hippocampal degeneration in old age, th alter the way it ages years later. Meaney's lab and I teamed up to test this and found exactly that. Do nothing more dramatic than pick a rat up an d handle it fifteen minutes a day for the first few weeks of its life, put it back in its cage feed forward cascade with the unhandled controls, come back two years later... and the handled rat is spared the entire of hippocampal damage, memory loss, and elevated glucocorticoid levels. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

198 Pa g e 198 of 212 Real rats in the real world don't get handled by graduate students. Is there a natural wo rld equivalent of "neonatal time licking and grooming at rat mothers who spend more handling" in the laboratory? Meaney went on to show th weeks induce the same handling phenomenon. It seems particularly pleasing that their pups in those critical first few this grim cascade of stress-rel ears earlier. No doubt by subtle mothering y ated degeneration in old age can be derailed riential factors that bias a ssful aging, a subject that rat toward successful or unsucce there are other genetic and expe now, however, is simply that this degeneration is not Meaney still pursues. Of greatest importance for our purposes inevitable. If the fates of inbred laboratory rats are this variable, how humans fare is likely to be even more diverse. Which of the material in chapter 12, plain ol humans age successfully? To review some d aging itself is more successful than social networks decrease in not decline with age. While many would guess. Levels of self-assessed contentment do the United States, the av erage eighty-five-year-old size, they don't decline in quality. In spends little time in an institution (a year and a half for women; half a year for men). The average person in th at age range, taking three to And another very good thing: despite eight medications a day, nevertheless ty pically categorizes herself as healthy. the inherent mathematical impossibility, the average aged pers on considers herself to be healthier and better off than the average aged person. successfully? As we saw in th Amid that good news, who are the people who age particularly e last chapter, one factor is making sure you pick parents who were not poor. But there are other factors as well. The psychiatrist George Vaillant has been looking at this for years, beginning with his famous Harvard aging study. In 1941, a Harvard dean picked out a couple of hundred undergraduates (all male back then, naturally), who would be studied for the rest of of the rest of their Harvard peers, their lives. For starters, at age sixty-fi ve, these men had half the mortality rate already a successfully aging crowd. Who we re the students picked by that dean? Students whom he considered to be age successfully and the ying to figure out how to a fifty-year-old woman tr "sound." Oh hell, you're thinking—I'm a 1940s Boston Brahmin with a pipe and tw eed jacket would consider me to be a prescription is to act in a way so that sound twenty-year-old fellow? Fortunately, Vaillant's research gives us more to work with than that. Among this population, which subset has had and longevity in old age? A su bset with an array of traits , apparent before age fifty: the greatest health, contentment, no smoking, minimal alcohol use, lots of exercise, normal body weight, absence of depression, a warm, stable style (which seems built around extrov ersion, social conn marriage, and a mature, resilient coping ectiveness, and low resilient coping style, or gets the capacity for a mature neuroticism). Of course, none of this tells you where someone the social means to have a stable marr iage. Nor does it control for the possibility that men who, for example, have been drinking excessively have done so because they've had to deal with more than their share of miserable stressors. Despite those confounds, findings like these have emerge d from other studies, and with more representative populations than Harvard graduates. Joseph Greenstein, "The Mighty Atom," in old age. An idol of my youth, Greenstein was still performing his feats of strength in Madison Square Garden as an octogenarian. He attributed it to clean, vegetarian living. Another literature shows the tremendous ge rontological benefits of being respect ed and needed in old age. This has been shown in many settings, but is best appreciated with our society's equivalents of village elders—the dramatically successful aging of Supreme Court justic es and conductors. It certainly fits with everything we learned about in chapter 13—you're eighty-five, and you get to influence your nation's laws for a century to come, or spend your days 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

199 Pa g e 199 of 212 aerobically exercising by waving your baton about and determining whether a whole orchestra full of adults gets a potty break before or after another run through Wagner's Ring Cycle.* The study of successful aging is a young field, and some mammoth longitudinal studies are under way that will traits predict successful aging, , not only about what but where those traits come from. produce a treasure trove of data lks out there who successfully see that there are lots of fo In the meantime, though, the point for this chapter is to navigate one of the most stressful passages of life. e highly publicized finding that winning an Oscar at any point in your life extends y * The issue of respect may help explain th our life expectancy tive to actors who were nominated but didn't win. about four years, rela Coping with Catastrophic Illness investigate whether psychological stress triggers the same In the early 1960s, when scientists were just beginning to hormonal changes that physical stressors do, a group of psychiatrists conducted what has become a classic study. It cancer and the high glucocorticoid leve ls that those pare nts secreted. There concerned the parents of children dying of of the parents secreted immense quantities of glucocorticoids; others were was great variance in this measure—some atric interviews, explored which parents were holding up in the normal range. The investigators, in in-depth psychi best to this horrible stressor, and identified a number of coping styles associated with lower glucocorticoid levels. One important variable was the ability of parents to displace a major worry onto something less threatening. A father for weeks. It's clear to ev eryone that he needs to get away for a few days, to has been standing vigil by his sick child gain some distance, as he is near a br eaking point. Plans are made for him to l eave, and just before he does, he is one extreme is the parent who says, "I've feeling great anxiety. Why? At seen how rapidly medical crises can develop at if she dies without me?" and dies while I am away? Wh at this stage. What if my daughter suddenly gets very sick ho can repackage the anxiety into someth ing more manageable—"Well, I'm just At the other extreme is the parent w worried that she'll be lonely without me, that the nurses wo n't have time to read her favorite stories." The latter style was associated with lower glucocorticoid levels. A second variable had to do with denial. When a child went into remission, which frequently happened, did the parent er with, there's nothing to worry about, we don't even want look at him and say to the doctor, "It's ov to hear the word every cough, every pain, every sly at the child, wondering if 'remission,' he's going to be fine"? Or did she peer anxiou instant of fatigue was a sign that the disease had returned? During periods of remission, parents who denied that relapse and death were likely and instead focused on the seemingly healthy moment had lower glucocorticoid levels (as we will see shortly, this facet of the study had a very different postscript). religious rationalization to explain the illness. At one A final variable was whether the parent had a structure of extreme was the parent who, while obviously profoundly distressed by her child's cancer, was deeply religious and ling an increase in her self- perceived the cancer to be God's test of her family. She ev en reported something resemb esteem: "God does not choose just anyo ne for a task like this; He chose d could handle this." At the other extr us because He knew we were special an eme was the parent who said, in effect, "Don't tell me that God works in mysterious ways. In fact, I don't want to hear about God." The researchers found that if you can look at your special task, you are likely to at God is choosing you for this child having cancer and decide th have less of a stress-response (the larger issue of re ligious belief and health w ill be considered shortly). Differences in Vulnerability to Learned Helplessness In chapter 14,1 described the learned helplessness mode l and its relevance to depression. I emphasized how generalized the model appears to be: anim als of many different species show some version of giving up on life in the face of something aversive and out of their control. about learned helplessness, there is the usual—bar graphs with T-shaped Yet when you look at research papers variance bars indicating large differences in response. For example, of the laboratory dogs put through one learned helplessness paradigm, about one-third wind up being resistan t to the phenomenon. This is the same idea as the one an when he went in. Some folks and captivity a mentally healthier person th out of ten hostages who comes out of some animals are much more resist ant to learned helplessness than average. Who are the lucky ones? Why are some dogs relatively resistant to learned helplessness? An important clue: dogs born and raised in poses, are more likely to succumb to learned helplessness than those who have laboratories, bred only for research pur come to the lab by way of the pound. Martin Seligman offers this explanation: if a dog has been out in the real world, experiencing life and fending for itself (as the dogs who wind up in a pound are likely to have done), it has learned e are in life. When the experience with an uncontrollable stressor occurs, the about how many controllable things ther ful, but it isn't the entire world." It resists globalizing the dog, in effect, is more likely to conclude that "this is aw locus of control—the of an internalized ess. In a similar vein, humans with more stressor into learned helplessn 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

200 Pa g e 200 of 212 perception that they are the masters of their own destiny—are more resistant in experimental models of learned helplessness. Lessons from the Baboons More Stress Management imates, and some critical variables that shaped social Chapters 15 and 17 introduced social pr success for them: experience of both, and perhaps ich rank occurs, the personal dominance rank, the society in wh llian world, we sa most important, the role played by pers w there is more to social success onality. In their Machiave and health for a male than just a lot of muscle or some rtant are social and political big sharp canines. Just as impo away from provocations. The skills, the ability to build coalitions, and the ability to walk personality traits associated e context of effective handling of psychological stressors— with low glucocorticoid levels certainly made sense in th actions with rivals, to exert some control over social the abilities to differentiate threatening from neutral inter ove all else, the ability to make social om bad, to displace frustration. And, ab conflicts, to differentiate good news fr connections—grooming, being groomed, playing with infants. So how do these variables pl ay out over time, as these animals age? for anywhere from fifteen to twenty-five years. Which Baboons are long-lived animals, sticking around the savanna means you don't get to follow an animal from its first awkward bloom of puberty into old age very readily. Twenty- me of these animals, and the five years into this project, I'm just beginning to get a se nse of the life histories of so dividual differences. development of their in onalities were likely to remain in the high-ranking cohort As a first finding, males with the "low glucocorticoid" pers nk-matched males with high glucocorticoid profiles. About three times longer. Among significantly longer than ra other things, that probably means that the low-glucocorticoid guys are outreproducing the other team. From the is is a big difference. It on—passing on copies of your genes, all that jazz—th standpoint of evoluti suggests that if you ennia, allow that differenti al selection to play out, were to go away for a couple of zillion mill and then return to finish your doctoral dissertation, your average baboon would be a descendent of these low-glucocorticoid guys, and the baboon social world would involve a lot of impulse control and gratification postponement. Maybe even toilet training. And what about the old ages of these individual baboons th at are alive today? The most dramatic difference I've uncovered concerns the variable of social affiliation. Your average male baboon has a pretty lousy old age, once he's gotten a paunch and some worn canines and dropped down to th e cellar of the hierarchy. Lo ok at the typical pattern of in the hierarchy is having most of his interactions with dominance interactions among the males. Usually, Number 3 stly concerned with 14 and 16 (excep Numbers 2 and 4, while Number 15 is mo t, of course, when 3 is having a bad then usually occur between animals someone way down). Most interactions day and needs to displace aggression on at the top-ranking ha of adjacent ranks. However, amid that pattern, you'll note th lf-dozen or so animals, nevertheless, are spending a dominance displays, displacing him from whatever he is lot of time subjecting poor Number 17 to a lot of humiliating eating, making him get up whenever he settles into a nice shady spot, just generally giving him a hard time. What's that about? Number 17 turns out to have been very high-ranking back when the current dominant animals were terrified adolescents. They remember, and it ex-king grovel anytime they feel can't believe they can make this decrep like it. So as he ages, your average male baboon gets a lot of grief from the current generation of thugs, and this often leads to a particularly painful way of passing your golden years—the treatment gets so bad that the male picks up and with an extremely high transfers to a different troop. That's a stressful, hazardous journey, mortality rate for even a ain, chancing predators on your own. All that to wind up in a new troop, prime-aged animal—moving across novel terr d age; namely, aging is a time of life subject to an extreme version of that to o-frequently-true truism about primate ol being low-ranking, aged, and ignored among strangers is spent among strangers. Clearly for a baboon in that position, better than being low-ranking, aged, and remembered by a vengeful generation. orticoid personality, spending lots of time affiliated with But what about males who, in their prime, had a low-glucoc females, grooming, sitting in contact, playing with kids? They just keep doing the same thing. They get hassled by the current rulers, but it doesn't seem to count as much as th baboons. They don't transfer e social connectedness to these ation for the rest of their liv es. That seems like a pretty troops, and continue the same pattern of grooming and socializ good definition of successful aging for any primate. APPLYING PRINCIPLES OF DEALING WITH PSYC HOLOGICAL STRESS: SO ME SUCCESS STORIES tal illness, a low-ranking baboon who has a network of Parents somehow shouldering the burden of their child's fa dividuals who, faced with a less than ess—these are striking examples of in friends, a dog resisting learned helplessn ideal situation, nevertheless excel at co ping. That's great, but what if you don't already happen to be that sort of 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

201 Pa g e 201 of 212 individual? When it comes to rats that wish to age successfully, the useful bit of advice a previous section generates is to make sure you pick the right sort of infancy. When it comes to humans who wish to cope with stress and achieve successful aging, you should be sure to pick the right parents' genes, and the right parents' soci oeconomic status as well. The other cases of successfully coping with stress may not be any more encouraging to the rest of us. What if we happen not to be the sort of baboon who looks at the bright side, the person who holds on to hope when others become hopeless, the parent of the child with cancer who somehow psychologically manages the unm ories of individuals who anageable? There are many st the world around us and to alter our ngifted ones, are there ways to change have supreme gifts of coping. For us u perceptions of it so that psychological st ress becomes at least a bit less stressful? rst thing to emphasize is that nge our coping styles. But a fi The rest of the chapter is devoted to ways in which to cha change the way we cope, both physiologically and psychologically. As the most obvious example, physical we can conditioning brought about by regular exercise will lower bl ood pressure and resting heart rate and increase lung erapy can change not only behaviors effects. Among Type-A people, psychoth capacity, just to mention a few of its but also cholesterol profiles, risk of heart attack, and risk of dying, independent of changes in diet or other physiological regulators of cholesterol. As another example, the pain and stressfulness of childbirth can be modulated by relaxation techniques such as Lamaze.* ivities can change the connection between your behavior and activation of your stress- Sheer repetition of certain act dy discussed earlier, Norwegian ute were examined over the response. In one classic stu soldiers learning to parach course of months of training. At the time of their first jump, they were all terrif ied; they felt like vats of Jell-O, and and epinephrine levels were elevated, their bodies reflected it. Glucocorticoids testosterone levels were suppressed— all for hours before and after the jump. As they repeated the experience, master ed it, stopped being terrified, their hormone secretion patterns changed. By the end of training they were no longer turning on their stress-response hours able to confine their stress -response to an appropriate before and after the jump, only at the actual time. They were ssor; the entire psychological component of the stress-response had been moment, when there was a physical stre habituated away. rkings of the stress-response can change over time. We grow, learn, adapt, get All of these examples show that the wo bored, develop an wonders for, like , * Well, I'm not so sure about that one. I' ve now watched my wife go through two deliver ies, and Lamaze worked maze class notes. lessly reviewing La quat, other than occupy me with point three minutes, after which it didn't do s interest, drift apart, mature, harden, fo the buttons we can use to manipulate rget. We are malleable beasts. What are the system in a way that will benefit us? ress are obviously critical: control, predictability, social The issues raised in the chapter on the psychology of st support, outlets for frustrati ve reported some laboratory success in on. Seligman and colleagues, for example, ha ed with an unsolvable task—if subjects are first given buffering people from learned helplessness when confront "empowering" exercises (various tasks that t this is a fairly artificial setting. they can readily master and control). Bu variables in the real world, even some of the grimmest Some classic studies have manipulated similar psychological two examples with startling results. parts of the real world. Here are SELF-MEDICATION AND CHRONIC PAIN SYNDROMES Whenever something painful happens to me, amid all the di stress I am surprised at being reminded of how painful pain is. That thought is always followed by another, "What if I hurt like this all the tim e?" Chronic pain syndromes are extraordinarily debilitating. Diabetic neuropathies, crushed sp inal nerve roots, severe burn s, recovery after surgery can all be immensely painful. This poses a medical problem, insofar as it is often difficult to give enough drugs to control nurse will attest, this also the pain without causing addiction or putting the person in da nger of an overdose. As any ds half the day hitting the call button, wanting to know poses a management problem, as the chronic pain patient spen when his next painkiller is coming, and the nurse has to spend half the day explaining that it is not yet time. A my father was hospitalized for something. In the room next memory that will always make me shudder: at one point, door was an elderly man who, seemingly around the clock, every thirty seconds, would plaintively shout in a heavy It hurts. It hurts! Nurse!" The first day it was horrifying. The second day it was Yiddish accent, "Nurse. Nurse! impact of the rhythmic chirping of crickets. irritating. By the third day, it had all the Awhile back some researchers got an utterly mad idea, the thought of frothing lunatics. Why not give the painkillers imagine the apoplexy that mainstream en they need medication? You can just to the patients and let them decide wh medicine had over that one—patients will overdose, become addicts, you can't let patients do that. It was tried 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

202 Pa g e 202 of 212 with cancer patients and postsurgical pa tients, and it turned out that the patients did just fine when they self- decreased. ount of painkillers consumed medicated. In fact, the total am n go down? Because when you are ly ing there in bed, in pain, un Why should consumptio certain of the time, uncertain if the nurse has heard your call or will have time to respond, uncertain of everything, you are asking for painkillers not only to stop the pain but also to stop the uncertainty. Reinstitute control and predictability, give the patient the knowledge that the medication is there fo r the instant that the pain becomes too severe, and the pain often becomes far more manageable. INCREASING CONTROL IN NURSING HOMES veal the nature of psychological stress than a nursing home. Under the best of I can imagine few settings that better re circumstances, the elderly tend to have a less active, less a ssertive coping style than young people. When confronted the former are more likely to by stressors, the latter are more likely to try to confront and solve the problem, while adjust their attitude toward it. Th distance themselves from the stressor or e nursing home setting worsens these from the social support which you are often isolated tendencies toward withdrawal and passivity: it's a world in network of a lifetime and in which you have little control over your daily activities, your finances, often your own are often treated like a child— "infantilized." Your easiest body. A world of few outlets for frustration, in which you prediction is "life will get worse." A number of psychologists have ventured into this world to try to apply some of the ideas about control and self- s of a nursing home were efficacy outlined in chapter 13. In one study, for example, resident given more responsibility for everyday decision making. They were made responsible for choosing their meals for the next day, signing up in their room, instead of ha and caring for a plant for ving one placed there and advance for social activities, picking out cared for by the nurses ("Oh, here, I'll water that, dear; why don't you just get back into bed?"). People became more themselves in questionnaire s as happier. Their health active—initiating more social interactions—and described improved, as rated by doctors unaware of whether they were in the increased-responsibility group or the control the former group was half that of the latter. group. Most remarkable of all, the death rate in In other studies, different variables of control were manipulated. Almost unanimously, these studies show that a moderate increase in control produces all the salutary effects just described; in a few studies, physiological measures ocorticoid levels or improved immune function. The forms were even taken, showing changes like reductions in gluc many. In one study, the baseline group was left alone, while the experimental that increased control could take were group was organized into a residents' council that made decisions about life in the nursing home. In the latter group, health improved and individuals showed more voluntary particip ation in social activities. In another study, residents in nce because of the financial collapse of the first moved to a different reside ng involuntarily a nursing home were bei institution. The baseline group was moved in the normal manner, while the experimental group was given extensive lectures on the new home and given control of a wide variety of issues connected with the move (the day of the move, the decor of the room they would liv ccurred, there were far fewer medical e in, and so on). When the move o complications for the latter group. The infantilizing effects of loss of control were shown explicitly in another study in encouraged them, performance improved; which residents were given a variety of tasks to do. When the staff present helped when the staff present them, performance declined. Another example of these principles: this study concerned visits by college students to people in nursing homes. One nursing-home group, the baseline group, received no student visitors. In a second group, students would arrive at unpredictable times to chat. There were va rious improvements in functioning and health in this group, testifying to the positive effects of increased social contact. In the th ird and fourth groups, control and predictability were introduced—in the third group, the residents could decide wh en the visit occurred, whereas in the fourth they could ng and health improved even more in when the visit would take place. Functioni not control it, but at least were told both of those groups, compared with the second. Control an d predictability help, even in settings where you think it won't make a dent in someone's unhappiness. STRESS MANAGEMENT: READING THE LABEL CAREEULLY ers to coping with stress that are far These studies generate some simple answ from simple to implement in everyday life. They emphasize the importance of manipulating feelings of control, predictability, outlets ing. In effect, the for frustration, social connect edness, and the perception of whether things are worsening or improv om the front lines in this war of coping. Their simple, nursing home and pain studies are encouraging dispatches fr empowering, liberating message: if manipulating such psychological variables can work in these trying circumstances, it certainly should for the more trivial psychological stressors that fill our daily lives. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

203 Pa g e 203 of 212 This is the message that fills stress management semina rs, therapy sessions, and the many books on the topic. ze finding means to gain at least some degree of control in difficult situations, viewing bad Uniformly, they emphasi e ones, finding appropriate outlets for frustration and than permanent or pervasiv situations as discrete events rather d solace in difficult times. means of social support an at simple. It is critical that That's great. But it is vital to realize that the story is not th one not walk away with the conclusion that in order to manage and minimize psychological stressors, the solution is always to have more of a social affiliation. These prin sense of control, more predictability, more outlets, more ciples of stress management work only in certain circumstances. And only for certain types of people with certain types of problems. I was reminded of this awhile back. Thanks to this book's having transformed me from being a supposed expert about rats' neurons to being a supposed one about human stress, I was talking to a magazine writer about the subject. She how to maintain that full satisfying sex life while being the wrote for a women's magazine, the type with articles about CEO of a Fortune 500 company. We were talking about stress and stress management, and I was giving an outline of some of the ideas in the chapter on ps ychological stress. All was going well, and toward the end, the writer asked me a for dealing with stress. I made the mistake of cle—what are my outlets personal question to include in the arti answering honestly—I love my work, I try to exercise daily, and I have a fabulous marriage. Suddenly, this hard- nosed New York writer blew up at me—"I can't write about your wonderful marriage! Don't tell me about your readers are? They're forty-five-year-old professionals who are unlikely to wonderful marriage! Do you know who my in this category as well. It ever get married and want to be told how great that is!" It st ruck me that she was, perhaps, rats and test tubes afterward, what an idiot I had been. You don't counsel war also struck me, as I slunk back to my d fats in their diet. You don't tell an overwhelmed single refugees to watch out about too much cholesterol or saturate mother living in some inner-city hellhole about the stress-reducing effects of a daily hobby And you sure don't tell the a soul mate for life. "More control, more predictability, more readership of a magazine like this how swell it is to have outlets, more social support" is not some sort of mantra to be handed out indiscriminately, along with a smile button. This lesson is taught with enormous power by two studies th at we have already heard about, which seem superficially to be success stories in stress management but turned out not to be. Back to the parents of children with cancer who children came out of remission and di were in remission. Eventually, all the ed. When that occurred, how did the along had accepted the possibility, even parents fare? There were those who all lapse, and there probability, of a re ing the period of remission the latter parents tended to were those who staunchly denied the possibility. As noted, dur t when their illusions were shattered and the disease returned, they had the be the low glucocorticoid secretors. Bu ocorticoid concentrations. largest increases in gluc rsing home study. Recall the one in which ng comes from a nu ion of this unfortunate endi An equally poignant vers residents were visited once a week by students—either un time predetermined by the announced, at an appointed e some good, but the people in the last choice. As noted, the sociality did everyon student, or at a time of the resident's two groups, with the increased predicta study, celebration, Wonderful, end of bility and control, did even better. the clear-cut and positive results, papers to be published, lectures to be given. Student everyone delighted with participants visit the people in the nursing home for a last time, offer an awkward, "You know that the study is over now, I, er, won't be coming back agai n, but, um, it's been great getting to know you." What happens then? Do the people whose functioning, happiness, and health improved now decline back to pre-experiment levels? No. They drop even further, winding up worse than before the study. This makes perfect sense. Think of how it is to get twenty-five shocks an hour when yesterday you got ten. Think of what it feels like to have your child come out of remission after you spent the last year denying the possibility that it could ever happen. And think about those nursing home residents: it is one thing to be in a nursing home, lonely, isolated, visited once a month by your bored children. It is ev ation and, having had a chance en worse to be in that situ ey aren't coming anymore. to spend time with bright, eager young people who seemed intere sted in you, to find now th loss. It is true that hope, All but the most heroically strong among us would slip anot her step lower in the face of this no matter how irrational, can sustain us in the darkest of times. But nothing can break us more effectively than hope given and then taken away capriciously. Manipulating these psychological variables is a powerful but double-edged sword. and when are When do these principles of in sociality, work predictability, of outlets, of jecting a sense of control, of me rules. Let's look at some specific stress management approaches and when they disastrous to apply? There are so they work, keeping those rules in mind. EXERCISE I start with exercise because this is the stress reduction approach I rely on frequently , and I'm deeply hoping that putting it first will mean that I'll live to be very old and healthy. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

204 Pa g e 204 of 212 Exercise is great to counter stress for a number of reasons. First, it decreases your risk of various metabolic and ress to worsen those diseases. e decreases the opportunity for st cardiovascular diseases, and therefor Next, exercise generally makes you feel good. There's a confound in this, in that most people who do a lot of exercise, athletics, have unneurotic, extroverted, optimistic personalities to begin with particularly in the form of competitive (marathon runners are exceptions to this). However, do a pr operly controlled study, even with neurotic introverts, and probably has something to do with exercise exercise improves mood. This causing the secretion of beta-endorphin. In ood stuff you try to recall cacy and achievement, that g when your thigh muscles addition, there's the sense of self-effi are killing you in the middle of the aerobics class. And most of all, the stress-response is about preparing your body for a sudden explosion of muscular activity. You reduce tension if you actually turn on the stress-response for that purpose, instead of merely stewing in the middle of some time-wasting meeting. nse to various psychological stressors. Finally, there's some evidence that ex ercise makes for a smaller stress-respo That's great. Now for some qualifiers: after the exercise session. ly for a few hours to a day Exercise enhances mood and blunts the stress-response on ■ ■ Exercise is stress reducing so long as it is something you actually want to do. Let rats voluntarily run in a running wheel and their health improv es in all sorts of ways. Force them to, even whil e playing great dance music, and their health worsens. lth (aerobic exercise is the at aerobic exercise is better ■ The studies are quite clear th than anaerobic exercise for hea sustained type that, while you're doing it, doesn't leave you so out of breath that you can't talk). careers are consumed figuring sustained period. While whole ■ Exercise needs to occur on a regular basis and for a cise works best (how often, for how long) , it's pretty clear that you need to out exactly what schedule of aerobic exer or thirty minutes at a time, a few times a week, to really get the health benefits. exercise a minimum of twenty be at least as bad as too little. Don't overdo it. Remember the ■ lessons of chapter 7—too much can MEDITATION When done on a regular, sustained basis (that is to say, some thing close to daily, for fifteen, thirty minutes at a time), ing glucocorticoid levels, sympathetic tone, and all the bad meditation seems to be pretty good for your health, decreas er can cause. Now the caveats: stuff that too much of eith showing physiological benefits First, the studies are clear in while someone is meditating. It's less clear that those good effects (for example, lowering blood pressure) persist for long afterward. Next, when the good effects of meditation do persist, there may be a subject bias going. Suppose you want to study randomly the effects of meditation on blo assign some people to the control group, od pressure. What do you do? You making sure they never meditate, and some to the group that now meditate an hour a day. But in most studies, there to be regular chosen isn't random assignment. In other words, you study blood pressure in people who have already random who chooses to meditate—maybe the physiological meditators, and compare them to non-meditators. It's not e traits even had something to do with their choosing to traits were there before they started meditating. Maybe thos meditate. Some good studies have avoided this confound, but most have not. s of meditation. Don't trust anyone who says that their special brand has been Finally, there are lots of different type ealth than the other flavors. Watch your wallet. proven scientifically to be better for your h GET MORE CONTROL, MORE PREDICTABILI TY IN YOUR LIFE . . . MAYBE More predictive information about impending stressors can be very stress-reducing. But not always. As noted in ese are basically chapter 13, it does little good to ge t predictive information about common events (because th (because you weren't anxious about them in the first place). It does little good inevitable) or ones we know to be rare to get predictive information a few s econds before something bad happens (becau se there isn't time to derive the vance of the event (because who's worrying being able to relax a bit) or way in ad psychological advantages of anyway?). things worse—for example, wh en the information tells you In some situations, predictive information can even make about your normal business but be extra careful"—Orange little. This turfs us back to our post-9/11 world of "Go Alerts. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

205 Pa g e 205 of 212 An overabundance of information can be stressful as well. One of the places I dreaded most in graduate school was nce journals received the prev e library, where all the scie the "new journal desk" in th ious week were displayed, teetering on the edge of panic thousands of pages of them. Everyone would circle around it, attacks. All that available felt—stupid, left behind, out of touch, and overwhelmed. information seemed to taunt us with how out of control we Manipulating a sense of control is playing with the variable in psychological stress that is most likely to be double- ng, whether the sense is accurate or not. An example: edged. Too much of a sense of control can be crippli When he was a medical student, a friend embarked on his surgery rotation. That first day, nervous, with no idea what at the back of a crowd of to expect, he went to his assigned operating room and stood doctors and nurses doing a kidney transplant. Hours into it, the chief surgeon suddenly turned to him: "Ah, you're the new medical student; good, come here, grab this retractor, hold it right here, steady, good boy." Surgery continued; my friend was ignored as he comfortable position the surgeon had put him in, leaning forward at an angle, one arm precariously maintained the un see what was going on. Hours passed. He grew woozy, faint thrust amid the crowd, holding the instrument, unable to ose—when the surgeon loomed ering, eyes beginning to cl from the tension of holding still. He found himself teet before him. "Don't move a muscle because you're going to screw up EVERYTHING!" Galvanized, pani cked, half-ill, he barely held on ... only to discover that the "you're going to screw up everything" een holding an inst scenario was a stupid hazing trick don e to every new med student. He had b rument over some irrelevant part of the body the entire time, fooled into feeling utterly responsible for the survival of the patient. (P.S.: medical specialty.) He chose another e is between stress As another example, recall the discussion in chapter 8 on how tenuous a link ther and cancer. It is clearly a travesty to lead cancer patients or their famili es to believe, misinterpreting the power of the few positive control over the causes and courses of cancers than actually studies in this field, that there is more possibility for the disease is their own fault, which is exists. Doing so is simply teaching the victims of cancer and their families that neither true nor conducive to reducing stress in an already stressful situation. So control is not always a good thing psychologically, and a principle of good stress management cannot be simply to plies, as we saw in chapter increase the perceived amount of control in one's life. It depe nds on what that perception im 13. Is it stress-reducing to feel a sense of control when something bad happens? If you think, "Whew, that was bad, but imagine how much worse it would have been if I hadn't been in charge," a sense of control is clearly working to buffer you from feeling more stressed. However, if you thin k, "What a disaster and it's all my fault, I should have prevented it," a sense of control is working to your detriment. This dichotomy can be roughly translated into the disastrous a stressor is, the worse it is to believe you had following rule for when something stressful occurs: the more e, because you are inevitably some control over the outcom led to think about how much better things would have turned out if only you had done something more. A sense of control works best for milder stressors. (Remember, this advice concerns the sense of control you perceive yourself as having, as opposed to how much control you actually have.) it gets a special name in pathogenic that one version of Having an illusory sense of control in a bad setting can be so the health psychology literature. It could have been included in chapter 15, but I saved it until now. As described by e American folk hero who, yism. The name refers to th Sherman James of Duke University, it is called John Henr l drill, tried to outrace a st ling through a mountain. John Henry beat the hammering a six-foot-long stee eam drill tunne machine, only to fall dead from the su perhuman effort. As James defines it, John Henryism involves the belief that rk hard enough. On questionnaires, John Henry individuals any and all demands can be vanquished, so long as you wo y I want them, it just makes me work even strongly agree with stat ements such as "When things don't go the wa harder," or "Once I make up my mind to do something, I stay with it until the job is com- believe that, with enough internal locus of control—they pletely done." This is the epitome of individuals with an can regulate all outcomes. effort and determination, they What's so wrong with that? Nothing, if you have the good fortune to live in the privileged, meritocratic world in ortable, middle-class world, rewards one gets, and in a comf which one's efforts truly do have something to do with the an internal locus of control does wonders . For example, always attr ibuting events in life to your own efforts (an internal locus of control) is highly predictive of lifelong health among that population of individuals who are the tum of society—Vaillant's cohort of Harvard graduates. However, in a world of people epitome of the privileged stra born into poverty, of limited educational or occupational oppor sm, it can be a disaster to tunities, of prejudice and raci be a John Henry, to decide that those insurmountable odds could have been surmounted, if only, if only, you worked nd cardiovascular disease. Strikingly, even harder—John Hen-ryism is associated wi th a marked risk of hypertension a James's pioneering work has shown that the dangers of John Henryism occur predominantly among the very people rsonality type that leads ng-class African Americans—a pe who most resemble the mythic John Henry himself, worki you to believe you can control the aversively uncontrollable. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

206 Pa g e 206 of 212 There's an old parable about the differen ce between heaven and hell. Heaven, we are told, consists of spending all of eternity in the study of the holy books. In contrast, hell consists of spending all of eternity in the study of the holy ons of events can determine whether the same external books. To a certain extent, our perceptions and interpretati and the second half of this book has explored the means to convert the latter circumstances constitute heaven or hell, to the former. But the key is, "to a certain extent." The realm of stress management is mostly about techniques to help is pretty effective in that sphere. But it just won't work to generate es that are less than disastrous. It deal with challeng echniques are blithely offered as a solution to the hell of a homeless street a cult of subjectivity in which these t udged to be one of society's Untouchables, person, a refugee, someone prej patient. Occasionally, or a terminal cancer there is the person in a situation like that with coping powers to make one gasp in wonder, who does indeed benefit from these techniques. Celebrate them, but that's never grounds for turning to the person next to them in the same boat and offering that as a feel-good incentiv ience, bad clinical practice, and, e just to get with the program. Bad sc en you could make the world a better ultimately, bad ethics. If any hell really could be converted into a heaven, th rself from your lounge place merely by rousing you victim of some horror whose fault it is if they are chair to inform a unhappy. SOCIAL SUPPORT This far into this book, this one should be a no brainer—so cial support makes stressors le ss stressful, so go get some. Unfortunately, it's not so simple. To begin, social affiliation is not always the solution to stressful psychological turmoil. We can easily think of people who would be the last ones on earth we would want to be stuck with when we are troubled. We can easily think of anyone troubled circumstance s where being with would make us feel worse. Physiological studies have demonstrated a social group. Th that has been housed alone and put it into this as well. Take a rodent or a primate e typical result is a massive stress-response. In the case of monkeys, this can go on for weeks or months while they tensely go about figuring out who dominates whom in the group's social hierarchy* were separated from their mothers. Predictably, they had In another demonstration of this principle, infant monkeys ations in glucocorticoid levels. The elev pretty sizable stress-responses, with elev ation could be prevented if the infant ly if the infant already knew those anim als. There is little to be derived in was placed in a group of monkeys— but on the way of comfort from strangers. oup will be socially dominant to any on average half of those in any gr Even once animals are no longer strangers, given individual, and havi ng more dominant an imals around is not necessa rily a comfort during tr ouble. Even intimate social affiliation is not always helpful. We saw in psychoim munity chapter 8 that being ma rried is associated with all thy people are less likely to d reverse causality trick—unheal sorts of better health outcomes. Some of it is due to the ol get married. Some is due to the fact that marriage often increases the material well-being of people and gives you someone to remind and cajole you arch; one well- ing of primates used for rese improve the psychological well-be * Some time back, the U.S. government proposed new guidelines to vidually during a study should, at least once a week, spend time intentioned but uninformed feature was that monkeys housed indi in a group of chronic social stress, and it was clear t hat the regulations n had been studied for years as a model of other monkeys. That precise social situatio some expert would do nothing but increase the psychological well-being of thes e animals. Fortunately, the proposed rules were changed after testimony. into cutting back on some lifestyle risk factors. After cont rolling for those factors, marriage , on average, is associated with improved health. But that chapter also noted an obvious but important exception to this general rule: for women, being in a bad marriage is associated with immune suppression. So a close, intimate relationship with the wrong person can be anything but stress-reducing. k of friends and, as we saw in the last chapter, to be in Expanding outward, it is also healthful to have a strong networ a community teeming with social capital. What's the potential downside of th at? Something I alluded to. Amid all that at a tightly cohesive, cooperative community with s the inconvenient fact th nice, Utopian social capital business lurk shared values may be all about homogeneity, conformity, and xenophobia. Maybe even brownshirts and jackboots. So social capital isn't always warm and fuzzy. Throughout this section I have been emphasizing getting social support from the right person, the right network of friends, the right community. Often, one of the strongest stress-reducing qualities of social support is the act of giving h-century philosopher Maimonides construc ted a hierarchy of the best ways to social support, to be needed. The twelft sly to an anonymous recipient. That's do charitable acts, and at the top was wh en the charitable person gives anonymou a great abstract goal, but often there is a staggering power in seeing the face that you have helped. In a world of world a better place, one the ability to make the l, an amazing source of control we all have is stressful lack of contro act at a time. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

207 Pa g e 207 of 212 RELIGION AND SPIRITUALITY The idea that religiosity or spirituality protects against di sease, particularly against stress-related disease, is earchers in this fiel that their read of immensely controversial. I've encountered some of the key res d, and have noticed ews. For that reason, I think it would be helpful to put my the literature often coincides with their personal religious vi cards on the table before tackling this subject. I had a highly orthodox religious upbringing and believed devoutly. no room in my life for spirituality of any kind, and believe that religion is Except that now I am an atheist, have phenomenally damaging. Except that I wish I could be religious. Except that it makes no sense to me and I'm baffled I'm also moved by them. So I' by people who believe. Except that m confused. On to the science. A huge literature shows that religious belief, religious practice, spirituality, and being prayed for can maintain good cidence of disease, decreases the morta health—that is to say, decreases the in lity rates caused by disease (put those very from disease. So what's the two effects together and you have ex tended life span), and accelerates reco controversy? irituality? The former is about an institutionalized system First, some definitional issues. What's religiosity versus sp rsonal. As pointed out by Ken Pargament of with a historical precedent and a lot of adherents; the latter is more pe Bowling Green University, the ean formal, outward-oriented, doctrinal, authoritarian, and former has also come to m inhibiting of expression, while the latter often implies subj ective, emotional, inward-oriented, and freely expressive. When comparing religious people with people who define th emselves as spiritual but without a religious affiliation, ated, and lower in socioeconomic status, the former tend to be older, less educ with a higher percentage of men. So t despite that, the health literature says roughly similar religiosity and spirituality can be very different things. Bu things about both, so I'm going to use them interchangeably here. any benefits. those studies showing health benefits, it's whether there really What's the controversy? Amid all are ecause many of the studies volve mistakes that should have are loony, or in Why so much uncertainty? For starters, b been sorted out in the middle school science fair. But even among the serious studies, it is very hard to carry out research in this area with approaches th the science business. For starters, most at would count as the gold standard in studies are retrospective. Moreover, people are usually assessing their own level of religiosity (including objective is sort of recall. y inaccurate at th gious services), and measures like how often they attend reli folks are notoriousl Another problem is one that should easily be avoided but rarely is. This is a subtle issue of statistics, and goes something like this—measure a ZILLION things related to religiosity (most of them overlapping), and measure a ZILLION things related to health (ditto), then see if anyt hing in the first category predicts anything in the second. and health, with enough correlations, something pops up as Even if there is no relationship at all between religiosity stop the presses, you've just proved that religion makes you healthy. Finally voila, eer chance and, significant by sh and most important in this area of science, you can't randomly assign people to different study groups ("You folks ten years to check everyone's and we'll meet back here in become atheists, and you guys start deeply believing in God, blood pressure"). So religiosity is a tough subject to do real science on, something the best people readily point out. Consider two leading thinkers in this field, Richard Sloan of Columbia University and Carl Thoresen of Stanford University. I'll be and one is a strong advocate of the health benefits ormously rigorous scientist, citing them a lot because each is an en of religiosity, while the other is as st subject and both devote half the space to rong a critic. Read their reviews of the the vast majority of studies in the field are plain awful and savaging the, er, heck out of the literature, pointing out that should be ignored. Once you've separated the wheat from the voluminous chaff, what's there? Interestingly, Sloan and Thoresen agree on ures, like number of days of hospitalization for an the next point. That is, when you cons ider objective medical meas illness, there's not a shred of evidence that praying for someone improves her health (independent of her knowing that she has the social support of someone rooting for her to the higher powers). This was something already concluded by their health prayed for by the nineteenth-century scientist, Francis Galton, who poin ted out that despite having than anyone else. overflowing churchfuls of loyal peasants each Sunday, European ro yals lived no longer legitimate link between that when you do see a Thoresen agree upon is Another thing that folks like Sloan and rst. Being religious may make you healthy, and being religiosity and good health, you don't know which came fi healthy may make you religious. They also agree that when you do see a link, even one in which religiosity gives rise , you still don't know if it has an This is because being religious ything to do with the religiosity. to good health typically gets you a religious community, and thus social su pport, meaningful social roles, good role models, social s, religiosity usually means fewer of those capital, all that good stuff. And because in a large percentage of religion drinking and smoking and carousing risk factors. So those need to be controlled for. e still mostly in agreement, which is that religiosity And once you've done that, remarkably, Thoresen and Sloan ar tent in a few areas of medicine. does predict good health to some ex 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

208 Pa g e 208 of 212 Thoresen has done the most detailed analys is of this, in some hard-nosed reviews of the field. He finds that regular ity rate and of a decreased risk of onably predictive of a decreased mortal attendance at religious services is reas ver, he also finds that religiosity doesn't predict much of anything about cardiovascular disease and depression. Howe cancer progression, cancer mortality rates, medical disability, and speed of recovery from an illness. Moreover, deeply ere are than the less deeply of what health benefits th religious people (by their own assessment) derive no more religious. His conclusion is that there's suggestive but in and of itself, improves health, but th not definitive evidence that religiosity, limited, and they're e effects are pretty ople staying alive and recovering faster. healthy than sick pe more about healthy people staying Here is where Sloan becomes a strong cr conclusion, but is most impressed by itic. He reaches pretty much the same doesn't remotely deserve the attention it has gotten. In how small these effects are and feels that the whole subject than in other, more mainstream areas of saying, "These aren't much smaller effects contrast, advocates respond by eryone argues back an d forth until the me subsets of people." And thus ev medicine, and they're big factors in so conference session is over with and it's time for all the scientists to go to lunch. To the extent that religiosity is good for health, once you control for social support and decreased risk factors, why is it healthful? For lots of reasons that have everything to do with stress, and with the type of deity(ies) you believe in. To start, you can have a deity whose rules are mysterious . This is the original Judeo-Christian Yahweh, a point emphasized by Thomas Cahill in his book, The Gift of the Jews. Prior to the monotheistic Yahweh, the gods made best tes—they didn't just want a the sense, in that they had familiar, if supra-human appeti lamb shank, they wanted lamb shank, wanted to seduce all the wood nymphs, and so on. But the early Jews invented a god with none of those be pants-wettingly terrifying.* So even if His actions are desires, who was so utterly unfathomable, unknowable, as to least get the stress-reducing advantages of attribution—it may not be clear mysterious, when He intervenes you at what the deity is up to, but you at least know who is resp onsible for the locust swarm or the winning lottery ticket. There is Purpose lurking, as an antidote to the existential void. s, the deity provides the comfort of both attribution and Next, if it is an intervening deity with discernible rule predictive information— carry out ritual X, or Y is going to happen. And thus, when things go wrong, there is an explanation.+ If it happens that things have really * Tapping into this notion, the satirical newspaper The Onion (25 October 2001) once began an article as follows: "new haven, ct: In a diagnosis that helps explain the confusing and contradictory aspects of the cosmos that have baffled philosophers, theologians, and other students of the illions of followers, and longtime deity to b creator of the universe human condition for millennia, God, was found Monday to su ffer from bipolar disorder." + to the affront of When I was young, I was taught that the Ho German Jewry inventin locaust was a logical response on God's part g the Reform ice had crumbled, caused immeasurable rage. iderable comfort and, once that whole edif movement. At the time, that caused me cons gone wrong just to you, there is the opportunity to reframe the event, in the extraordinary way achieved by some of the parents of children with that he can't entrust to just anyone. cancer—God has entrusted you with a burden If it is a deity who does all the above, and will respond to your personal and sp ecific entreaties (especi ally if the deity preferentially responds to people who look/talk/eat/dress/pray like you), there is an added layer of control introduced. ntages must be extraordinary. If you And if on top of all that, the deity is viewed as benign, the stress-reducing adva can view cancer and Alzheimer's disease, you can view the inevitable cessation the Holocaust and ethnic cleansing, if of the beating of the hearts of all your loved ones, all in the context of a loving plan, that must constitute the greatest source of support imaginable. ent: both Sloan and Thoresen are made very nervous by the idea that findings in this Two additional areas of agreem dvising their patients to become religious. Both note that amid this very measured good field will lead to physicians a news, religiosity can make health, mental or otherwise, a lot worse. As noted by Sharon Packer of the New School for Social Research, religion can be very good at reducing stressors, but is often the inventor of those stressors in the first place. PICKING THE RIGHT STRATEGY AT TH E RIGHT TIME: COGNITIVE FLEXIBILITY forms. You can problem-solve, cognitive task tackling the In the face of some stressor, "coping" can take a variety of of figuring out if it makes more sense to try to alter the stressor or alter your perception of it. Or you can focus on emotions—it can be stress-reducing to me rely admit that you're hurting emotionally from this stressor. You can focus on relationships and social support as a means of feeling less stressed. People obviously vary as to which st yle they gravitate toward. For exampl e, an endless source of tension in onship-based coping styles, nd toward emotion- or relati heterosexual relationships is that women, on average, te whereas men tend toward pr oblem-solving approaches.* 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

209 Pa g e 209 of 212 But regardless of which is your most natural coping style, a key point is that different styles tend to work better in s a big exam looming. One version of coping with it is idiotic example, suppose there' different circumstances. As an to study; another is to reframe the * This point is made brilliantly in a book called book should be required reading You Just Don't Understand by the linguist Deborah Tannen; this for newlyweds. person who is good at other things ..."). life than this class, I'm still a good meaning of a bad grade ("There's more to Obviously, before the exam, the stress-reduction-by-studying strategy should dominate, while you should hold off on ingful example, consider a major until after the exam. As a more mean the stress-reduction-by-reframing approach difficult decisions looming, versus a death in the family. illness in the family, complete with a bunch of brutally Typically, problem-solving approaches work better in the illness scenario; emotion- and relationship-based coping works better in the case of a death. Another version of this need for switching strategies crops up in the work of Martin Seligman. Amid all the good how counterproductive it can om the John Henryism example press that an inner locus of control gets, we just saw fr lthy it is to be able to switch loci of control. When be. Seligman's work has demonstrated how useful and hea something good happens, you want to believe that this outcome arose from your efforts, and has broad, long-lasting implications for you. When the outcome is bad, you want to believe that it was due to something out of your control, and is just a transient event with very local, limited implications. Implicit in switching to the optimal strategy for the particular circumstance is having the cognitive flexibility to switch strategies, period. This was something emphasized by Anto novsky, one of the pioneers of SES and health research. For him, what was the predictor of h ealth in a person? Coping responses built around fixed rules and flexible strategies. This requires that we fight a reflex common to most of us. If something bad is happening and our attempts d just try twice as hard to to, well, go back in there an to cope are not working, one of our most common responses is that's rare. During times of stress, finding the resources cope in the usual way. Although that sometimes does the trick, to try something new is really hard and is often just what's needed. WHAT WAS HE GOING ON ABOUT WITH THAT! of the themes of this book is the goal of contrasts. feel half-baked yet. One Here's an additional idea that doesn't even Physical stressor, you want to activate a stress-response; psychological stressor, you don't. Basal conditions, as little glucocorticoid secretion as poss ible; real stressor, as much as possible. Onset of stress, ra pid activation; end of stress, rapid recovery. achute: the first time they ian soldiers learning to par Consider a schematic version of this, based on those Norweg jumped, their blood pressure was through the roof at the time of the jump (Part B). But in addition it was up for hours before with anticipatory terror (Part A), a nd for hours after—still weak-kneed (Part C). By the zillionth time they jumped, what was the profile lik e? The same massive stress-res ponse during the jump (Part about what they're going to have for thing—the parachuters are just thinking B), but two seconds before and after, no lunch. This is what "conditioning" is about. Sharpening the contrasts between on and off, between foreground and one has gotten a is book, when some e ratio. Framed in the context of th background. Increasing the signal-to-nois ey turn on the stress-response only during the actual stressor. As discussed zillion jumps' worth of experience, th nd C—the psychological stress-response. by that experience are parts A a earlier, what have been winnowed away This is great. But what I'm grasping at is an idea about a subtler goal. This thinking owes a lot to conversations with , an engineering professor who also happe ns to be a hospital chaplain. This Manjula Waldron of Ohio State University spout, being a short, h ypomanic guy with feels embarrassingly Zen-ish for me to a Brooklyn accent, but here goes: high level of activation. Maybe the idea is ze the contrast between a low baseline and a Maybe the goal isn't to maximi to have both simultaneously. Huh? Maybe the goal would be for your baseline to be something more than the mere absence of activation, a mere default, but to instead be an energized calm, a proactive choice. And for the ceiling to crazed arousal. I have felt this a few times consist of some sort of equ ilibrium and equanimity threading through the y physiological e or not, ever ment when, successful outcom playing soccer, inept as I am at it, where there's a mo system is going like mad, and my body does something that my mind didn't even dream of, and the two seconds when the arousal isn't that happened seemed to take a lot long ess about the calm amid er than it should have. But this busin just another way of talking about "good stress" (a stimulat a threat). Even when the ing challenge, as opposed to stressor is bad and your heart is racing in crisis, the goal should be to some how make the fraction of a second between and allows you to regroup. ant that expands in time each heartbeat into an inst 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

210 Pa g e 210 of 212 There, I have no idea what I'm talking about, but I think there might be something important lurking there. Enough said. JUST DO IT: THE 80/20 QUALITY OF STRESS MANAGEMENT le. In retail business, it takes the form of, "20 percent of There's this idea in a number of disciplines called the 80/20 ru als account for criminology, it's, "20 percen the customers account for 80 percent of the complaints." In t of the crimin 80 percent of the crime." Or, "20 percent of the research an d design team accounts for 80 percent of the new ideas." The numbers are not meant to be literal; it's just a way of stating that causality is not equally distributed in a population of causal agents. reduction is accomplished with the first 20 I would apply the 80/20 rule to stress management: 80 percent of the stress . What do I mean by this? Suppose you're a Type-A nightmare, this hostile, curt, tightly wound percent of effort misery to those around you. No number of times that friends and loved ones sit you down, warmly look you in the ss will cause anything to change. No number of doctor visits eyes, and then yell at you about your being a pain in the a with elevated blood pressure readings are going to make a difference. It's not going to happen until you've decided to change, and really decided, not just decided to try to make everyone else stop hassling you over some nonexistent problem. in therapy is desperately trying to This is an essential truth for mental h ealth professionals—the whole family that's get the one individual to make some changes, and nothing is going to happen if all he's doing is staring sullenly at the Siggie Freud action figure on the shrink's bookshelf. But once you sincerely want to change, the mere act of making d people feel significantly better simply by scheduling a an effort can do wonders. Fo r example, clinically depresse eans they've recognized ther first appointment to see a therapist—it m e's a problem, it means they've fought their way up through the psychomotor quagmire to actually do something, it means they've turned a corner. cs of the most effective ion has examined characteristi This has obvious relevance for stress management. This sect il you figure out the perfect forms of stress management. But don't get crazed, holding off on do ing something unt approach for you. On a certain level, it doesn't matter what management technique you use (beyond it not being eet corner in a toga reciting abusive to those around you). If your special stress reduction tr ick is to stand on a busy str you're going to benefit from that, simply because you've d ecided that making a change is Teletub-bies monologues, enough of a priority that you're willing to say no to all the things that can't be said no to, in Is there anyone here who specializes in stress management?" " order to do that Tinkie-Winkie soliloquy. Don't save your stre ss management for the weekend, or for when you're on hold on the phone for thirty seconds. Take the time out to do it almost daily. And if you manage that, change has 80 percent, but at least a the way there—maybe not really become important enough to you that you're already a lot of great start. A SUMMING UP So what have we learned? In the face of terrible news beyond evention, beyond healing, thos ■ e who are able to find the control, beyond pr means to deny tend to cope best. Such denial is not only permitted, it may be the only means of sanity; truth and ions like these. In the face of lesser problems, one t not necessarily in situat mental health often go hand in hand, bu 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

211 Pa g e 211 of 212 should hope, but protectively and rationally. Find ways to view even the most stressful of situations as holding the promise of improvement but do not deny the possibility th at things will not improve. Balance these two opposing trends carefully. Hope for the best and let that dominate most of your emotions, but at the same time let one small e for the worst. piece of you prepar Those who cope with stress successfully tend to seek control in the face of present ■ stressors but do not try to try to control future events that are uncontrollable and do control things that have already come to pass. They do not are not broken or that are brok en beyond repair. When faced with the large wall of a stressor, not try to fix things that solution that makes the wall crumble. But often, a solution instead will be a it is great if there emerges one singular l, each one small but still capab series of footholds of contro ll allow you to scale the wall. le of giving support, that wi n is not useful if it comes ■ It is generally helpful to seek predictable, accurate inform ation. However, such informatio too soon or too late, if it is unnecessary, itself, or if the stressful in and of if there is so much information that it is information is about news far worse than one wants to know. Find that outlet for your frustrations and do it regularly. Make the outlet benign to those around you—one should ■ each new form of supposed not give ulcers in order to avoid getting them. Read the fine print and the ingredient list on anti-stress salvation, be skeptical of hype, figure out what works for you. It is important to find sources of social affiliation and support. Even in our obsessively individualistic society, most ■ of us yearn to feel part of something larger than ourselve s. But one should not mistake true affiliation and support for mere socializing. A person can feel vastly lonely in a va st crowd or when faced with a supposed intimate who has proved to be a stranger. Be patient; most of us spend a lifetime learning how to be truly good friends and spouses. Some of these ideas are encompasse d in Reinhold Niebuhr's famous prayer, adopted by Alcoholics Anonymous: things I cannot change, courage to chan ge the things I can, and wisdom to God grant me the serenity to accept the know the difference. Have the wisdom to pick your battles. And once you have, the flexibility and resiliency of strategies to use in those a Quaker meeting: ng I once heard in battles is summarized in somethi In the face of strong winds, let me be a blade of grass. In the face of strong walls, let me be a gale of wind. Constantin Brancusi, limestone, 1912. The Kiss, s. But sometimes it consists Sometimes, coping with stress consists of blowing down wall of being a blade of grass, buffeted and bent by the wind but still standing when the wind is long gone. 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

212 Pa g e 212 of 212 Stress is not everywhere. Every twinge of dysfunction in our bodies is not a manifestation of stress-related disease. It is true that the real world is full of bad things that we can finesse away by altering our outlook and psychological iminated by a change in attitude, no matter how heroically, makeup, but it is also full of awful things that cannot be el we may wish. Once we are actually sick wi th the illness, the fantasy of which fervently, complexly, or ritualistically keeps us anxiously awake at two in the morning, the things th at will save us have little to do with the content of this , once a tumor has metastasized, once our brain has been badly deprived of book. Once we have that cardiac arrest oxygen, little about our psychological outlook is likely to help. We have entered the realm where someone else—a highly trained physician—must use the most high-tech of appropriate medical interventions. These caveats must be emphasized repeat and what attributio ns to make when edly in teaching what cures to seek id this caution, there remains a whole confronted with many diseases. But am d disease that is realm of health an sensitive to the quality of our minds—our thoughts and emotions and behaviors. And sometimes whether or not we morning will reflect this realm of the mind. It is here that at frighten us at two in the become sick with the diseases th we must turn from the physicians and their ability to cl ean up the mess afterward and recognize our own capacity to some of these problems beforehand in the small steps with which we live our everyday lives. prevent Perhaps I'm beginning to sound like your grandmother, advising you to be happy and not to worry so much. This advice may sound platitudinous, trivial, or both. But change the way even a rat perceives its world, and you getting a disease. These ideas are no dramatically alter the likelihood of its mere truisms. They are powerful, potentially liberating forces to be harnessed. As a physiologi st who has studied stress for many years, I clearly see that than the psychology. We retu rn to the catalogue at the the physiology of the system is often no more decisive ssful— traffic jams, money worrie s, overwork, the anxieties of beginning of the first chapter, the things we all find stre the sense that that zebra or that lion would understand. In our privileged lives, relationships. Few of them are "real" in we are uniquely smart enough to have invented these stressors and uniquely foolish enough to have let them, too be uniquely wise enough to banish their stressful hold. often, dominate our lives. Surely we have the potential to THE END Notes not scanned! 8/9/2009 file://C:\Users\OMID \Documents\Downloads\Compressed\zebras\Wh y_ Zebras.htm

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