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1 Why Don’t Zebras Get Ulcers?

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Social support An additional way we can interact with another organism to minimize the impact of a stressor on us is considerably more encouraging for the future of our planet than is displacement 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 the same stressor while in a room full of other primates and…it depends. If hose primates are strangers, the stress-response gets worse. But if they are friends, the stress-response 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.

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The same is seen with primates in the wild. While I mostly do laboratory research on how stress and glucocorticoids 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 carefully search for some tuber to eat and clean it off, only to have it stolen by 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).

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Social support is certainly protective for humans as well. This can be demonstrated even in transient instances of support. In a number of subtle studies, subjects were exposed to a stressor such as having to give a public speech or perform a mental arithmetic task, or having two strangers argue with them, with or without a supportive friend present. In each case, social support translated into less of a cardiovascular stress-response. Profound and persistent differences in degrees of social support can influence human physiology as well: within the same family, there are significantly higher glucocorticoid levels among stepchildren than among biological children. Or, as another example, among women with metastatic breast cancer, the more social support, the lower the resting cortisol levels.

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As noted in chapter 8, people with spouses or close friends have longer life expectancies. When the spouse dies, the risk of dying rises. Recall also from that chapter the study of parents of Israeli soldiers killed in the Lebanon war: in the aftermath of this stressor, there was no notable increase in risk of diseases or mortality, except among those who were already divorced or widowed. Some additional examples concern the cardiovascular system. People who are socially isolated have overly active sympathetic nervous systems. Given the likelihood that this will lead to higher blood pressure and more platelet aggregation in their blood vessels (remember that from chapter 3?), they are more 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 with severe coronary heart disease, Redford Williams of Duke University and colleagues found that half of those lacking social support were dead within five years—a rate three times higher than was seen in patients who had a spouse or close friend, after controlling for the severity

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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.

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Predictability Weiss’s rat studies uncovered another variable modulating the stress-response. The rat gets the same pattern of electric shocks, but this time, just before each shock, it hears a warning bell. Fewer ulcers. Predictability makes stressors less stressful. The rat with the warning gets two pieces of information. It learns when something dreadful is about to happen. The rest of the time, it learns that something dreadful is not about to happen. It can relax. The rat without a warning can always be a half-second away from the next shock. In effect, information that increases predictability tells you that there is bad news, but comforts you that it’s not going to be worse—you are going to get shocked soon, but it’s never going to be sprung on you without warning.

Note: variable reward

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By being given news about the stressor to come, you are also implicitly being comforted by now knowing what stressors are not coming.

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Why Is Psychological Stress Stressful?

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As another variant on the helpfulness of predictability, organisms will eventually habituate to a stressor if it is applied 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, and a smaller stress-response is triggered. One classic demonstration involved men in the Norwegian military going through parachute training—as the process went from being hair-raisingly novel to something they could do in their sleep, their anticipatory stress-response went from being gargantuan to nonexistent.

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The power of loss of predictability as a psychological stressor is shown in an elegant, subtle study. A rat is going about its business in its cage, and at measured intervals the experimenter delivers a piece of food down a chute into 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 less predictably, and up go glucocorticoid levels. There is not a single physically stressful thing going on in the rat’s world. It’s not hungry, pained, running for its life—nothing is out of allostatic balance. In the absence of any stressor, loss of predictability triggers a stress-response.

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There are even circumstances in which a stress-response can be more likely to occur in someone despite the reality that the outside world is less stressful. Work by the zoologist John Wingfield of the University of Washington has shown an example of this with wild birds. Consider some species that migrates between the Arctic and the tropics. Bird #1 is in the Arctic, where the temperature averages 5 degrees and where it is, indeed, 5 degrees outside that day. In contrast, Bird #2 is in the tropics, where the average temperature is 80 degrees, but today it has dropped down to 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 tropics is 20 degrees colder than anticipated.

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A human version of the same idea has been documented. During the onset of the Nazi blitzkrieg bombings of 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 predictability. There was a significant increase in the incidence of ulcers during that time. Who developed more ulcers? The suburban population. (As another measure of the importance of unpredictability, by the third month of the bombing, ulcer rates in all the hospitals had dropped back to normal.)

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Despite the similarity between the responses of humans and of other animals to a lack of predictability, I suspect that there they are not identical, and in an important way. The warning of impending shocks to a rat has little effect on the size of the stress-response during the shocks; instead, allowing the rat to feel more confident about when it doesn’t have to worry reduces the rat’s anticipatory stress-response the rest of the time. Analogously, when the dentist says, “Only two more times and then we’re done,” it allows us to relax at the end of the second burst of drilling. But I suggest, although I cannot prove it, that unlike the case for the rat, proper information will also lower our stress-response during the pain. If you were told “only two times more” versus “only ten times more,” wouldn’t you use 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; you 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.

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We often wish for information about the course of some medical problem because it aids our strategizing about how we will cope. A simple example: you have some minor surgery, and you’re given predictive information—the first 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 optimize our coping strategies when we request the most devastating piece of medical information any of us will ever face: “How much time do I have left?”

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Control Rat studies also demonstrate a related facet of psychological stress. Give the rat the same series of shocks. This time, however, you study a rat that has been trained to press a lever to avoid electric shocks. Take away the lever, shock it, and the rat develops a massive stress-response. It’s as if the rat were thinking, “I can’t believe this. I know what to do about electric shocks; give me a damned lever and I could handle this. This isn’t fair.” Ulceration city (as well as higher glucocorticoid levels, poorer immune function, and faster tumor growth). Give the trained rat a lever to press; even if it is disconnected from the shock mechanism, it still helps: down goes the stress-response. So long as the rat has been 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.

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The identical style of experiment with humans yields similar results. Place two people in adjoining rooms, and expose both to intermittent noxious, loud noises; the person who has 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 bother to press it did just as well as those who actually pressed the button. Thus, the exercise of control is not critical; rather, it is the belief that you have it. An everyday example: airplanes are safer than cars, yet more of us are phobic about flying. Why? Because your average driver believes that he is a better-than-average driver, thus more in control. In an airplane, we have no control at all. My wife and I tease each other on plane flights, exchanging control: “Okay, you rest for a while, I’ll take over concentrating on keeping the pilot from having a stroke.”

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occupational stress is built more around lack of control, work life spent as a piece of the machine. Endless studies have shown that the link between occupational 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 assembly line, the combination of stressors that makes for Marx’s alienation of the workers. The control element is more powerful than the demand one—low demand and low control is more damaging to one’s health than high demand and high control.

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The stressfulness of lack of control on the job applies in only certain domains, however. For example, there is the issue of what product is made, and lack of control in this realm tends not to be all that stressful—few people are ulcerating because of their deep conviction that all of their capable and motivated fellow workers 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 much control you have over them, how authoritarian the authorities are.

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These issues can apply just as readily to some less expected workplaces, ones that can be highly prestigious and desirable. For example, professional musicians in orchestras generally have lower job satisfaction and more stress than those in small chamber groups (such as a string quartet). Why? One pair of researchers suggest that this is because of the lack of autonomy in an orchestra, where centuries of tradition hold that orchestras are subservient to the dictatorial whims of the maestro conducting them. For example, it was only in recent years that orchestra unions won the right for regularly scheduled bathroom breaks during rehearsals, instead of having to wait until the conductor cared to note how squirmy the reed players had become.*

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So the variable of control is extremely 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 food (so long as the task is not too difficult) over having the food delivered freely—a theme found in the activities and statements of many scions of great fortunes, who regret the contingency-free nature of their lives, without purpose or striving.

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Loss of control and lack of predictive information are closely related. Some researchers have emphasized this, pointing out that the common theme is that the organism is subjected to novelty. You thought you knew how to 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 suppresses its immune system. Others have emphasized that these types of stressors cause arousal and vigilance, as you search for the new rules of control and prediction. Both views are different aspects of the same issue.

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11 Stress and a Good Night’s Sleep

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15

Personality, Temperament, and Their Stress-Related Consequences

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Your style, your temperament, your personality have much to do with whether you regularly perceive opportunities for control or safety signals when they are there, whether you consistently interpret ambiguous circumstances as implying good news or bad, whether you typically seek out and take advantage of social support. Some folks are good at modulating stress in these ways, and others are terrible. These fall within the larger category of what Richard Davidson has called “affective style.” And this turns out to be a very important factor in understanding why some people are more prone toward stress-related diseases than others.

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We start with a study in contrasts. Consider 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’s good at what he does, and what he does is compete—he’s already Number 2 and breathing down the neck of Number 1, who’s grown complacent and a bit slack. Things are good and likely to get better.

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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 rockets him into a tensely agitated state, and he views every interaction with a potential competitor as an in-your-face 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, fearful berth because of his tendency to take any frustration out on them. He behaves the same toward Kathleen, and barely knows their daughter Caitland—this is the sort of guy who is completely indifferent to the cutest of infants. And when he looks at all he’s accomplished, all he can think of is that he is still not Number 1.

Hostile strength

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Gary’s profile comes with some physiological correlates. Elevated basal glucocorticoid levels—a constant low-grade stress-response because life is one big stressor for him. An immune system that you wouldn’t wish on your worst enemy. Elevated resting blood pressure, an unhealthy ratio of “good” to “bad” cholesterol, and already the early stages of serious atherosclerosis. And, looking ahead a bit, a premature death in late middle-age.

Friendly strength

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Contrast that with Kenneth. He’s also prime-aged and Number 2 in his world, but he got there through a different route, one reflecting the different approach to life that he’s had ever since 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 aid, and they in turn to his. Consensus builder, team player, and if he’s ever frustrated about anything, and it isn’t all that certain he ever is, he certainly doesn’t take it out on those around him.

Friendly strength

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A few years ago, Kenneth was poised for a move to the Number 1 spot, but he did something extraordinary—he walked away from it all. Times were good enough that he wasn’t going to starve, and he had reached the realization 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.

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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. 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 have published papers on animal personality. Some have concerned lab rats. Some rats have an aggressive proactive style for dealing with stressors—put a new object in their cage and they bury it in the bedding. These animals don’t have much in the way of a glucocorticoid stress response. In contrast, there are reactive animals who respond to a menacing by avoiding it. They have a more marked glucocorticoid stress-response. And then there are studies about stress-related personality differences in geese. There’s even been a great study published about sunfish personalities (some of whom are shy, and some of whom are outgoing social butterflies). Animals are strongly individualistic, and when it comes to primates, there are astonishing differences in their personalities, temperaments, and coping styles. These differences carry some distinctive physiological consequences and disease risks related to stress. This is not the study of what external stressors have to do with health. This is, instead, the study of the impact on health of how an individual perceives, responds to, and copes with those external stressors. The lessons learned from some of these animals can be strikingly relevant to humans.

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Stress and the Successful Primate

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Baboons there work perhaps four hours a day, foraging through the fields and trees for fruits, tubers, and edible grasses. This has a critical implication for me, which has made them the perfect study subjects when I’ve snuck away from my laboratory to the Serengeti during the summers of the past two decades. If baboons are spending only four hours a day filling their stomachs, that leaves them with eight hours a day of sunlight to be vile to one another.

Anarcho communism moment

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Social competition, coalitions forming to gang up on other animals, big males in bad moods beating up on someone smaller, snide gestures behind someone’s back—just like us.

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I am not being facetious. Think about some of the themes of the first chapter—how few of us are getting our ulcers because we have to walk ten miles a day looking for grubs to eat, how few of us become hypertensive because we are about to punch it out with someone over the last gulp from the water hole. We are ecologically buffered and privileged enough to be stressed mainly over social and psychological matters. Because the ecosystem of the Serengeti is so ideal for savanna baboons, they have the same luxury to make each other sick with social and psychological stressors. Of course, like ours, theirs is a world filled with affiliation, friendships, relatives who support each other; but it is a viciously competitive society as well. If a baboon in the Serengeti is miserable, it is almost always because another baboon has worked hard and long to bring about 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 differences in stress-related physiology and disease. I watched the baboons, collected detailed behavioral data, and then would anesthetize the animals under 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.*

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The cases of Gary and Kenneth already give us a sense of how different male baboons can be. Two males of similar 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 smaller. Two students, Justina Ray and Charles Virgin, and I analyzed years of behavioral data to try to formalize different elements of style and personality among these animals. We found some fascinating correlations between personality styles and physiology.

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Among males who were in the higher-ranking half of the hierarchy, we observed a cluster of behavioral traits associated with low resting glucocorticoid levels independent of their specific ranks. Some of these traits were related to how males competed with one another. The first trait was whether a male could tell the difference between a threatening and a neutral interaction with a rival. How does one spot this in a baboon? Look at a particular male and two different scenarios. First scenario: along comes his worst rival, sits down next to him, and makes a threatening gesture. What does our male subject do next? Alternative 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?

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Some males can tell the difference between these situations. Threatened from a foot away, they get agitated, vigilant, prepared; when they instead see their rival is taking a nap, they keep doing whatever they were doing. They can tell that one situation is bad news, the other is meaningless. But some males get agitated even when their rival is taking a nap across the field—the sort of situation that happens five times a day. If a male baboon can’t tell the difference between the two situations, on the average his resting glucocorticoid levels are twice as high as those of the guy who can tell the difference—after correcting for rank as a variable. If a rival napping across the field throws a male into turmoil, the latter’s going to be in a constant state of stress. No wonder his glucocorticoid levels are elevated. These stressed baboons are similar to the hyperreactive macaque monkeys that Jay Kaplan has studied. As you will recall from chapter 3, these are individuals who respond to every social provocation with an overactivation of their stress-response (the sympathetic nervous system) and carry the greater cardiovascular risk.

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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 there passively, abdicating control, have much higher glucocorticoid levels than the take-charge types, after rank is eliminated as a factor in the analysis. We see the same pattern in low-ranking as well as high-ranking males.

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The View from the Bottom

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Toward the end of the first chapter, I voiced a caveat—when I discuss a way in which stress can make you sick, that is merely shorthand for discussing how stress can make you more likely to get diseases that make you sick. That was basically a first pass at a reconciliation between two very different camps that think about poor health.

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At one extreme, you have the mainstream medical crowd that is concerned with reductive biology. For them, poor health revolves around issues of bacteria, viruses, genetic mutations, and so on. At the other extreme are the folks anchored in mind-body issues, for whom poor health is about psychological stress, lack of control and efficacy, and so on.

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This has come in the form of showing how sensitive reductive biology can be to some of those psychological factors, and exploring the mechanisms that account for this. And it has come in the form of criticizing the extremes of both camps: on the one hand, trying to make clear how limiting it is to believe that humans can ever be reduced to a DNA sequence, and on the other, trying to indicate the damaging idiocy of 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 the most reductive of diseases, cannot be appreciated without considering the person who is ill.

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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 many meals consisting of Coke and Cheetos, or living in a crummy overcrowded apartment 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 consider disease outside the context of the person who is ill, we also can’t consider it outside the context of the society in which that person has gotten ill, and that person’s place in that society.

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And then I found out a bit about Rudolph Virchow. As a young physician, he came of age with two shattering events—a massive typhus outbreak in 1847 that he attempted to combat firsthand and the doomed European revolutions of 1848. The first was the perfect case for teaching that disease can be as much about appalling living conditions as it is about microorganisms. The second taught just how effectively the machinery of power can subjugate those in appalling living conditions. In its aftermath, he emerged not just as someone who was a scientist plus a physician plus a public health pioneer plus a progressive politician—that would be plenty unique. But in addition, through a creative synthesis, he saw all those roles as manifestations of a single whole. “Medicine is a social science, and politics nothing but medicine on a large scale,” he wrote. And, “Physicians are the natural attorneys of the poor.”

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Pecking orders Among
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they exist in all sorts of species. Resources, no matter how plentiful, are rarely divvied up evenly. Instead of every contested item being fought for with bloodied tooth and claw, dominance hierarchies emerge. As formalized systems of inequities, these are great substitutes for continual aggression between animals smart enough to know their place.

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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 ranking can rip it off from you. You spend hours sweet-talking someone into grooming you, getting rid of those 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 canines. (Such third-party “displacement aggression” accounts for a huge percentage of baboon violence. A middle-ranking male gets trounced in a fight, turns and chases a subadult male, who lunges at an adult female, who bites a juvenile, who slaps an infant.) For a subordinate animal, life is filled with a disproportionate share not only of physical stressors but of psychological stressors as well—lack of control, of predictability, of outlets for frustration.

Note: Stressed parents

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It’s not surprising, then, that among subordinate male baboons, resting levels of glucocorticoids are significantly higher than among dominant individuals—for a subordinate, everyday basal circumstances are stressful. And that’s just the start of subordinates’ problems with glucocorticoids. When a real stressor comes along, their glucocorticoid response is smaller and slower than in dominant individuals. And when it’s all passed, their recovery appears to be delayed. All these are features that count as an inefficient stress-response.*

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More problems for subordinate individuals: elevated resting blood pressure; sluggish cardiovascular response to real stressors; a sluggish recovery; suppressed levels of the good HDL cholesterol; among male subordinates, testosterone levels that are more easily suppressed by stress than in dominant males; fewer circulating white blood cells; and lower circulating levels of something called insulin-like growth factor-I, which helps heal wounds. As should be clear umpteen pages into this book, all these are indices of bodies that are chronically stressed.

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Recently, Abbott and I drew on the collaborative efforts of a large number of colleagues who have studied rank/stress physiology issues in nonhuman primates. We formalized what features of a primate society predict whether it is the dominant or the subordinate animals who have the elevated stress-responses. To the experts on each primate species, we posed the same questions: in the species that you study, what are the rewards of being dominant? How much of a role does aggression play in maintaining dominance? How much grief does a subordinate individual have to take? What sources of coping and support (including the presence of relatives) do subordinates of that species have available to them? What covert alternatives to competition are available? If subordinates cheat at the rules, how likely are they to get caught and how bad is the punishment? How often does the hierarchy change? Amid seventeen questions asked concerning the dozen different species for which there are decent amounts of data available, 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.

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So rank means different things in different species. It turns out that rank can also mean different things in different social groups within the same species. Primatologists these days talk about primate “culture,” and this is not an anthropomorphic term. For example, chimps in one part of the rain forest can have a very different culture from the folks four valleys over—different frequencies of social behaviors, use of similar vocalizations but with different meanings (in other words, something approaching the concept of a “dialect”), different types of tool use. And intergroup differences influence the rank-stress relationship.

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One example is found among female rhesus monkeys, where subordinates normally take a lot of grief and have elevated basal glucocorticoid levels—except in one social group that was studied, which, for some reason, had high 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 example 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 (implying, ironically, that for a subordinate animal, an environmental stressor can be a blessing, insofar as it saves you from a more severe social stressor).

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A critical intergroup difference in the stress-response concerns the stability of the dominance hierarchy. Consider an animal who is, say, Number 10 in the hierarchy. In a stable system, that individual is getting trounced 95 percent of the time by Number 9 but, in turn, thrashes Number 11 95 percent of the time. In contrast, 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 ranks reinforce the status quo. Under those conditions, dominant individuals are stably entrenched and have all the psychological perks of their position—control, predictability, 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.

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In contrast, there are rare periods when the hierarchy becomes unstable—some key individual has died, someone influential has transferred into the group, some pivotal coalitional partnership has formed or come apart—and a revolution results, with animals changing ranks left and right. Under those conditions, it is typically the dominant individuals who are in the very center of the hurricane of instability, subject to the most fighting, the most challenges, and who are most affected by the see-sawing of coalitional politics.* During such unstable periods among those same primate species, the dominant individuals no longer have the healthiest stress-responses.

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So while rank is an important predictor of individual differences in the stress-response, the meaning of that rank, the psychological baggage that accompanies it in a particular society, is at least as important. Another critical variable is an animal’s personal experience of both its rank and society. For example, 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 might predict stress-responses throughout the troop thanks to this destabilizing brute. But, instead, the pattern reflects the individual experience of animals—for those lucky enough never to be attacked by this character, there were no changes in immune function. In contrast, among those attacked, the more frequently that particular baboon suffered at this guy’s teeth, the more immunosuppressed she was. Thus, you ask the question, “What are the effects of an aggressive, stressful individual on immune function in a social group?” The answer is, “It depends—it’s not the abstract state of living in a stressful society which is immunosuppressive. Instead, it is the concrete state of how often your own nose is being rubbed in that instability.”*

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As a final variable, it is not just rank that is an important predictor of the stress-response, not just the society in which the rank occurs, or how a member of the society experiences both; it’s also personality—the topic of chapter 15. As we saw, some primates see glasses as half empty and life as full of provocations, and they can’t take advantage of outlets or social support—those are the individuals with overactive stress-responses. For them, their rank, their society, their personal experiences might all be wonderfully salutary, but if their personality keeps them from perceiving those advantages, their hormone levels and arteries and immune 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 among primates. It’s reasonable to expect the picture to be that much more complicated and subtle when considering humans. Time for a surprise.

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I am skeptical about the notion of ranking systems for humans.

Part of the problem is definitional, in that some supposed studies of human “dominance” are actually examining Type-A features—people defined as “dominant” are ones who, in interviews, have hostile, competitive contents to their answers, or who speak quickly and interrupt the interviewer. This is not dominance in a way that any zoologist would endorse.

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Other studies have examined the physiological correlates of individual differences in humans who are competing directly against one another in a way that looks like dominance. Some have examined, for example, the hormonal responses in college wrestlers depending on whether they won or lost their match. Others have examined the endocrine correlates of rank competition in the military. One of the most fruitful areas has been to examine ranks in 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.

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Collectively, these studies have produced some experimentally reliable correlations. I’m just a bit dubious as to what they mean. For starters, I’m not sure what a couple of minutes of competitive wrestling between two highly conditioned twenty-year-olds teaches us about which sixty-year-old gets clogged arteries. At the other end, I wonder what the larger meaning is of rankings among business executives—while primate hierarchies can ultimately indicate how hard you have to work for your calories, corporate hierarchies are ultimately about how hard you have to work for, say, a plasma TV. Another reason for my skepticism is that for 99 percent of human history, societies were most probably strikingly unhierarchical. This is based on the fact that contemporary hunter-gatherer bands are remarkably egalitarian.

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But my skepticism is most strongly anchored in two reasons having to do with the complexity of the human psyche. First, humans can belong to a number of different ranking systems simultaneously, and ideally are excelling in at least one of them (and thus, may be giving the greatest psychological weight to that one). So, the lowly subordinate in the mailroom of the big corporation may, after hours, be deriving tremendous prestige and self-esteem from being the deacon of his church, or the captain of her weekend softball team, or may be at the top of the class at the adult-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.

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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 which people finish the race. Runner 1 dominates 5, who clearly dominates 5,000. But what 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 runner 5 had spent the previous week reading in the sports section that someone of their world-class quality should certainly finish in the top three, maybe even blow away the field. No Martian on earth could predict correctly who is going to feel exultantly dominant afterward.

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People are as likely to race against themselves, their own previous best time, as against some external yardstick. This can be seen in the corporate world as well. An artificial example: the kid in the mailroom is doing a fabulous job and is rewarded, implausibly, with a $50,000ayearsalary.Aseniorvicepresidentscrewsupbig-timeandispunished,evenmoreimplausibly,witha$50,001 a year salary. By the perspective of that Martian, or even by a hierarchically minded wildebeest, it’s obvious that the vice president is in better shape to acquire the nuts 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, rationalizing games with rank based on their knowledge of what determined their placement. Consider the following fascinating example: guys who win at some sort of competitive interaction typically show at least a small rise in their circulating testosterone levels—unless they consider the win to have come from sheer luck.

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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 social animal, an equivalent that carries with it atypically high rates of 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.

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Socioeconomic Status,
Stress, and Disease

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If you want to see an example of chronic stress, study poverty. Being poor involves lots of physical stressors. Manual labor and a greater risk of work-related accidents. Maybe even two or three exhausting jobs, complete with chronic sleep deprivation. Maybe walking to work, walking to the laundromat, walking back from the market with the heavy bag of groceries, instead of driving an air-conditioned car. Maybe too little money to afford a new mattress that might help that aching back, or some more hot water in the shower for that arthritic throb; and, of course, maybe some hunger thrown in as well…. The list goes on and on.

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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 one laid off when economic times are bad—and studies show that the deleterious effects of unemployment on health begin not at the time the person is laid off, but when the mere threat of it first occurs. Wondering if the money will 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) because they weren’t allowed to go to the bathroom at work as often as they needed to when taking the drugs.

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As a next factor, being poor means that you often can’t cope with stressors very efficiently. Because you have no resources in reserve, you can never plan for the future, and can only respond to the present crisis. And when you do, 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 from a loan shark. Everything has to be reactive, in the moment. Which increases the odds that you’ll be in even worse shape to deal with the next stressor—growing strong from adversity is mostly a luxury for those who are better off.

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Along with all of that stress and reduced means of coping, poverty brings with it a marked lack of outlets. Feeling a little stressed with life and considering a relaxing vacation, buying an exercycle, or taking some classical guitar lessons to get a little peace of mind? Probably not. Or how about quitting that stressful job and taking some time off at 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 regularly to get some exercise and let off some steam? Statistically, a poor person is far more likely to live in a crime-riddled neighborhood, and jogging may wind up being a hair-raising stressor.

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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.

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All these hardships suggest that low socioeconomic status (SES—typically measured by a combination of income, occupation, housing conditions, and education) should be associated with chronic activation of the stress-response. Only a few studies have looked at this, but they support this view. One concerned school kids in Montreal, a city with fairly stable communities and low crime. In six-and eight-year-old children, there was already a tendency for lower-SES kids to have elevated glucocorticoid levels. By age ten, there was a step-wise gradient, with low-SES kids averaging almost 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.

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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 more diseases, period. And is it ever.

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The health risk of poverty turns out to be a huge effect, the biggest risk factor there is in all of behavioral medicine—in other words, if you have a bunch of people of the same gender, age, and ethnicity and you want to make some predictions about who is going to live how long, the single most useful fact to know is each person’s SES. If you want to increase the odds of living a long and healthy life, don’t be poor. Poverty is associated with increased risks of cardiovascular disease, respiratory disease, ulcers, rheumatoid disorders, psychiatric diseases, and a number of types of cancer, just to name a few.* It is associated with higher rates of people judging themselves to be of poor health, of infant mortality, and of mortality due to all causes. Moreover, lower SES predicts lower birth weight, after controlling 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 old, spend the rest of your life double-dating with Donald Trump, and you’re still going to have a statistical increase in some realms of disease risk for the rest of your life.

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Is the relationship between SES and health just some little statistical hiccup in the data? No—it can be a huge effect. In the case of some of those diseases sensitive to SES, if you cling to the lowest rungs of the socioeconomic ladder, it can mean ten times the prevalence compared with those perched on top.* Or stated another way, this translates into a five-to ten-year difference in life expectancy in some countries when comparing the poorest and wealthiest, and decades’ worth of differences when comparing subgroups of the poorest and wealthiest.

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Findings such as these go back centuries. For example, one study of men in England and Wales demonstrated a steep SES gradient in mortality in every decade of the twentieth century. This has a critical implication that has been pointed out by Robert Evans of the University of British Columbia: the diseases that people were dying of most frequently a century ago are dramatically different from the most common ones now. Different causes of death, but same SES gradient, same relationship between SES and health. Which tells you that the gradient arises less from disease than from social class. Thus, writes Evans, the “roots [of the SES health gradient] lie beyond the reach of medical therapy.”

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So SES and health are tightly linked. What direction is the causality? Maybe being poor sets you up for poor health. 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 one point in life predicts important features of your health later on. For example, poverty early in life has adverse effects on health forever after—harking back to chapter 6 and the fetal origins of adult disease. One 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. Despite controlling for all these variables, in old age their patterns of disease, of dementia, and of longevity were still predicted by the SES status they had when they became nuns more than half a century before.

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Thus, SES influences health, and the greater cumulative percentage of your life you’ve spent poor, the more of an adverse impact on health.* Why should SES influence health? A century ago in the United States, or today in a developing country, the answer would be obvious. It would be about poor people getting more infectious diseases, less food, and having an astronomically higher infant mortality rate. But with our shift toward the modern prevalence of slow, degenerative diseases, the answers have shifted as well.

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The Puzzle of
Health Care Access

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Let’s start with the most plausible explanation. In the United States, poor people (with or without health insurance) don’t have the same access to medical care as do the wealthy. This includes fewer preventive check-ups with doctors, a longer lag time for testing when something bothersome has been noted, and less adequate care when something has actually been discovered, especially if the medical care involves an expensive, fancy technique. As one example of this, a 1967 study showed that the poorer you are judged to be (based on the neighborhood you live in, your home, your appearance), the less likely paramedics are to try to revive you on the way to the hospital. In more recent studies, for the same severity of a stroke, SES influenced your likelihood of receiving physical, occupational, or speech therapy, and how long you waited until undergoing surgery to repair the damaged blood vessel that caused the stroke.

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This sure seems like it should explain the SES gradient. Make the health care system equitable, socialize that medicine, and away would go that gradient. But it can’t be only about differential health care access, or even mostly about it.

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For starters, consider countries in which poverty is robustly associated with increased prevalence of disease: Australia, Belgium, Denmark, Finland, France, Italy, Japan, the Netherlands, New Zealand, the former Soviet Union, Spain, Sweden, the United Kingdom, and, of course, the U.S. of A. Socialize the medical care system, socialize the whole country, turn it into a worker’s paradise, and you still get the gradient. In a place like England, the SES gradient has gotten worse over this century, despite the imposition of universal health care allowing everyone equal health care access.

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You could cynically and correctly point out that systems of wonderfully egalitarian health care access are probably egalitarian in theory only—even the Swedish health care system is likely to be at least a smidgen more attentive to the wealthy industrialist, sick doctor, or famous jock than to some no-account poor person cluttering up a clinic. Some people always get more of their share of equality than others. But in at least one study of people enrolled in a prepaid health plan, where medical facilities were available to all participants, poorer people had more cardiovascular disease, despite making more use of the medical resources.

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A second vote against the importance of differential health care access is because the relationship forms the term I’ve been using, namely, a gradient. It’s not the case that only poor people are less healthy than everyone else. Instead, for every step lower in the SES ladder, there is worse health (and the lower you get in the SES hierarchy, the bigger is each step of worsening health). This was a point made screamingly clear in the most celebrated study in the field, the Whitehall studies of Michael Marmot of University College of London. Marmot considered a system where gradations in SES status are so clear that occupational rank practically comes stamped on people’s foreheads—the British civil service system, which ranges from unskilled blue-collar workers to high-powered executives. Compare the highest and lowest rungs and there’s a fourfold difference in rates of cardiac disease mortality. Remember, this is in a system where everyone has roughly equal health care access, is paid a living wage, and, very important in the context of the effects of unpredictability, is highly likely to continue to be able to earn that living wage.

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A final vote against the health care access argument: the gradient exists for diseases that have nothing to do with access. Take a young person and, each day, scrupulously, give her a good medical examination, check her vitals, peruse her blood, run her on a treadmill, give her a stern lecture about good health habits, and then, for good measure, centrifuge her a bit, and she is still just as much at risk for some diseases as if she hadn’t gotten all that attention. Poor people are still more likely to get those access-proof diseases. Theodore Pincus of Vanderbilt University has carefully documented the existence of an SES gradient for two of those diseases, juvenile diabetes and rheumatoid arthritis.

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Thus, the leading figures in this field all seem to rule out health care access as a major part of the story. This is not to rule it out completely (let alone suggest that we not bother trying to establish universal health care access). As evidence, sweaty capitalist America has the worst gradient, while the socialized Scandinavian countries have the weakest. But they still have hefty gradients, despite their socialism. The main cause has to be somewhere else. Thus, we move on to the next most plausible explanation.

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The Whitehall Study, Mortality by Professional Level of Follow-up.

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Poorer people in westernized societies are more likely to drink and smoke excessively (sufficiently so that it’s been remarked that smoking is soon going to be almost exclusively a low-SES activity). 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 world, it means having trouble affording healthy food. Thanks to industrialization, fewer jobs in our society involve physical exertion and, when combined with the costs of membership in some tony health club, the poor get less exercise. They’re more likely to be obese, and in an appleish way. They are less likely to use a seat belt, wear a motorcycle helmet, own a car with air bags. They are more likely to 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 endless, and they all adversely impact health.

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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 something, they aren’t informed. As one example that boggles me, substantial numbers of people are apparently not aware that cigarettes do bad things to you, and the studies show that these aren’t folks too busy working on their doctoral dissertations to note some public health trivia. Other studies indicate that, for example, poor women are the least likely to know of the 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 people who, despite their poverty, could still be eating somewhat more healthfully, using seat belts or crash helmets, 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 think that following them is important. Moreover, a high degree of education generalizes to better problem-solving skills across the board. Statistically, being better educated predicts that your community of friends and relatives is better educated as well, with those attendant advantages.

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However, the SES gradient isn’t much about risk factors and protective factors. To show this requires some powerful statistical techniques in which you see if an effect still exists 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 of smoking. So control for smoking—comparing only people who smoke—does the incidence of lung cancer still increase with declining SES? Take it one step further—for the same amount of smoking, does lung cancer incidence still increase? For the same amount of smoking and drinking, does…and so on. These types of analyses show that these risk factors matter—as Robert Evans has written, “Drinking sewage is probably unwise even for Bill Gates.” They just don’t matter that much. For example, in the Whitehall studies, smoking, cholesterol levels, blood pressure, and level of exercise explain away only about a third of the SES gradient. For the same risk factors and same lack of protective factors, throw in poverty and you’re more likely to get sick.

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So differential exposure to risk factors or protective factors does not explain a whole lot. This point is brought home in another way. Compare countries that differ in wealth. One can assume that being in a wealthier country gives you more opportunities to buy protective factors and to avoid risk factors. For example, you find the least pollution in very poor and very wealthy countries; the former because they are nonindustrial and the latter because they either do it cleanly or farm it out to someone else. Yet, when you consider the wealthiest quarter or so countries on earth, there is no relationship between a country’s wealth and the health of its citizens.* This is a point heavily emphasized by 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 citizens live longer, healthier lives than our own.*

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So out go major roles for health care access, and risk factors. This is where things get tense at the scientific 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, including stress. In a similar way, among the “social epidemiologists” who think about the SES/health gradients, the mainstream view has long focused on health care access and risk factors. And thus, they too have had to make room for psychological factors. Including stress. Big-time.

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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?

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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 chronic daily stressors. Second, when one examines the SES gradient for individual diseases, the strongest gradients occur for diseases with the greatest sensitivity to stress, such as heart disease, diabetes, Metabolic syndrome, and psychiatric disorders. Finally, once you’ve rounded up the usual suspects—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 epidemiologists were willing to let in some of those psychologists and stress physiologists, but through the back door, and—Cook, find them something to eat in the kitchen, if you please.

So that was the stress argument a half decade back. But since then, striking new findings make the stress argument very solid.

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A central concept of this book is that stress is heavily rooted in psychology once you are dealing with organisms who aren’t being chased by predators, and who have adequate shelter and sufficient calories to sustain good health. Once those basic needs are met, it is an inevitable fact that if everyone is poor, and I mean everyone, then no one is. In order 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 really about a distribution that bottoms out at being poor. It’s not about being poor. It’s about feeling poor, which is to say, it’s about feeling poorer than others around you.

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Beautiful work regarding this has been carried out by Nancy Adler of the University of California at San Francisco. Instead of just looking at the relationship between SES and health, Adler looks at what health has to do with what someone thinks and feels their SES is—their “subjective SES.” Show someone a ladder with ten 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.

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First off, if people were purely accurate and rational, the answers across a group should average out to the middle of 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 the children are above average); in contrast, Chinese-Americans, from a culture with less chest-thumping individualism, average out to below the 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.

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Once you’ve done that, look at what health measures have to do with one’s subjective SES. Amazingly, it is at least as good a predictor of these health measures as is one’s actual SES, and, in some cases, it is even better. Cardiovascular measures, metabolism measures, glucocorticoid levels, obesity in kids. Feeling poor in our socioeconomic world predicts poor health.

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This really isn’t all that surprising. We can be an immensely competitive, covetous, invidious species, and not particularly rational in how we make those comparisons. Here’s an example from a realm 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 mood, with lower self-esteem, than before seeing the pictures (and even more depressingly, show those same pictures to men and afterward what declines is their stated satisfaction with their wives).

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So it’s not about being poor. It’s about feeling poor. What’s the difference? Adler shows that subjective SES is built around education, income, and occupational position (in other words, the building blocks of subjective SES), plus satisfaction with standard of living and feeling of financial security about the future. Those last two measures are 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 financial security” tapping into? Anxiety So SES reality plus your satisfaction with that SES plus your confidence about how predictable your SES is are collectively better predictors of health than SES alone.

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This is not a hard and fast rule, and Adler’s most recent work shows that subjective SES is not necessarily that great of a predictor in certain ethnic groups—stay tuned for more, no doubt. But overall, this strikes me as immensely impressive—when you’re past the realm of worrying about having adequate shelter and food, being poor is not as bad for you as feeling poor.

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Poverty Versus
Poverty Amid Plenty

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In many ways, an even more accurate tag line for this whole phenomenon is, It’s about being made to feel poor. This point is made clearer when considering the second body of research in this area, championed by Richard Wilkinson of the University of Nottingham in England. Wilkinson took a top-down approach, looking at the “How are you doing?” ladder from the societal level.

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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 $5.50anhour.Thusthecompanyispayingoutatotalof$55/hour in salary, and the average income is $5.50/hour.Withthatdistribution,thewealthiestemployeeismaking$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,thenext$2/hour, the next $3,andsoon.Onceagain,thecompanypaysatotalof$55/hour in salary, and the average salary is again $5.50/hour.Butnowthewealthiestemployee,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,andthetenthearns$46/hour. Again, the company pays a total of $55/hour,andtheaveragesalaryis$5.50/hour. And here, the wealthiest employee takes home 84 percent of the total income ($46/$55).

What we have here are businesses of increasingly unequal incomes. What Wilkinson and others have shown is that 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 society, the worse the health and mortality rates.

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This has been shown repeatedly, and at multiple levels. For example, income inequality predicts higher infant mortality rates across a bunch of European countries. Income inequality predicts mortality rates across all ages (except the elderly) in the United States, whether you consider this at the level of states or cities. In a world of science often filled with wishy-washy data, the effect is extremely reliable—income inequality across American states is a really strong predictor of mortality rates among working men. When you compare the most egalitarian state, New Hampshire, with the least egalitarian, Louisiana, the latter has about a 60 percent higher mortality rate.* Finally, Canada is both markedly more egalitarian and healthier than the United States—despite being a “poorer” country.

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Amid extraordinary findings like that, the relationship between income inequality and poor health doesn’t seem to be universal. Note how flat the curve is for Canada—moreover, you don’t find it when considering adults throughout Western Europe, particularly in countries with well-established social welfare systems like Denmark. In other words, 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. But it’s a reasonably robust relationship in the United Kingdom, while the flagship for the health/income inequality relationship is the United States, where the top 1 percent of the SES ladder controls nearly 40 percent of the wealth, and it’s a huge effect (and persists even after controlling for race).

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These studies of nations, states, and cities raise the issue of whom someone is comparing themselves to when they think of where they are on a how-are-you-doing ladder. Adler tries to get at this by asking her question twice. First, you’re asked to place yourself on the ladder with respect to “society as a whole,” and second, with respect to “your 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 literature has given a clear answer yet, but 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.”

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This is obviously the case in traditional settings where all people know about is the immediate community of their village—look at how many chickens he has, I’m such a loser. But thanks to urbanization, mobility, and the media that makes for a global village, something absolutely unprecedented can now occur—we can now be made to feel poor, or poorly about ourselves, by people we don’t even know. You can feel impoverished by the clothes of someone you pass in a midtown crowd, by the unseen driver of a new car on the freeway, by Bill Gates on the evening news, even by a fictional character in a 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.

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Income inequality seems really important for making sense of the SES/health gradient. But maybe it isn’t that important. Maybe the inequality business is just a red herring built around the fact that places with big inequalities tend to be poor places as well (in other words, back to the key thing being “poverty,” instead of “poverty amid plenty”). But, control for absolute income, and the inequality data still stand.

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There’s a second potential problem (WARNING: skip this paragraph if you’re math-phobic—as a synopsis of the plot, the income inequality hypothesis is menaced by math villains but is saved in a cliffhanger finish). Moving up the SES ladder is associated with better health (by whatever measure you are using) but, as noted, each incremental step gets smaller. A mathematical way of stating this is that the SES/health relationship 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 range. So if you examine wealthy nations, you are examining countries where SES averages out to somewhere in the flat part of the curve. Therefore, compare two equally wealthy nations (that is to say, which have the same average SES on the flat part of the curve) that differ in income inequality. By definition, the nation with the greater inequality will have more data points coming from the steeply declining part of the curve, and thus must have a lower average level of health. In this scenario, the income inequality phenomenon doesn’t really reflect some feature of society as a whole, but merely emerges, as a mathematical inevitability, from individual data points. However, some fairly fancy mathematical modeling studies show that this artifact can’t explain all of the health-income inequality relationship in the United States.

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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 the 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 of the wealthy a little worse, and the health of the poor a lot better. A little worse in the few wealthy plus a lot better in the numerous poor and, overall, you’ve got a healthier society. That wouldn’t be very interesting in the context of stress and psychological factors. But Wilkinson makes an extraordinary point—in societies that have more income equality, both the poor and the wealthy are healthier than their counterparts in a less equal society with the same average income. There is something more profound happening here.

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How Does Income Inequality and Feeling
Poor Translate into Bad Health?

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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 heavily upon a concept in sociology called “social capital.” While “financial capital” says something about the depth and range of financial resources you can draw on in troubled times, social capital refers to the same in the social realm. By definition, social capital occurs at the level of a community, rather than at the level of individuals or individual social networks.

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What makes for social capital? A community in which there is a lot of volunteerism and numerous organizations that people can join which make them feel like they’re part of something bigger than themselves. Where people don’t lock their doors. Where people in the community would stop kids from vandalizing a car even if they don’t know whose car it is. Where kids don’t try to vandalize cars. What Kawachi shows is that the more income inequality in a society, the lower the social capital, and the lower the social capital, the worse the health.

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Obviously, “social capital” can be measured in a lot of ways and is still evolving as a hard-nosed measure, but, broadly, it incorporates elements of trust, reciprocity, lack of hostility, heavy participation in organizations for a common good (ranging from achieving fun—a bowling league—to more serious things—tenant organizations or a union) and those organizations accomplishing something. Most studies get at it with two measures: how people 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 states, provinces, cities, and neighborhoods, low social capital tends to mean poor health, poor self-reported health, and high mortality rates.*

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Findings such as these make perfect sense to Wilkinson. In his writing, he emphasizes that trust requires reciprocity, and reciprocity requires equality. In contrast, hierarchy is about domination, not symmetry and equality. By definition, you can’t have a society with both dramatic income inequality and lots of social 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 invisible member of society. To recognize 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.

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So income inequality, minimal trust, lack of social cohesion all go together. Which causes which, and which is most predictive of poor health? To figure this out, you need some fancy statistical techniques called path analysis. An example we’re comfortable with by now from earlier chapters: chronic stress makes for more heart disease. Stress can do this by directly increasing blood pressure. But stress also makes lots of people eat less healthfully. How much is the path from stress to heart disease directly via blood pressure, and how much by the indirect route of changing diet? 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.

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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).

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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 in the next chapter, this isn’t always a great thing. Sometimes, communities 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.

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Research by Kawachi and others shows another feature of income inequality that translates into more physical and psychological stress: the more economically unequal a society, the more crime—assault, robbery, and, particularly, homicide—and the more gun ownership. Critically, income inequality is consistently a better predictor of crime than 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 looked at the prevalence of displacement aggression, poverty amid plenty predicts more crime—but not against the wealthy. The have-nots turn upon the have-nots.

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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 pathway is one that, once you grasp it, is so demoralizing that you immediately want to man the barricades and sing revolutionary songs from Les Miz. It goes as follows:

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If you want to improve health and quality of life, and decrease the stress, for the average person in a society, you do so by spending money on public goods—better public transit, safer streets, cleaner water, better public schools, universal health care. The bigger the income inequality is in a society, the greater the financial distance between the wealthy and the average. The bigger the distance between the wealthy and the average, the less benefit the wealthy will feel from expenditures on the public good. Instead, they would derive much more benefit by spending the same (taxed) money on their private good—a better chauffeur, a gated community, bottled water, private schools, private health insurance. As Evans writes, “The more unequal are incomes in a society, the more pronounced will be the disadvantages to its better-off members from public expenditure, and the more resources will those members have [available to them] to mount effective political opposition.” He notes how this “secession of the wealthy” pushes 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 wealthy, this is because of the costs of walling themselves off from the rest of society, and for the rest of society, this is because they have to live in it.

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So this is a route by which an unequal society makes for a more stressful reality. But this route certainly makes for more psychological stress as well—if the skew in society biases the increasingly wealthy 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.

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So we’ve got income inequality, low social cohesion and social capital, class tensions, and lots of crime all forming an unhealthy cluster. Let’s see a grim example of how these pieces come together. By the late 1980s, life expectancy in Eastern Bloc countries was less than in every Western European country. As analyzed by Evans, these were societies in which there was a fair equity of income distribution, but a highly unequal distribution of freedoms of movement, speech, practice of beliefs, and so on. And what has happened to Russia since the dissolution of the Soviet Union? A massive increase in income inequality and crime, a decline in absolute wealth—and an overall decline in life expectancy that is unprecedented in an industrialized society.

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One more grim example of how this works. America: enormous 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 the street from his parents? Isn’t that a little, er, stunted?) Get a new accent, get a new culture, get a new name, unlist your phone number, reboot your life. All of which are the antitheses of developing social capital. This helps to explain something subtle about the health-income inequality relationship. Compare the United States and Canada. As shown, the former has more income inequality and worse health. But restrict your analysis to a subset of atypical American systems chosen to match the low inequality of Canada—and those U.S. cities still have worse health and a steeper SES/health gradient. Some detailed analyses show what this is about: it’s not just that America is a markedly unequal society when it comes to income. It’s that even for the same degree of worsening income inequality, social capital is driven down further in the United States.

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Our American credo is that people are willing to tolerate a society 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 pyramid. Over the last quarter-century, poverty and income inequality have steadily risen, and every social capital measure of trust, community participation, and voter participation has declined.* And what about American health? We have disparity between the wealth of our nation and the health of our citizens that is also unprecedented. And getting worse.

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This is pretty depressing stuff, given its implications. Adler, writing around the time when universal health insurance first became a front-page issue (as was the question of whether Hillary’s hairstyle made her a more or less effective advocate for it), concluded that such universal coverage would “have a minor impact on SES-related inequalities in 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.

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This is relevant to an even larger depressing thought. I initially reviewed what social rank has to do with health in nonhuman primates. Do low-ranking monkeys have a disproportionate share of disease, more stress-related disease? And the answer was, “Well, it’s actually not that simple.” It depends on the sort of society the animal lives in, its personal experience of that society, its coping skills, its personality, the availability of social support. Change some of those variables and the rank/health gradient can shift in the exact opposite direction. This is the sort of finding that primatologists revel in—look how complicated and subtle my animals are.

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The second half of this chapter looked at humans. Do poor humans have a disproportionate share of disease? The answer was “Yes, yes, over and over.” Regardless of gender or age or race. In societies with 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 societies in which the central mythology is a capitalist credo of “Living well is the best revenge” and those in which it is a socialist anthem of “From each according to his ability, to each according to his needs.”

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What does this dichotomy between our animal cousins and us signify? The primate relationship is nuanced and filled with qualifiers; the human relationship is a sledgehammer that obliterates every societal difference. Are we humans actually less complicated and sophisticated than nonhuman primates? Not even the most chauvinistic primatologists holding out for their beasts would vote for that conclusion. I think it suggests something else. Agriculture is a fairly recent human 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 that the punch line of the primate-human difference is that when humans invented poverty, they came up with a way of subjugating the low-ranking like nothing ever before seen in the primate world.

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18

Managing Stress

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This far into this book, this one should be a no brainer—social support makes stressors less 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 troubled circumstances where being with anyone would make us feel worse. Physiological studies have demonstrated this as well. Take a rodent or a primate that has been housed alone and put it into a social group. The 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.*

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In another demonstration of this principle, infant monkeys were separated from their mothers. Predictably, they had pretty sizable stress-responses, with elevations in glucocorticoid levels. The elevation could be prevented if the infant was placed in a group of monkeys—but only if the infant already knew those animals. There is little to be derived in the way of comfort from strangers.

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Even once animals are no longer strangers, on average half of those in any group will be socially dominant to any given individual, and having more dominant animals around is not necessarily a comfort during trouble. Even intimate social affiliation is not always helpful. We saw in psychoimmunity chapter 8 that being married is associated with all sorts of better health outcomes. Some of it is due to the old reverse causality trick—unhealthy people are less likely to 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 into cutting back on some lifestyle risk factors. After controlling 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.

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Expanding outward, it is also healthful to have a strong network of friends and, as we saw in the last chapter, to be in a community teeming with social capital. What’s the potential downside of that? Something I alluded to. Amid all that nice, utopian social capital business lurks the inconvenient fact that a tightly cohesive, cooperative community with shared values may be all about homogeneity, conformity, and xenophobia. Maybe even brownshirts and jackboots. So social capital isn’t always warm and fuzzy.

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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 social support, to be needed. The twelfth-century philosopher Maimonides constructed a hierarchy of the best ways to do charitable acts, and at the top was when the charitable person gives anonymously to an anonymous recipient. That’s a great abstract goal, but often there is a staggering power in seeing the face that you have helped. In a world of stressful lack of control, an amazing source of control we all have is the ability to make the world a better place, one act at a time.

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13 Why Is Psychological Stress Stressful?

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14

Stress and Depression

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The defining feature of a major depression is loss of pleasure.

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This trait is called anhedonia: hedonism is “the pursuit of pleasure,” anhedonia is “the inability to feel pleasure”

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This is the classic picture of depression, and some recent research, much of it built around work of the psychologist Alex Zautra of the University of Arizona, shows that the story is more complex. Specifically, positive and negative emotions are not mere opposites. If you take subjects and, at random times throughout the day, have them record how they are feeling at that moment, the frequencies of feeling good and feeling bad are not inversely correlated. There’s normally not much of a connection between how much your life is filled with strongly positive emotions and how much with strongly negative ones. Depression represents a state where those two independent axes tend toward collapsing into one inverse relationship—too few positive emotions and too many negative ones. Naturally, the inverse correlation isn’t perfect, and a lot of current research focuses on questions like: Are different subtypes of depression characterized more by the absence of positive emotions or the overabundance of negatives?

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Accompanying major depression are great grief and great guilt. We often feel grief and guilt in the everyday sadnesses that we refer to as “depression.” But in a major depression, they can be incapacitating, as the person is overwhelmed with the despair. There can be complex layers of these feelings: not just obsessive guilt, for example, 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 overcome depression, a life lived but once and wasted amid this disease. Small wonder that, worldwide, depression accounts for 800,000 suicides per year.*

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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 facts are distorted, over- or underinterpreted to the point where one must conclude that things are terrible and getting worse, hopeless.

An example: a middle-aged man, out of the blue, has a major heart attack. Overwhelmed by his implied mortality, the transformation of his life, he slips into a major depression. Despite this, he is recovering from the attack reasonably well, and there is every chance that he will resume a normal life. But each day he’s sure he’s getting worse.

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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 distorted, negative way. Beck and colleagues have conducted striking studies that provide evidence for this. For example, they might show a subject two pictures. In the first, a group of people are gathered happily around a dinner table, feasting. In the second, the same people are gathered around a coffin. Show the two pictures rapidly or simultaneously; which one is remembered? Depressives see the funeral scene at rates higher than chance. They are not only depressed about something, but see the goings-on around them in a distorted way that always reinforces that feeling. Their glasses are always half empty.

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Another frequent feature of a major depression is called psychomotor retardation. The person moves and speaks slowly. Everything requires tremendous effort and concentration. She finds the act of merely arranging a doctor’s appointment exhausting. Soon it is too much even to get out of bed and get dressed. (It should be noted that not all depressives show psychomotor retardation; some may show the opposite pattern, termed psychomotor agitation.)

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major depressives often experience elevated levels of glucocorticoids. This is critical for a number of reasons that will be returned to, and helps to clarify what the disease is actually about. When looking at a depressive sitting on the edge of the bed, barely able to move, it is easy to think of the person as energy-less, enervated. A more accurate picture is of the depressive as a tightly coiled spool of wire, tense, straining, active—but all inside. As we will see, a psychodynamic view of depression shows the person fighting an enormous, aggressive mental battle—no wonder they have elevated levels of stress hormones.

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glucocorticoids can impair aspects of memory that depend on the hippocampus, and the frequently elevated glucocorticoid levels in depression may help explain another feature of the disease, which is problems with hippocampal-dependent memory.

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the pure process of storing and retrieving memories via the hippocampus is often impaired. As we’ll see shortly, this fits extraordinarily well with recent findings showing that the hippocampus is smaller than average in many depressives.

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it is a real disease, rather than merely the situation of someone who simply cannot handle everyday ups and downs.

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There are multiple types of depressions, and they can look quite different. In one variant, unipolar depression, the sufferer fluctuates from feeling extremely depressed to feeling reasonably normal. In another form, the person fluctuates between deep depression and wild, disorganized hyperactivity. This is called bipolar depression or, more familiarly, manic depression.

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Here we run into another complication because, just as we use depression in an everyday sense that is different from the medical sense, mania has an everyday connotation as well. We may use the term to refer to madness, as in made-for-television homicidal maniacs. Or we could describe someone as being in a manic state when he is buoyed by some unexpected good news—talking quickly, laughing, gesticulating. But the mania found in manic depression is of a 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 three Cadillacs with money from loan sharks. And, get this, she doesn’t even know how to drive. People in manic states will go for days on three hours of sleep a night and feel rested, will talk nonstop for hours at a time, will be vastly distractible, unable to concentrate amid their racing thoughts. In outbursts of irrational grandiosity, they will behave in ways that are foolhardy or dangerous to themselves and others—at the extreme, poisoning themselves in attempting to prove their immortality, burning down their homes, giving away their life savings to strangers. It is a profoundly destructive disease.

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Why is it likely that there is something wrong with norepinephrine, serotonin, or dopamine in depression? The best evidence is that most of the drugs that lessen depression increase the amount of signaling by these neurotransmitters.

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On an incredibly simplistic level, you can think of depression as occurring when your cortex thinks an abstract negative thought and manages to convince the rest of the brain that this is as real as a physical stressor. In this view, people with chronic depressions are those whose cortex habitually whispers sad thoughts to the rest of the brain. Thus, an astonishingly crude prediction: cut the connections between the cortex and the rest of a depressive’s brain, and the cortex will no longer be able to get the rest of the brain depressed.

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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.*

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Obviously, this is a simplified picture—no one actually disconnects the entire cortex from the rest of the brain. After all, the cortex does more than mope around feeling bad about the final chapter of Of Mice and Men. The surgical procedure, called a cingulotomy, or a cingulum bundle cut, actually disconnects just one area toward the front of the cortex, called the anterior cingulate cortex (ACC). The ACC is turning out to have all the characteristics of a brain 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.

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And the emotions that the ACC is involved in seem to be negative ones. Induce a positive state in someone by showing something amusing, and ACC metabolism decreases. In contrast, if you electrically stimulate the ACC in people, they feel a shapeless sense of fear and foreboding. Moreover, neurons in the ACC, including in humans, respond to pain of all sorts. But the ACC response isn’t really about the pain; it more concerns feelings about the pain. As was discussed in chapter 9, give someone a hypnotic suggestion that they will not feel the pain of dipping their hand into ice water. The primary parts of the brain that get pain projections from the spinal cord get just as active as if there were no hypnotic suggestion. But this time, the ACC doesn’t activate.

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In addition, the ACC and adjacent brain regions activate when you show widows pictures of their lost loved ones (versus pictures of strangers). As another 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 that, over time, the other two (actually, a computer program) gradually begin just playing with each other, excluding the test subject. Neuronal activity in the ACC lights up, and the more left out the person feels, the more intensely the ACC activates. How do you know this has something to do with that dread junior high school feeling of being picked last for the team? Because of a clever control in the study: set the person up to play with the supposed other two players. Once again, it winds up that the other two only play against each other. The difference, this time, though, is that early on the subject is told there’s been a technical glitch and that their computer console isn’t working. Excluded because of a snafu in the technology, there’s no ACC activation.

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Given these functions of the ACC, it is not surprising that its resting level of activity tends to be elevated in people with a depression—this is the fear and pain and foreboding churning away at those neurons. Interestingly, another part of the brain, called the amygdala, seems to be hyperactive in depressives as well. We will hear lots about the role of the amygdala in fear and anxiety in the next chapter. However, in depressives, the amygdala seems to have been recruited into a different role. Show a depressed person a fearful human face and his amygdala doesn’t activate all that much (in contrast to the response you’d see in the amygdala of a control subject). But show him a sad face and the amygdala gets a highly exaggerated activation.

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Sitting just in front of the ACC is the frontal cortex which, as we saw in chapter 11, is one of the most distinctly 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 lateralized way. Specifically, activation of the left PFC is associated with positive moods, and activation of the right PFC, with negative. For example, induce a positive state in 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, and the right PFC dominates. Similarly, separate an infant monkey from its mother and right PFC metabolism rises while left PFC decreases. Thus, not surprisingly, in depressives, there is decreased left PFC activity and elevated activity in the right PFC.

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It is hard to look at the biology of anything these days without genes coming into the picture, and depression is no exception. Depression has a genetic component. As a first observation, depression runs in families. For a long time, that would have been sufficient evidence for some folks that there is a genetic link, but this conclusion is undone by 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.

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So we look for a tighter relationship. The more closely related two individuals are, the more genes they share in common and, as it turns out, the more likely they are to share a depressive trait. As one of the most telling examples of this, take any two siblings (who are not identical twins). They share something like 50 percent of their genes. If one of them has a history of depression, the other has about a 25 percent likelihood, considerably higher than would be expected by chance. Now, compare two identical twins, who share all of their genes in common. And if one of them is depressive, the other has a 50 percent chance. This is quite impressive—the more genes in common, the more likelihood of sharing the disease. But there remains a confound: the more genes people share within a family, the more environment they share as well (starting with the fact that identical twins grow up treated more similarly than are non-identical twins).

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Tighten the relationship further. Look at children who were adopted at an early age. Consider those whose biological mother had a history of depression, but whose adoptive mother did not. They have an increased risk of depression, suggesting a genetic legacy shared with their biological mother. But the confound there, as we saw in chapter 6, is that “environment” does not begin at birth, but begins much earlier, with the circulatory environment shared in utero with one’s biological mother.

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For any card-carrying molecular biologist in the twenty-first century, if you want to prove that genes have something to do with depression, you’re going to have to identify the specific genes, the specific stretches of DNA that code for specific proteins that increase the risk for depression. As we’ll see shortly, precisely that has occurred in recent years.

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people who are undergoing a lot of life stressors are more likely than average to succumb to a major depression, and people sunk in their first major depression are more likely than average to have undergone recent and significant stress.

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Laboratory studies also link stress and the symptoms of depression. Stress a lab rat, and it becomes anhedonic. Specifically, it takes a stronger electrical current than normal in the rat’s pleasure pathways to activate a sense of pleasure. The threshold for perceiving pleasure has been raised, just as in a depressive.

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Critically, glucocorticoids can do the same. A key point in chapter 10 was how glucocorticoids and stress could disrupt memory. Part of the evidence for that came from people with Cushing’s syndrome (as a reminder, that is a 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 from people prescribed high doses of glucocorticoids to treat a number of ailments. It has also been known for decades that a significant subset of Cushingoid patients and patients prescribed synthetic glucocorticoids become clinically depressed, independent of memory problems.

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This has been a bit tricky to demonstrate. First, when someone is initially treated with synthetic glucocorticoids, the tendency is to get, if anything, euphoric and even manic, perhaps for a week or so before the depression kicks in. You can immediately guess that we are dealing with one of our dichotomies between short- and long-term stress physiology; chapter 16 will explore in even more detail where that transient euphoria comes from.

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As a second complication, does someone with Cushing’s syndrome or someone taking high pharmacological doses of synthetic glucocorticoids get depressed because glucocorticoids cause that state, or is it because they recognize they have a depressing disease? You show it is the glucocorticoids that are the culprits by demonstrating higher depression rates in this population than among people with, for example, the same disease and the same severity but not receiving glucocorticoids. At this stage, there’s also not much of a predictive science to this phenomenon. For example, no clinician can reliably predict beforehand which patient is going to get depressed when put on high-dose glucocorticoids, let alone at what dose, and 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.

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Stress and glucocorticoids tangle up with biology in predisposing a person toward depression in an additional, critical way. Back to that business about there being a genetic component to depression. Does this mean that if you have “the gene” (or genes) “for” depression, that’s it, you’re up the creek, it’s inevitable? Obviously not, and the best evidence for this is that factoid about identical twins. One has depression and the other, sharing all the same genes, has about a 50 percent chance of having the disease as well, a much higher rate than in the general population. There, pretty solid evidence for genes being involved. But flip this the other way. Share every single gene with someone who is depressive and you still have a 50 percent chance of not having the disease.

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Genes are rarely about inevitability, especially when it comes to humans, the brain, or behavior. They’re about vulnerability, propensities, tendencies. In this case, genes increase the risk of depression only in certain environments: you guessed it, only in stressful environments. This is shown in a number of ways, but most dramatically in a recent study by Avshalom Caspi at King’s College, London. Scientists identified a certain gene in humans that increases the risk of depression. More specifically, it is a gene that comes in a few different “allelic versions”—a few different types or flavors that differ slightly in function; have one of those versions, and you’re at increased risk. What that gene is I’m not telling yet; I’m saving it for the end of this chapter, as it is a doozy But the key thing is that having version 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 depressed. Version X increases depression risk only when coupled with a history of repeated major stressors. Amazingly, the same has been shown with 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 the gene interacts with a certain environment. More specifically, a gene that makes you vulnerable in a stressful environment.

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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 disease—an incapacitating physical and psychological exhaustion. Just as is the case with chronic fatigue syndrome, atypical depression is characterized by lower than normal glucocorticoid levels. However, the far more common feature of depression is one of an overactive stress-response—somewhat of an overly activated sympathetic nervous system and, even more dramatically, elevated levels of glucocorticoids. This adds to the picture that depressed people, sitting on the edge of their beds without the energy to get up, are actually vigilant and aroused, with a hormonal profile to match—but the battle is inside them.

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Research stretching back some forty years has explored why, on a nuts-and-bolts level, glucocorticoid levels are often elevated in depression. The elevated levels appear to be due to too much of a stress signal from the brain (back to chapter 2—remember that the adrenals typically secrete glucocorticoids only when they are commanded to by the brain, via the pituitary), rather than the adrenals just getting some depressive glucocorticoid hiccup all on their own now and then. Moreover, the excessive secretion of glucocorticoids is due to what is called feedback resistance—in other words, the brain is less effective than it should be at shutting down glucocorticoid secretion. Normally, the levels of this hormone are tightly regulated—the brain senses circulating glucocorticoid levels, and if they get higher than desired (the “desired” level shifts depending on whether events are calm or stressful), the brain stops secreting CRH. Just like the regulation of water in a toilet bowl tank. In depressives, this feedback regulation fails—concentrations of circulating glucocorticoids that should shut down the system fail to do so, as the brain does not sense the feedback signal.*

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the glucocorticoid angle fits well, in that the hormones can alter features of all three neurotransmitter systems—the amount of neurotransmitter synthesized, how fast it is broken down, how many receptors there are for each neurotransmitter, how 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 those stress effects are most important, simply because it is not clear which neurotransmitter or neurotransmitters are most important. However, it is probably safe to say that whatever neurochemical abnormalities wind up being shown definitively to underlie depression, there is precedent for stress and glucocorticoids causing those same abnormalities.

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there may be problems with the hippocampus in people with major depression. This speculation was reinforced by the fact that the type of memory most often impaired in depression—declarative memory—is mediated by the hippocampus. As was discussed in chapter 10, there is atrophy of the hippocampus in long-term depression. The atrophy emerges as a result of the depression (rather than precedes it), and the longer the depressive history, the more atrophy and the more memory problems. While no one has explicitly shown yet that the atrophy occurs only in those depressives with the elevated glucocorticoid levels, the atrophy is most common in the subtypes of depression in which the glucocorticoid excess is most common. Chronic depression has also been associated in some studies with decreased volume in the frontal cortex. This was initially puzzling for those of us who view the world through glucocorticoid-tinted glasses, but has recently been resolved. In the rat, the hippocampus is overwhelmingly the target in the brain for glucocorticoid action, as measured by the density of receptors for the hormone; however, in the primate brain, the hippocampus and frontal cortex seem to be equally and markedly sensitive to glucocorticoids.

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So some pretty decent circumstantial evidence suggests that the glucocorticoid excess of depression may have something to do with the decreased volume of the hippocampus and frontal cortex. Chapter 10 noted an array of bad things that glucocorticoids could do to neurons. Some obsessively careful studies have shown loss of cells in the frontal cortex accompanying the volume loss in depression—as one point of confusion, it is those supportive glial 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 cellular level, it appears to be permanent; years to decades after these major depressions have been gotten under control (typically with medication), the volume loss is still there.

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—why is it that most of us can have occasional terrible experiences, feel depressed, and then recover, while a few of us collapse into major depression (melancholia)?

Note: because they don’t know how to deal with it. Or overactive stress response

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we saw that certain features dominated as psychologically stressful: a loss of control and of predictability within certain contexts, a loss of outlets for frustration, a loss of sources of support, a perception of life worsening. In one style of experiment, pioneered by the psychologists Martin Seligman and Steven Maier, animals are exposed to pathological amounts of these psychological stressors. The result is a condition strikingly similar to a human depression.

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Although the actual stressors may differ, the general approach in these studies always emphasizes repeated stressors with a complete absence of control on the part of the animal. For example, a rat may be subjected to a long series of frequent, uncontrollable, and unpredictable shocks or noises, with no outlets.

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After awhile, something extraordinary happens to that rat. This can be shown with a test. Take 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, electricity 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-the-mill rat can learn this “active avoidance task” easily, and within a short time it readily and calmly shifts the side of the room it sits in according to the signal. Simple. Except for a rat who has recently been exposed to repeated uncontrollable stressors. That rat cannot learn the task. It does not learn to cope. On the contrary, it has learned to be helpless.

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This phenomenon, called learned helplessness, is quite generalized; the animal has trouble coping with all sorts of varied tasks after its exposure to uncontrollable stressors. Such helplessness extends to tasks having to do with its 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 receiving the shocks or, instead, the psychological stressor of having no control over or capacity to predict the shocks. It is the latter. The clearest way to demonstrate this is to “yoke” pairs of rats—one gets shocked under conditions marked by predictability and a certain degree of control, the other rat gets the identical pattern of shocks, but without the control or predictability. Only the latter rat becomes helpless.

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Seligman argues persuasively that animals suffering from learned helplessness share many psychological features with depressed humans. Such animals have a motivational problem—one of the reasons that they are helpless is that they often do not even attempt a coping response when they are in a new situation. This is quite similar to the depressed person who doesn’t even try the simplest task that would improve her life. “I’m too tired, it seems overwhelming to take on something like that, it’s not going to work anyway….”

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Animals with learned helplessness also have a cognitive problem, something awry with how they perceive the world and think about it. When they do make the rare coping response, they can’t tell whether it works or not. For example, if you tighten the association between a coping response and a reward, a normal rat’s response rate increases (in other words, if the coping response works for the rat, it persists in that response). In contrast, linking rewards more closely to the rare coping responses of a helpless rat has little effect on its response rate. Seligman believes that this is not a consequence of helpless animals somehow missing the rules of the task; instead, he thinks, they have actually learned not to bother paying attention. By all logic, that rat should 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 therapists 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.

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It takes surprisingly little in terms of uncontrollable unpleasantness to make humans give up and become helpless in a generalized way. In one study by Donald Hiroto, student volunteers were exposed to either escapable or inescapable loud noises (as in all such studies, the two groups were paired so that they were exposed to the same amount of noise). Afterward, they were given a learning task in which a correct response turned off a loud noise; the “inescapable” group was significantly less capable of learning the task. Helplessness can even be generalized to nonaversive learning situations. Hiroto and Seligman did a follow-up study in which, again, there was either controllable or uncontrollable noise. Afterward the latter group was less capable of solving simple word puzzles. 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 task 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 task. Seligman and colleagues have also demonstrated that unsolvable tasks induced helplessness afterward in social coping situations.

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Thus humans can be provoked into at least 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 able to identify the students who came into the experiment with a strongly “internalized locus of control”—a belief that they were the masters of their own destiny and had a great deal of control in their lives—and, in contrast, the markedly “externalized” volunteers, who tended to attribute outcomes to chance and luck. In the aftermath of the uncontrollable stressor, the externalized students were far more vulnerable to learned helplessness. Transferring that to the real world, with the same external stressors, the more that someone has an internal locus of control, the less the likelihood of a depression.

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But life is full of more significant examples. 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 intellectually incapable of reading? Apparently not. The psychologists circumvented the students’ resistance to learning to read by, instead, teaching them Chinese characters. Within hours they were capable 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.

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A major depression, these findings suggest, can be the outcome of particularly severe lessons in uncontrollability for those of us who are already vulnerable. This may explain an array of findings that 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 exposed to stressors early in life have a lifelong increase in CRH levels in their brain.

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“According to our model,” writes Seligman, “depression is not generalized pessimism, but pessimism specific to the effects of one’s own skilled actions.” Subjected to enough uncontrollable stress, we learn to be helpless—we lack the motivation to try to live because we assume the worst; we lack the cognitive clarity to perceive when things are actually going fine, and we feel an aching lack of pleasure in everything.*

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1

Why Don’t Zebras Get Ulcers?

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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, consider the leading causes of death in the United States in 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.

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Our current patterns of disease would be unrecognizable to our great-grandparents or, for that matter, to most mammals. Put succinctly, we get different diseases and are likely to die in different ways from most of our ancestors (or from most humans currently living in the less privileged areas of this 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.

Note: yeah I don’t really think these diseases are caused by old age

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The diseases that plague us now are ones of slow accumulation of damage—heart disease, cancer, cerebrovascular disorders. While none of these diseases is particularly pleasant, they certainly mark a big improvement over succumbing at age twenty after a week of sepsis or dengue fever.

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Perhaps the best way to begin is by making a mental list of the sorts of things we find stressful. No doubt you would immediately come up with some obvious examples—traffic, deadlines, family relationships, money worries. But what if I said, “You’re thinking like a speciocentric human. Think like a zebra for a second.” Suddenly, new items might appear at the top of your list—serious physical injury, predators, starvation. The need for that prompting illustrates something critical—you and I are more likely to get an ulcer than a zebra is. For animals like zebras, the most upsetting things in life are acute physical crises. You are that zebra, a lion has just 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 stressfully, you are that lion, half-starved, and you had better be able to sprint across the savanna at top speed and grab something to eat or you won’t survive. These are extremely stressful events, and they demand immediate physiological adaptations if you are going to live. Your body’s responses are brilliantly adapted for handling this sort of emergency.

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An organism can also be plagued by chronic physical challenges. The locusts have eaten your crops, and for the next 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, but central events in the lives of non-westernized humans and most other mammals. The body’s stress-responses are reasonably good at handling these sustained disasters.

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Critical to this book is a third category of ways to get upset—psychological and social disruptions. Regardless of how poorly we are getting along with a family member or how incensed we are about losing a parking spot, we rarely settle that sort of thing with a fistfight. Likewise, it is a rare event when we have to stalk 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 purely in our heads. How many hippos worry about whether Social Security is going to last as long as they will, or what they are going to say on a first date? Viewed from the perspective of the evolution of the animal kingdom, sustained psychological stress is a recent invention, mostly limited to humans and other social primates. We can experience wildly strong emotions (provoking our bodies into an accompanying uproar) linked to mere thoughts.* Two people can sit facing each other, doing nothing more physically strenuous than moving little pieces of wood now and then, yet this can be an emotionally taxing event: chess grand masters, during their tournaments, can place metabolic demands on their bodies that begin to approach those of athletes during the peak of a competitive event.* Or a person can do nothing more exciting than sign a piece of paper: if she has just signed the order to fire a hated rival after months of plotting and maneuvering, her physiological responses might be shockingly similar to those of a savanna baboon who has just lunged and slashed the face of a competitor. And if someone spends months on end twisting his innards in anxiety, anger, and tension over some emotional problem, this might very well lead to illness.

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This is the critical point of this book: if you are that zebra running for your life, or that lion sprinting for your meal, your body’s physiological response mechanisms are superbly adapted for dealing with such short-term physical emergencies. For the vast majority of beasts on this planet, stress is about a short-term crisis, after which it’s either over with or you’re over with. When we sit around and worry about stressful things, we turn on the same physiological responses—but they are potentially a disaster when provoked chronically. A large body of evidence suggests that stress-related disease emerges, predominantly, out of the fact that we so often activate a physiological system that has evolved for responding to acute physical emergencies, but we turn it on for months on end, worrying about mortgages, relationships, and promotions.

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This difference between the ways that we get stressed and the ways a zebra does lets us begin to wrestle with some definitions. To start, I must call forth a concept that you were tortured with in ninth-grade biology and hopefully have not had to think about since—homeostasis. Ah, that dimly remembered concept, the idea that the body has an ideal level of oxygen that it needs, an ideal degree of acidity, an ideal temperature, and so on. All these different variables are maintained in homeostatic balance, the state in which all sorts of physiological 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 working definitions that would suffice for a zebra or a lion. A stressor is anything in the outside world that knocks you out of homeostatic balance, and the stress-response is what your body does to reestablish homeostasis.

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But when we consider ourselves and our human propensity to worry ourselves sick, we have to expand on the notion of stressors merely being things that knock you out of homeostatic balance. A stressor can also be the anticipation of 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 occurred. Some aspects of anticipatory stress are not unique to humans—whether you are a human surrounded by a bunch of thugs in a deserted subway station or a zebra face to face with a lion, your heart is probably racing, even though nothing physically damaging has occurred (yet). But unlike less cognitively sophisticated species, we can turn on the stress-response by thinking about potential stressors that may throw us out of homeostatic balance far in the future. For example, think of the African farmer watching a swarm of locusts descend on his crops. He has eaten an adequate breakfast and is not suffering the homeostatic imbalance of starving, but that farmer will still be undergoing a stress-response. Zebras and lions may see trouble coming in the next minute and mobilize a stress-response in anticipation, but they can’t get stressed about events far in the future.

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And sometimes we humans can be stressed by things that simply make no sense to zebras or lions. It is not a general mammalian trait to become anxious about mortgages or the Internal Revenue Service, about public speaking or fears of what you will say in a job interview, about the inevitability of death. Our human experience is replete with psychological stressors, a far cry from the physical world of hunger, injury, blood loss, or temperature extremes. 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 defenses can be quite protective, in that a lot of what the stress-response is about is preparative. But when we get into a physiological uproar and activate the stress-response for no reason at all, or over something we cannot do anything about, we call it things like “anxiety,” “neurosis,” “paranoia,” or “needless hostility.”

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Thus, the stress-response can be mobilized not only in response to physical or psychological insults, but also in expectation of them. It is this generality of the stress-response that is the most surprising—a physiological system 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 facetious, stress physiology exists as a discipline because this man was both a very insightful scientist and lame at handling lab rats.

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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 research career. A biochemist down the hall had just isolated some sort of extract from the ovary, and colleagues were 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 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 sink, and so on. At the end of a number of months of this, Selye examined the rats and discovered something extraordinary: the rats had peptic ulcers, greatly enlarged adrenal glands (the source of two important stress hormones), and shrunken immune tissues. He was delighted; he had discovered the effects of the mysterious ovarian extract.

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Being a good scientist, he ran a control group: rats injected daily with saline alone, instead of the ovarian extract. And, thus, every day they too were injected, dropped, chased, and chased back. At the end, lo and behold, the control rats had the same peptic ulcers, enlarged adrenal glands, and atrophy of tissues of the immune system.

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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 ovarian extract after all, since the same changes occurred in both the control and the experimental groups. What did the two groups of rats have in common? Selye reasoned that it was his less-than-trauma-free injections. Perhaps, he 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 enlargement, and atrophy of immune tissues.

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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 unpleasantness 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.

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The homeostasis concept has been modified in recent years in work originated by Peter Sterling and Joseph Eyer of the University of Pennsylvania and extended by Bruce McEwen of Rockefeller University.* They have produced a new framework that I steadfastly tried to ignore at first and have now succumbed to, because it brilliantly modernizes the homeostasis concept in a way that works even better in making sense of stress (although not all folks in my business have embraced it, using “old wine in a new bottle” imagery).

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The original conception of homeostasis was grounded in two ideas. First, there is a single optimal level, number, amount for any given measure in the body. But that can’t be true—after all, the ideal blood pressure when you’re sleeping is likely to be different than when you’re ski jumping. What’s ideal under basal conditions is different than during stress, something central to allostatic thinking. (The field uses this Zen-ish sound bite about how allostasis is about “constancy through change.” I’m not completely sure I understand what that means, but it always elicits meaningful and reinforcing nods when I toss it out in a lecture.)

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The second idea in homeostasis is that you reach that ideal set point through some local regulatory mechanism, whereas allostasis recognizes that any given set point can be regulated in a zillion different ways, each with its own consequences. Thus, suppose there’s a water shortage in California. Homeostatic solution: mandate smaller toilet tanks.* Allostatic solutions: smaller toilet tanks, convince people to conserve water, buy rice from Southeast Asia instead of doing water-intensive farming in a semi-arid state. Or suppose there’s a water shortage in your body. Homeostatic solution: kidneys are the ones that figure this out, tighten things up there, produce less urine for water conservation. Allostatic solutions: brain figures this out, tells the kidneys to do their thing, sends signals to withdraw water from parts of your body where it easily evaporates (skin, mouth, nose), makes you feel thirsty. Homeostasis is about tinkering with this valve or that gizmo. Allostasis is about the brain coordinating body-wide changes, often including changes in behavior.

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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 point that has gone awry. It can also make allostatic changes in anticipation of a set point that is likely to go awry. And thus we hark back to the critical point of a few pages back—we don’t get stressed being chased by predators. We activate the stress-response in anticipation of challenges, and typically those challenges are the purely psychological and social tumult that would make no sense to a zebra. We’ll be returning repeatedly to what allostasis has to say about stress-related disease.

3

Voodoo Death

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10

Stress and Memory

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All etched forever in your mind, when it’s inconceivable that you can recall the slightest thing about incidents in the twenty-four hours before that life-changing event. Arousing, exciting, momentous occasions, including stressful ones, get filed away readily. Stress can enhance memory.

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And some of these instances of failed memory revolve around infinitely greater traumas—the combat vet who went through some unspeakable battle catastrophe, the survivor of childhood sexual abuse—for whom the details are lost in an amnesiac fog. Stress can disrupt memory.

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By now, this dichotomy should seem quite familiar. If stress enhances some function under one circumstance and disrupts it under another, think time course, think 30-second sprints across the savanna versus decades of grinding worry. Short-term stressors of mild to moderate severity enhance cognition, while major or prolonged stressors are disruptive.

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To begin, memory is not monolithic, but instead comes in different flavors. One particularly important 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, where you went to college. Neuropsychologists are coming to recognize that there is a specialized subset of long-term 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 separate from more recent long-term memories. Often, in patients with a dementia that devastates most long-term memory, the more remote facets can remain intact.

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Another important distinction in memory is that between explicit (also known as declarative) memory and implicit (which includes an important subtype called procedural memory) memory. Explicit memory concerns facts and events, along with your conscious awareness of knowing them: I am a mammal, today is Monday, my dentist has thick eyebrows. Things like that. In contrast, implicit procedural memories are about skills 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, doing the fox-trot.

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Memories can be transferred between explicit and implicit forms of storage. For example, you are learning a new, difficult passage from a piece of piano music. Each time that stretch approaches, you must 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.

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Memory can be dramatically disrupted 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 adversary has pulled off some amazing backhand, then offer a warm smile and say, “You are a fabulous tennis player. I mean it; you’re terrific. Look at that shot you just made. How did you do that? When you do a backhand like that, do 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, “You can’t think and hit at the same time.” Imagine descending a flight of stairs in an explicit manner, something you 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.

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Just as there are different types of memory, there are different areas of the brain involved in memory storage and retrieval. One critical site is the cortex, the vast and convoluted surface of the brain. Another is a region tucked just underneath part of the cortex, called the hippocampus.

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Both of these are regions vital to memory—for example, it is the hippocampus and cortex that are preferentially damaged in Alzheimer’s disease. If you want a totally simplistic computer metaphor, think of the cortex as your hard drive, where memories are stored, and your hippocampus as the keyboard, the means by which you place and access memories in the cortex.

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There are additional brain regions relevant to a different kind of memory. These are structures that regulate body movements. What do these sites, such as the cerebellum, have to do with memory? They appear to be relevant to implicit procedural memory, the type you need to perform reflexive, motor actions without even consciously thinking about them, where, so to speak, your body remembers how to do something before you do.

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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 belief among many who studied the cortex was that each individual cortical neuron would, in effect, turn out to have a single task, a single fact that it knew. This was prompted by some staggeringly important work done in the 1960s by David Hubel and Torstein Wiesel of Harvard on what was, in retrospect, one of the simpler outposts of the cortex, an area that processed visual information. They found a first part of the visual cortex in which each neuron responded to one thing and one thing only, namely a single dot of light on the retina. Neurons that responded to a sequence of adjacent dots of light would funnel their projections to one neuron in the next layer. And thus, what was this neuron responding to? A straight line. A series of these neurons would project to the next level in a way that each neuron in that cortical level would respond to a particular moving line of light. This led people to believe that there would be a fourth level, where each neuron responded to a particular collection of lines, and a fifth and sixth layer, all the way up until, at the umpteenth layer, there would be a neuron that responded to one thing and one thing only, namely your grandmother’s face at a particular angle (and next to it would be a neuron that recognized her face at a slightly 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 stimulation. With time, it became apparent that there could be very few such neurons in the cortex, because you simply don’t have enough neurons to go around to allow each one to be so narrow-minded and overspecialized.

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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.

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A highly hypothetical neural network involving a neuron that “knows” about Impressionist paintings.

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The first layer of neurons (neurons 1, 2, and 3) are classical Hubel and Wiesel type neurons, which is to say that each 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 neurons in the brain, but help illustrate well what neural networks are about.) Those three neurons project—send information to—the second layer in this network, comprising neurons A to E. Note the projection pattern: 1 talks to A, B, and C; 2 talks to B, C, and D; 3 talks to C, D, and E.

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What “knowledge” does neuron A have? It gets information only from neuron 1 about Gauguin paintings. Another 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 those Impressionists.” It has knowledge that does not come from any single informational input, but emerges from the convergence of information feeding into it. Neurons B and D are also Impressionism neurons, but they’re just not as good at it as neuron C, because they have fewer examples to work with. Most neurons in your cortex process memory like neurons B through D, not like A or E.

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We take advantage of such convergent networks whenever we are trying to pull out a memory that 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 guy; if I can remember her name, I bet I can remember his…wow, remember that time I was at the museum and there was that really cute person I tried to talk to in front of one of his paintings…oh, what was the stupid pun about that guy’s name, about the train tracks being too loose. With enough of those nets being activated, you finally stumble into the one fact that is at the intersection of all of them: Toulouse-Lautrec, the equivalent of a neuron C.

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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 between the thready branches of two neurons, gaps called synapses. When a neuron has heard some fabulous gossip and wants to pass it on, when a wave of electrical excitation sweeps over it, this triggers the release of chemical messengers—neurotransmitters—that float across the synapse and excite the next neuron. There are dozens, probably hundreds, of different kinds of neurotransmitters, and synapses in the hippocampus and cortex disproportionately make use of what is probably the most excitatory neurotransmitter there is, something called glutamate.

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Besides being superexcitatory, “glutamatergic” synapses have two properties that are critical to memory. The first is that these synapses are nonlinear in their function. What does this mean? In a run-of-the-mill synapse, a little bit of 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 synapses, some glutamate is released and nothing happens. A larger amount is released, nothing happens. It isn’t until a certain threshold of glutamate concentration is passed that, suddenly, all hell breaks loose in the 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 fact goes in one ear and out the other. It is repeated again—and, again, it fails to sink in. Finally, the hundredth time it is repeated, a lightbulb goes on, “Aha!” and you get it. On a simplistic level, when you finally get it, that nonlinear threshold of glutamate excitation has just been reached.

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The second feature is even more important. Under the right conditions, when a synapse has just had a sufficient number of superexcitatory glutamate-driven “aha’s,” something happens. The synapse becomes persistently more excitable, so that next time it takes less of an excitatory signal to get the aha. That synapse 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.

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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 potentiating of pre-existing ones) or, even more radically, the formation of new neurons themselves.

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The first point, of course, is that mild to moderate short-term stressors enhance memory. This makes sense, in that this is the sort of optimal stress that we would call “stimulation”—alert and focused. This effect has been shown in laboratory animals and in humans. One particularly elegant study in this realm was carried out by Larry Cahill and James McGaugh at the University of California at Irvine. Read a fairly unexciting story to a group of control subjects: a boy and his mother walk through their town, pass this store and that one, cross the street and enter the hospital where the boy’s father works, are shown the X-ray room…and so on. Meanwhile, the experimental subjects are read a story that differs in that the central core of it contains some emotionally laden material: a boy and his mother walk through their town, pass this store and that one, cross the street where…the boy is hit by a car! He’s rushed to the hospital 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, such as a crime they witnessed. Memory for the emotional components is enhanced (although the accuracy isn’t necessarily all that good), whereas memory for the neutral details is not.

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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. Importantly, it’s not simply the case that propranolol disrupts memory formation. Instead, it disrupts stress-enhanced memory formation (in other words, the experimental subjects did as well as the controls on the boring parts of the story, but simply didn’t have the boost in memory for the emotional middle section).

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The sympathetic nervous system pulls this off by indirectly arousing the hippocampus into a more alert, activated state, facilitating memory consolidation. This involves an area of the brain that is 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 mobilizing glucose into the bloodstream and increasing the force with which blood is being pumped up into the brain.

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These changes are quite adaptive. When a stressor 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 formation (“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 increased delivery of glucose to the brain, making more energy available to neurons, and therefore better memory formation and retrieval.

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Thus, the sympathetic arousal during stress indirectly fuels the expensive process of remembering the faces of the crowd chanting ecstatically about Classic Coke. 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 potentiation. Finally, there are some obscure mechanisms by which moderate, short-term stress makes your sensory receptors more sensitive. Your taste buds, your olfactory receptors, the cochlear cells in your ears all require less stimulation to get excited under moderate stress and 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.

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What we’ve just seen is how moderate and transient stress can enhance the sort of explicit memories that are the purview of the hippocampus. It turns out that stress can enhance another type of memory. This is one relevant to emotional memories, a world apart from the hippocampus and its dull concern with factoids. This alternative type of memory, and its facilitation by stress, revolves around that brain area mentioned before, the amygdala. The response of the amygdala during stress is going to be critical to understanding anxiety and post-traumatic stress disorder in chapter 15.

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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.

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The decline has been shown in numerous studies with lab rats, and with an array of stressors—restraint, shock, exposure to the odor of a cat. The same has been shown when high levels of glucocorticoids are administered to rats instead. But this may not tell us anything interesting. Lots of stress or of glucocorticoids may just be making for a generically messed-up brain. Maybe the rats would now be lousy 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, such as implicit memory, are fine. Maybe it’s not so much that learning and memory are impaired, as much as the rat being so busy paying attention to that cat smell, or so agitated by it, that it doesn’t make much headway solving whatever puzzle is in front of it. And within that realm of explicit memory problems, the retrieval of prior memories seems more vulnerable to stress than the formation of new ones. Similar findings have been reported with nonhuman primates.

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What about humans? Much the same. In a disorder called Cushing’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 problems, the works. And it’s been known for decades that they get memory problems, specifically explicit memory 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 problems as well. But maybe this is due to the disease, rather than to the glucocorticoids that were given for the disease. Pamela Keenan of Wayne State University has studied individuals with these inflammatory diseases, comparing those treated with steroidal anti-inflammatory compounds (that is, glucocorticoids) and those getting nonsteroidals; memory problems were a function of getting the glucocorticoids, not of the disease.

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As the clearest evidence, just a few days of high doses of synthetic glucocorticoids impairs explicit memory in healthy volunteers. As one problem in interpreting these studies, these synthetic hormones work a bit differently from the real stuff, and the levels administered produce higher circulating glucocorticoid levels than the body normally produces, even during stress. Importantly, stress itself, or infusion of stress levels of the type of glucocorticoid that naturally occurs in humans, disrupts memory as well. As with the nonhuman studies, implicit memory is fine, and it’s the recall, the retrieval of prior information, that is more vulnerable than the consolidation of new memories.

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There are also findings (although fewer in number) showing that stress disrupts something called “executive function.”

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Rather than this being the cognitive realm of storing and retrieving facts, this concerns what you do with the facts—whether you organize them strategically, how they guide your judgments and decision making.

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Stress can disrupt long-term potentiation in the hippocampus even in the absence of glucocorticoids (as in a rat whose adrenal glands have been removed), and extreme arousal of the sympathetic nervous system seems responsible for this. Nonetheless, most of the research in this area has focused on 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 enhances long-term potentiation, that process by which the connection between two neurons “remembers” by becoming more excitable. Instead, glucocorticoids now disrupt the process. Furthermore, similarly high glucocorticoid levels enhance something called long-term depression, which might be a mechanism underlying the process of forgetting, the flip side of hippocampal aha-ing.

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9 Stress and Pain

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16

Junkies, Adrenaline Junkies, and Pleasure

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“dopaminergic” projection begins in a region deep in the brain called the ventral tegmentum.

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The relationship between dopamine and pleasure is subtle and critical. On first pass, one might predict that the neurotransmitter is about pleasure, about reward. For example, take a monkey who has been trained in a task: a distinctive bell sounds, which means that the monkey now presses a lever ten times; this leads, ten seconds later, to a desirable food reward. You might initially guess that activation of the dopamine pathway causes neurons in the frontal cortex to become their most active in response to the reward. Some brilliant studies by Wolfram Schultz of the University in Fribourg in Switzerland showed something more interesting. Yes, frontal neurons become excited in 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 of, “This feels great.” It’s about mastery and expectation and confidence. It’s “I know what that light means. I know the rules: IF I press the lever, THEN I’m going to get some food. I’m all over this. This is going to be great.” The pleasure is in the anticipation of a reward; from the standpoint of dopamine, the reward is almost an afterthought.

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Psychologists refer to the period of anticipation, of expectation, of working for reward as the “appetitive” stage, one filled with appetite, and call the stage that commences with reward the “consummatory” stage. What Schultz’s findings show is that if you know your appetite is going to be sated, pleasure is more about the appetite than about the sating.*

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The next key thing to learn is that the dopamine and its associated sense of pleasurable anticipation fuels the work 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 and has showed with the best time resolution to date that the burst comes just before the behavior. Then, in the clincher, he artificially stimulated dopamine release and, suddenly, the rat would start lever pressing. The dopamine does indeed fuel the behavior.

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The next critical point is that the strength of these pathways can change, just like in any other part of the brain. There’s the burst of dopaminergic pleasure once that light comes on, and all that is required is to train for longer and longer intervals between light and reward, for those anticipatory bursts of dopamine to fuel ever-increasing amounts of lever pressing. This is how gratification postponement works—the core 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.

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Recent work by Schultz adds a twist to this. Suppose in one setup, the subject gets a signal, does a task, and then gets a reward. In the second situation, there’s the signal, the task, and then, rather than a certainty of reward, there’s simply a high probability of it. In other words, within a generally benevolent context (that is, the outcome is still likely to be good), there’s an element of surprise. Under those conditions, there is even greater release of dopamine. Right after the task is completed, dopamine release 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 neurons spritz dopamine all over the place in anticipation. This is the essence of why, as we learned in Intro Psych, intermittent reinforcement is so reinforcing. What these findings show is that if you think there’s a reasonably good chance that your appetite is going to be sated, but you’re not positive, pleasure becomes even more about the appetite than about the sating.

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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 pleasure, reward, and anticipation. For example, rats can still respond to reward to some extent even when artificially depleted of dopamine in those pathways. Opioids probably play a role in the other pathways involved. Moreover, the dopamine pathway might be most relevant to spiky, intense versions of anticipation. A recent and fascinating study shows this. Get some college students (either gender) who are in what they believe to be their “one true love” relationship. Put them in a scanner and flash up various familiar but neutral faces. Somewhere along the way, flash up a picture of the student’s beloved. For people who were in the first few months of the relationship, the dopamine pathways lit up. For people whose relationship was more on the order of years, that’s not what happened. Instead, there was activation of the anterior cingulate, that part of the brain discussed in the chapter on depression. The tegmentum/accumbens dopamine system seems to be about edgy, make-you-crazy-with-anticipation passion. Two years later, it’s the cingulate weighing in, mediating something akin, perhaps, to comfort and warmth…or maybe even a nonhyperventilating version of love.

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Stress and Reward

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So the really good thing about being tickled is the anticipation of being tickled. The element of surprise and lack of 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 anticipatory pleasure, and when is it the core of what makes psychological stress stressful?

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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 by something really good, like hand-holding. In contrast, if it’s Slobodan Milosovic who is tickling you, maybe, just 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, her running hot and cold is all that’s needed to start you off on a fifty-year courtship. Part 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 a good one, especially for someone as lucky and special as you…so long as you keep putting in those coins and pressing that lever.

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What makes for the benign sort of environment in which uncertainty is pleasurable, rather than stressful? One key element is how long the experience goes on. Pleasurable lack of control is all about transience—it’s not for nothing that roller-coaster rides are three minutes rather than three weeks long. Another thing that biases toward uncertainty being pleasurable is if it comes bound within a larger package of control and predictability. No matter how real and viscerally gripping the scary movie may be, you still know that Anthony Perkins is stalking Janet Leigh, not you. No matter how wild and scary and unpredictable and exhilarating the bungee jumping is, it’s still in the context of having assured yourself that these folks have a license from the Bungee Jumping Safety Police. This is the essence of play. 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.

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Time now to introduce some really unexpected neurochemistry that ties this all together. Glucocorticoids, those hormones which have been discovered at the scene of the crime for virtually all the stress-related pathology we’ve been learning about, those same villainous glucocorticoids…will trigger the release of dopamine from pleasure pathways. It’s not some generic effect upon all the dopamine pathways in the brain. Just the pleasure pathway. Most remarkably, Pier Vincenzo Piazza and Michel Le Moal of the University of Bordeaux in France have shown that lab rats will even work in order to get infused with glucocorticoids, will lever-press the exact amount needed to maximize the amount of dopamine released by the hormone.

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And what is the pattern of glucocorticoid exposure that maximized dopamine release? You can probably guess already. A moderate rise that doesn’t go on for too long. As we’ve seen, experience severe and prolonged stress, and learning, synaptic plasticity, and immune defenses are impaired. As we saw, experience moderate and transient stress, and memory, synaptic plasticity, and immunity are enhanced. Same thing here. Experience severe and prolonged glucocorticoid exposure, and we’ve returned to chapter 14—dopamine depletion, dysphoria, and depression. But with moderate and transient glucocorticoid elevation you release dopamine. And transient activation of the amygdala releases dopamine as well. Couple the glucocorticoid rise with the accompanying activation of the sympathetic nervous system, and you’re also enhancing glucose and oxygen delivery to the brain. You feel focused, alert, alive, motivated, anticipatory. You feel great. We have a name for such transient stress. We call it “stimulation.”*

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What does this tell us about the subset of people who thrive on stress and risk-taking,

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We can make some pretty informed guesses. Maybe they release atypically low amounts of dopamine. Or, as another version of the same problem, maybe they have versions of dopamine receptors that are atypically unresponsive to a dopamine signal.

Note: or… they have lowered there dopamine receptor quantity??

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Find something else that’s thrilling and, of necessity, a bit riskier, in order to achieve the same dopamine peak of the prior time. Afterward, your baseline drops a bit lower. Necessitating another, and another stimulant, each one having to be bigger, in the search for the giddy heights of dopamine that you reached that first time.

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This is the essence of the downward ratcheting of addiction. Once, a long time ago, the sixteen-year-old Evel Knievel, 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.

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Addiction

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There’s an astonishing number of substances that different cultures have come up with that can cause you to be ruinously addicted, to compulsively take the substance despite negative consequences. The field of addiction research 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.

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Amid this variety, though, there’s a critical commonality, which is that these compounds all cause the release of dopamine in the ventral tegmentum-nucleus accumbens pathway. Not all to the same extent. Cocaine, which directly causes the release of dopamine from those neurons, is extremely good at doing it. Other drugs which do so through intervening steps are much less potent—alcohol, for example. But they all do to 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 addictive substance—you anticipate how pleasurable it will be and thus come back for more.

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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 parking 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 levels rise 50 to 100 percent in this pathway. But give the rat some cocaine and there is a THOUSAND-FOLD increase in dopamine release.

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What’s the neurochemical consequence of this tidal wave of dopamine? We considered a related version in chapter 14. If someone always yells at you, you stop listening. If you flood a synapse with a gazillion times more of a neurotransmitter than is usually the case, the recipient neuron has to compensate by becoming less sensitive. No one is sure what the mechanism is for what’s termed an “opponent process” that counteracts the dopamine blast. Maybe fewer dopamine receptors, maybe fewer of whatever the dopamine receptors connect to. But regardless of the mechanism, the next time, it is going to take even more dopamine release to have the same impact on that neuron. This is the addictive cycle of escalating drug use.

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Around this point, there is a transition in the process of addiction. Early on, addiction is about “wanting” the drug, 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 this 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 the dopamine lows are without the drug. The stranglehold of addiction is when it is no longer the issue of how good the drug feels, but how bad its absence feels. It’s about the motivation to avoid the punishment of not having the drug. George Koob of the Scripps Research Institute has shown that when rats are deprived of a drug they are addicted to, there is a tenfold increase in levels of CRH in the brain, particularly in pathways mediating fear and anxiety, such as in the amygdala. No wonder you feel so awful. Brain-imaging studies of drug users at that stage show that viewing a film of actors pretending to use drugs activates dopamine pathways in the brain more than does watching porn films.

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This process emerges in the context of the uncertainty and intermittent reinforcement that we discussed earlier. You’re pretty sure you’ve scraped together enough money, you’re pretty sure you can find a dealer, you’re pretty sure you won’t get caught, you’re pretty sure it will be good stuff—but still, there’s that element of uncertainty amid the anticipation, and that stokes the addictiveness like crazy.

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So this tells us something about the acquisition of addiction, the downward spiral of tolerance to the drug, and the psychological contexts in which those processes can occur. There’s a last basic 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 new life. It’s been months, years, even decades since he’s gone near the drug. But uncontrollable circumstances put him back where he always used the drug back when—back on that same street corner, in that same music studio, back in the same overstuffed armchair near the bar in the country club—and the craving comes roaring back like it was yesterday. The capacity to induce that craving doesn’t necessarily decline with time; as many drug abusers in that situation will say, it is as if they had never stopped using.

Note: solution = mindfulness

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This process of associating drug use with a particular setting is a type of learning, and 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 repeatedly activated and eventually become potentiated, strengthened, in the same ways as the hippocampal synapses we learned about in chapter 10. When those projections get strong enough, if you return to that setting, the dopamine anticipation of the drug gets triggered merely by the context. In a lab rat in this situation, you don’t even need to place the animal back into the same setting. Just electrically stimulate those pathways that project onto the dopamine neurons, and you reinstate the drug craving. As goes one of the clichés of addiction, there’s really no such thing as an ex-addict—it is simply an addict who is not in the context that triggers use.

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Stress and Substance Abuse

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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.

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In general, the evidence is pretty decent for this, given a few provisos. People do generally report themselves as feeling less stressed, less anxious, if a stressor occurs after some psychoactive drug’s effects have kicked in. Alcohol is best known for this, and is formally termed an anxiolytic, a drug that “lyses,” or disintegrates anxiety. You can show this with a lab rat. As discussed in the last chapter, rats hug the dark corners when put into a brightly lit cage. 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? Alcohol decreases the time to do this, as do many other addictive compounds.

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How does this work? Many drugs, including alcohol, raise glucocorticoid levels when they are first taken. But with more sustained use, various drugs can blunt the nuts and bolts of the stress-response. Alcohol, for example, has been reported in some cases to decrease the extent of sympathetic nervous system arousal and to dampen CRH-mediated anxiety. In addition, drugs may change the cognitive appraisal of the stressor. What does that jargon mean? Basically, if you’re in such a mess of an altered state that you can barely remember what species you are, you may not pick up on the subtle fact that something stressful has occurred.

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Intrinsic in that explanation is the downside of the anxiety-reducing consequences of getting wasted. As the blood levels of the drug drop, as the effects wear off, the cognition and reality sneak back in and, if anything, the drugs become just the opposite, become anxiety-generating. The dynamics 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 shorter than the amount of time that they are dropping. So what’s the solution? Drink, ingest, inhale, shoot up, snort all over again.

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So various psychostimulants can decrease stress-responses, secondary to blunting the machinery of the stress-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 clear punch line is that stress pushes you toward more drug use and a greater chance of relapse, although it’s not completely clear how stress does this.

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The first issue is the effect of stress on initially becoming addicted. Set up a rat in a situation where if it presses a lever 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 likely to self-administer to the point of addiction. And just as you’d expect from chapter 13, unpredictable stress drives a rat toward addiction more effectively than does predictable stress. Similarly, put a rat or a monkey in a position of being socially subordinate, and the same increased risk occurs. And, no surprise, stress clearly increases alcohol consumption in humans as well.

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Importantly, stress increases the addictive potential of a drug only if the stressor comes right before the drug exposure. In other words, short-term stress. The type that boosts dopamine levels transiently. Why does stress have this effect? 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 anticipatory 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 has just happened—where can you get some more? Thus, acute stress increases the reinforcing potential of a drug.

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All that makes sense. But, naturally, things get more complicated. Stress increases the likelihood of self-administering a drug to an addictive extent, but this time we’re talking about stress during childhood. Or even as a fetus. Stress a pregnant rat and her offspring will have an increased propensity 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 if stressing a rat in its infancy. The same works in nonhuman primates—separate a monkey from its mother during development, and that animal is more likely to self-administer drugs as an adult. The same has been shown in humans.

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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.

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What about once the addiction has occurred—what does ongoing stress do to the extent of abuse? No surprise, it increases it. How does this work? Maybe because of transient stressors briefly boosting dopamine levels and giving 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 where it depletes dopamine. And what happens if you add additional stress on top of that? All that the extra glucocorticoids can do in this scenario is make the dopamine depletion even worse. Thus increasing the craving for that drug-induced boost of dopamine.

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What about that rare individual who manages to stop abusing whatever drug she’s addicted to and successfully goes 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 cage with the drug-associated lever and there’s an increased likelihood that the rat will try lever pressing for the drug again. Infuse the rat with a bit of the drug just before returning it to that familiar locale and it’s even more likely to start self-administering again—you’ve reawakened the taste for that drug. If you stress the rat right before you return it to the cage, it’s even more likely to restart the drug use. As usual, unpredictable and uncontrollable stressors are the ones that really revive the drug use. And, as usual, the human studies show basically the same thing.

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How does stress do this? It’s not entirely clear. The effects of glucocorticoids on dopamine release may be relevant, but I have not seen a clear model built around their interaction. Maybe it’s the stress-induced increase in sympathetic arousal, mediated by CRH in the amygdala. There’s also some evidence suggesting that stress will increase the 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 irresistibly clever idea: “I know, why don’t I start taking that drug again which nearly destroyed my life.”

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So stress can increase the odds of abusing a drug to the point of addiction in the first place, make withdrawal harder, and make relapse more likely. Why do all the above happen more readily to some people than others? Immensely interesting work by Piazza and Le Moal has started to answer this.

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Remember those apples and pears in chapter 5? Who are the individuals who are more prone toward putting on fat around their gut, becoming apples, the less healthy version of fat deposition? We saw that they are likely to be people with more of a tendency to secrete glucocorticoids in response to stressors, and to have a slower recovery from such a stress-response. Same thing here. 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 are “high reactors,” who are most behaviorally disrupted by being placed in a novel environment, who are more reactive to stress. They secrete glucocorticoids longer than the other rats in response to a stressor, causing them to pour out more dopamine when they are first exposed to the drug. So if you’re the kind of rat who is particularly thrown out of kilter by stress, you’re atypically likely to try something that temporarily promises to make things right.

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The Realm of Synthetic Pleasure

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Chapter 13 raised the important point that positive and negative affect are not 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 to self-medicate away pain, depression, fear, anxiety, and stress. This dual purpose transitions us to the next chapter with its theme that society does not evenly distribute healthy opportunities for 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.”

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Peter Sterling, of allostasis fame, has written brilliantly about how our sources of pleasure have become so narrowed and artificially strong. His thinking centers around the fact that our anticipatory pleasure pathway 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 experience and sensation and pleasure evoke unnaturally strong degrees of habituation. This has two consequences. As the first, soon we hardly notice anymore the fleeting whispers of pleasure caused by leaves in autumn, or by the 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, after awhile, we even habituate to those artificial deluges of intensity and moment-ness. If we were nothing but machines of local homeostatic 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.