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What a growing body of research reveals about the biology of human happiness-and how to navigate the (temporary) slump in middle age

All photos by Chris Buck

This summer, a friend called in a state of unhappy perplexity. At age 47, after years of struggling to find security in academia, he had received tenure. Instead of feeling satisfied, however, he felt trapped. He fantasized about escape. His reaction had taken him by surprise. It made no sense. Was there something wrong with him? I gave him the best answer I know. I told him about the U-curve.

Not everyone goes through the U-curve. But many people do, and I did. In my 40s, I experienced a lot of success, objectively speaking. I was in a stable and happy relationship; I was healthy; I was financially secure, with a good career and marvelous colleagues; I published a book, wrote for top outlets, won a big journalism prize. If you had described my own career to me as someone else's, or for that matter if you had offered it to me when I was just out of college, I would have said, "Wow, I want that!" Yet morning after morning (mornings were the worst), I would wake up feeling disappointed, my head buzzing with obsessive thoughts about my failures. I had accomplished too little professionally, had let life pass me by, needed some nameless kind of change or escape.

My dissatisfaction was whiny and irrational, as I well knew, so I kept it to myself. When I thought about it-which I did, a lot-I rejected the term midlife crisis, because I was holding a steady course and never in fact experienced a crisis: more like a constant drizzle of disappointment. What annoyed me most of all, much more than the disappointment itself, was that I felt ungrateful, the last thing in the world I was entitled to be. Hopeful that rationality might prevail, I would count my blessings, quite literally-making lists mentally, and sometimes also on paper of all that I had to be thankful for. Reasoning with myself might help for a little while, but then the disappointment would return. As the weeks turned into months, and then into years, my image of myself began to change. I had always thought of myself as a basically happy person, but now I seemed to be someone who dwelt on discontents, real or imaginary. I supposed I would have to reconcile myself to being a malcontent.

As I moved into my early 50s, I hit some real setbacks. Both of my parents died, one of them after suffering a terrible illness while I watched helplessly. My job disappeared when the magazine I worked for was restructured. An entrepreneurial effort-to create a new online marketplace that would match journalists who had story ideas with editors looking for them-ran into problems. My shoulders, elbows, and knees all started aching. And yet the fog of disappointment and self-censure began to lift, at first almost imperceptibly, then more distinctly. By now, at 54, I feel as if I have emerged from a passage through something. But what?

Long ago, when I was 30 and he was 66, the late Donald Richie, the greatest writer I have known, told me: "Midlife crisis begins sometime in your 40s, when you look at your life and think, Is this all? And it ends about 10 years later, when you look at your life again and think, Actually, this is pretty good." In my 50s, thinking back, his words strike me as exactly right. To no one's surprise as much as my own, I have begun to feel again the sense of adventure that I recall from my 20s and 30s. I wake up thinking about the day ahead rather than the five decades past. Gratitude has returned.

I was about 50 when I discovered the U-curve and began poking through the growing research on it. What I wish I had known in my 40s (or, even better, in my late 30s) is that happiness may be affected by age, and the hard part in middle age, whether you call it a midlife crisis or something else, is for many people a transition to something much better-something, there is reason to hope, like wisdom. I wish someone had told me what I was able to tell my worried friend: nothing was wrong with him, and he wasn't alone.

In the 1970s, an economist named Richard Easterlin, then at the University of Pennsylvania, learned of surveys gauging people's happiness in countries around the world. Intrigued, he set about amassing and analyzing the data, in the process discovering what came to be known as the Easterlin paradox: beyond a certain point, countries don't get happier as they get richer. Today he is at the University of Southern California and is celebrated as the founder of a new branch of economics, focused on human well-being. At the time, though, looking at something as subjective as happiness seemed eccentric to mainstream economists. His findings, Easterlin says, were for many years regarded as a curiosity, more a subject for cocktail conversation than for serious research.

A generation later, in the 1990s, happiness economics resurfaced. This time a cluster of labor economists, among them David Blanchflower of Dartmouth and Andrew Oswald of the University of Warwick, got interested in the relationship between work and happiness. That led them to international surveys of life satisfaction and the discovery, quite unexpected, of a recurrent pattern in countries around the world. "Whatever sets of data you looked at," Blanchflower told me in a recent interview, "you got the same things": life satisfaction would decline with age for the first couple of decades of adulthood, bottom out somewhere in the 40s or early 50s, and then, until the very last years, increase with age, often (though not always) reaching a higher level than in young adulthood. The pattern came to be known as the happiness U-curve.

Meanwhile, Carol Graham, a development economist (she is now at the Brookings Institution, where I'm a senior fellow), was looking at Peruvians who had emerged rapidly from poverty. "How do these people think they've done?" she wanted to know. She told me she was startled to find that objective life circumstances did not determine subjective life satisfaction; in Peru, as in other countries, many people who had moved out of poverty felt worse off than those who had stayed poor. "I didn't know how to explain it," she said. Hunting around, she discovered the sparse literature on the economics of happiness, plunged into survey data, and found the same U-shaped pattern, first in Latin America and then in the rest of the world. "It was a statistical regularity," she said. "Something about the human condition."

The U-curve emerges in answers to survey questions that measure satisfaction with life as a whole, not mood from moment to moment. The exact shape of the curve, and the age when it bottoms out, vary by country, survey question, survey population, and method of statistical analysis. The U-curve is not ubiquitous; indeed, one would be suspicious if a single pattern turned up across an immensely variegated landscape of surveys and countries and generations and analyses. Still, the pattern turns up much too often to ignore. For example, in a 2008 study, Blanchflower and Oswald found the U-curve-with the nadir, on average, at age 46-in 55 of 80 countries where people were asked, "All things considered, how satisfied are you with your life as a whole these days?" Graham and Milena Nikolova recently looked at an international survey that asked people in 149 countries to rate their lives on a zero-to-10 scale where 10 "represents the best possible life for you" and zero the worst. They found a relationship between age and happiness in 80 countries, and in all but nine of those, satisfaction bottomed out between the ages of 39 and 57 (the average nadir was at about age 50).

The apes' well-being bottomed out at ages comparable, in people, to between 45 and 50-implying that the happiness curve is not uniquely human.

The curve tends to evince itself more in wealthier countries, where people live longer and enjoy better health in old age. Sometimes it turns up directly in raw survey data-that is, people just express less overall satisfaction in middle age. But here's a wrinkle: in many cases (including the two analyses I just cited), the age-based U-curve emerges only after researchers adjust for such variables as income, marital status, employment, and so on, thus looking through to the effects of age alone. Some scholars-including Easterlin, the grand old man of the field-take a dim view of making such adjustments. Carol Ryff, a psychologist who directs the University of Wisconsin's Institute on Aging, told me, "To my mind, that's how you obscure the story; that's not how you clean it up." But filtering out important life circumstances suggests something intriguing: there may be an underlying pattern in life satisfaction that is independent of your situation. In other words, if all else is equal, it may be more difficult to feel satisfied with your life in middle age than at other times. Blanchflower and Oswald have found that, statistically speaking, going from age 20 to age 45 entails a loss of happiness equivalent to one-third the effect of involuntary unemployment.

"I view this as a first-order discovery about human beings that will outlive us by hundreds of years," Oswald told me. Not everyone is prepared to go so far. Many psychologists have their doubts, partly because the U-curve is a statistical regularity that emerges from large data sets, and psychologists prefer to study actual people, whether individually or in experimental groups, and ideally across their whole lives. "I think it's a mistake to generalize about life-course patterns," Ryff told me. "In the final analysis, you're not talking about real people when you tell these big, generic stories." Heretofore, when psychologists have gone looking for evidence of midlife crisis-that is, of a distinctive phenomenon of middle age, rather than just stress or difficulty that might come at any point in life-they haven't found it, and they are cool to the possibility that the smoking gun has turned up in economics, of all places.

In recent work, however, U-curve researchers have begun to find evidence that is harder to dismiss as mere statistical correlation. Oswald, Terence Cheng, and Nattavudh Powdthavee have found the U-curve in four longitudinal data sets from three countries: an important kind of evidence, because it traces the lived experiences of individuals over time, rather than comparing people of various ages in a statistical snapshot. Likewise, Blanchflower and Oswald, looking at samples from 27 European countries, have found a "strong hill-shaped pattern" in the use of antidepressants, peaking in people's late 40s. Being middle-aged "nearly doubles" a person's likelihood of using antidepressants. The same pattern appears, they've found, in the two U.S. states that collect the relevant data (New Hampshire and New Mexico).

And a lot of eyebrows went up when Oswald and four other scholars, including two primatologists, found a U-shaped curve in chimpanzees' and orangutans' state of mind over time. Zookeepers, researchers, and other animal caretakers filled out a questionnaire rating the well-being of their primate charges (more than 500 captive chimps and orangutans in Australia, Canada, Japan, Singapore, and the United States). The apes' well-being bottomed out at ages comparable, in people, to between 45 and 50. "Our results," the authors concluded in a 2012 paper, "imply that human wellbeing's curved shape is not uniquely human and that, although it may be partly explained by aspects of human life and society, its origins may lie partly in the biology we share with closely related great apes."

I think where the evidence points is this: being satisfied is perfectly possible in midlife, but for a great many of us it is harder. That is how the U-curve felt to me, and how it feels to some of the people I unscientifically surveyed for this article.

"I think it must be something internal," my 45-year-old friend S. told me. He described his 20s as exciting and fun ("I was really dumb but thought I knew a lot") and his 30s as a time of hard work and steady rewards ("I felt on track ... Things looked like white picket fences and the American dream"), but said he was bushwhacked in his 40s by an unexpected divorce, unmarried fatherhood, and a heart attack. He said he now experiences difficulty feeling contentment, leading to some of the same self-doubt that I felt: a creeping suspicion that he is fated to be whiny. He also wondered whether his dissatisfaction has been a cause of some of his problems, not just an effect. "Professionally, things looked pretty good," S. told me. "But maybe something was going on. Something sufficient for my wife to leave. If I did a deep psychological dive, I might say that nothing will ever make me content. Maybe there's something deeply psychologically wrong with me. I see life as a challenge to overcome rather than an adventure to be enjoyed. I've thought of running away to Brazil-changing my name and becoming a hotel clerk. Maybe that will change in my 50s."

I was happy to tell him that the odds are in his favor.

My friend K. is a 54-year-old woman whose trajectory somewhat resembles S.'s. She had an exciting launch in her 20s (working "my dream job"), a sense of continuing achievement but slowing momentum in her 30s ("sort of a slog"), and an ambush in her 40s, when her father died, her mother had a stroke, her husband left her after their daughter was born, and she was laid off. Despite coping with all of that and doing well professionally, even with her layoff ("I did better in my career; I made more money"), she developed what she describes as a dark sense of humor about her life, ruefully telling herself that at least she had so many troubles that she couldn't dwell on all of them at once.

In the past few years, things have turned upward, markedly so. K.'s 50s have brought not only less external turbulence but less on the inside, too. "On a day-to-day basis, I probably do the same things, but I feel different," she says. Her values have shifted away from work: "I could see that was not going to be a big source of achievement. I measure my worth now by how I can help others and contribute to the community. I enjoy the relationships that I've been able to nurture over these years-longer-term friends, growing with those friends. It was always striving and looking ahead, as opposed to being in the now and feeling grateful for the now. I think I feel a great gratitude. When I am in a situation when I can moan a little bit or feel bad about some of the difficult things that have happened, the balance sheet is hugely on the side of all the great things that have happened. And I think that gratitude has helped me be both more satisfied and more giving." She describes her 50s, so far, as good and improving.

The same has been true for me. Though I still have my share of gloomy days, I find it far easier than I did in my 40s to appreciate what I have, even without writing down lists of good things, as I had to resort to doing a decade ago. It certainly helps that my pet cause, gay marriage, has met with success, and that I myself achieved legal marriage at age 50. But something has changed inside, too, because in my 40s, I had plenty of success and none of it seemed adequate, which was why I felt so churlish. For me, after a period when gratitude seemed to have abandoned me, its return feels like a gift.

It turns out that there is good science about this gift: studies show quite strongly that people's satisfaction with their life increases, on average, from their early 50s on through their 60s and 70s and even beyond-for many until disability and final illness exact their toll toward the very end (at which point it's hard to generalize). In a 2011 study, for example, the Stanford University psychologist Laura Carstensen and seven colleagues found that "the peak of emotional life may not occur until well into the seventh decade"-a finding that is "often met with disbelief in both the general population and the research community," despite its strength. Carstensen described to me this pattern in her own life. "Forties were, for me, the worst," she said. "You're never good enough professionally. I think you're coming out of the fog in the 50s." Now, at 60, she said, "I feel so privileged. I feel it now." Elaine Wethington, a professor of human development and sociology at Cornell, whose research likewise finds that people become more satisfied and more optimistic later in life, is in her early 60s and reports her own turning point at about age 50. "I feel like I've reached a kind of flow in my work and career," she told me. No guarantees, of course, but reporting this article has led me to think that the upturn I've felt in my 50s is likely to continue. As Andrew Oswald exclaimed to me when I mentioned my own post-40s upswing: "Just wait until you're 60!"

Of course, the most interesting question, and unfortunately also the hardest question, is: Why is happiness so often U-shaped? Why the common dissatisfaction in middle age? And why the upswing afterward?

Part of the answer likely involves what researchers call selection bias: unhappier people tend to die sooner, removing themselves from the sample. Also, of course, middle age is often a stressful time, burdened with simultaneous demands from jobs, kids, and aging parents. Those explanations don't seem adequate by themselves, though. I can attest that I experienced the U-curve without dying off in the process; so do other people, as we know from happiness research that follows individuals over time. And recall that the U-curve often emerges after adjusting for other variables in life (children, income, job, marriage), so it is not purely situational.

A common hypothesis, and one that seems right to me, is alluded to by Carstensen and her colleagues in their 2011 paper: "As people age and time horizons grow shorter," they write, "people invest in what is most important, typically meaningful relationships, and derive increasingly greater satisfaction from these investments." Midlife is, for many people, a time of recalibration, when they begin to evaluate their lives less in terms of social competition and more in terms of social connectedness. In my 40s, I found I was obsessively comparing my life with other people's: scoring and judging myself, and counting up the ways in which I had fallen behind in a race. Where was my best seller? My literary masterpiece? Barack Obama was younger than I, and look where he was! In my 50s, like my friend K., I find myself more inclined to prize and enjoy people and relationships, which mercifully seem to be pushing the unwinnable status competition into the background. Also, Carstensen told me, "when the future becomes less distant, more constrained, people focus on the present, and we think that's better for emotional experience. The goals that are chronically activated in old age are ones about meaning and savoring and living for the moment." These are exactly the changes that K. and others in my own informal research sample reported.

In my own case, however, what seems most relevant is a change frequently described both in popular lore and in the research literature: for some reason, I became more accepting of my limitations. "Goals, because they're set in temporal context, change systematically with age," Carstensen says. "As people perceive the future as increasingly constrained, they set goals that are more realistic and easy to pursue." For me, the expectation of scaling ever greater heights has faded, and with it my sense of disappointment and failure.

The idea that the expectations gap closes with age has recently received some empirical backing, in the form of fascinating findings by Hannes Schwandt, a young economist at Princeton University's Center for Health and Wellbeing. He used a German longitudinal survey, with data from 1991 to 2004, that, unusually, asked people about both their current life satisfaction and their expected satisfaction five years hence. That allowed him to compare expectations with subsequent reality for the same individuals over time. To his own surprise, he found the same result regardless of respondents' economic status, generation, and even whether they lived in western or eastern Germany (two very different cultures): younger people consistently and markedly overestimated how satisfied they would be five years later, while older people underestimated future satisfaction. So youth is a period of perpetual disappointment, and older adulthood is a period of pleasant surprise. What's more, Schwandt found that in between those two periods, during middle age, people experienced a sort of double whammy: satisfaction with life was declining (that's the U-curve, which manifested itself clearly), but expectations were also by then declining (in fact, they were declining even faster than satisfaction itself). In other words, middle-aged people tend to feel both disappointed and pessimistic, a recipe for misery. Eventually, however, expectations stop declining. They settle at a lower level than in youth, and reality begins exceeding them. Surprises turn predominantly positive, and life satisfaction swings upward. And the crossover, in Schwandt's sample, happened about where you would expect: in the 50s.

"This finding," Schwandt writes, "supports the hypothesis that the age U-shape in life satisfaction is driven by unmet aspirations that are painfully felt during midlife but beneficially abandoned and felt with less regret during old age."

Okay, but why does this abandonment and reorientation seem to happen so reliably in midlife? Firm explanations are some years away. Still, clues have emerged from the realm of brain science, and they hint at an answer that is both heartening and ancient.

Dilip V. Jeste is a distinguished psychiatrist with an unusual pedigree. On the "distinguished" side of the ledger are his multiple professorial titles at the University of California at San Diego, his recent presidency of the American Psychiatric Association, and his record as one of the country's most prolific geriatric psychiatrists. Awards and certifications take up an entire wall of his office and range from the American College of Psychiatrists' Award for Research in Geriatric Psychiatry to San Diego Magazine 's "Top Doctors 2013." On the "unusual" side is his upbringing in a small town in India (he speaks with a lilting Marathi accent), his decision to focus his medical career on helping the elderly age successfully rather than on merely treating their ailments-and his belief that wisdom is a concept that belongs not just to Aesop and Aristotle but to cutting-edge neuroscience. Jeste, who is 70 and thin enough to look frail until you notice his nimble gait, is no mystic. He and his colleagues use magnetic-scanning technology and batteries of psychological tests to peer into the brain for clues to how the mind and emotions work.

As a teenager in India, Jeste came across Freud's The Interpretation of Dreams. "It was like an Agatha Christie mystery," he says, and it put him on the path to a degree in psychiatry and a research career in the United States, first at the National Institutes of Health and then at UCSD. Studying elderly schizophrenics, he was startled to find that they did better as they aged. That led him to explore how people can age successfully-that is, happily-despite health problems and other adverse circumstances. In 2006, and again in 2013, he published findings that people feel better, not worse, about their lives as they move through their later decades, even with the onset of chronic health problems that would lead one to expect distress or depression. "It was really a big surprise," he says.

"The question I asked," Jeste told me, "was, 'Is there anything cognitive that actually improves with aging?' That led me to think about wisdom. I started wondering whether the life satisfaction we were seeing in older people was related to their becoming wiser with age, in spite of physical disability."

His medical colleagues were skeptical, to say the least, telling him that the study of wisdom should be left to philosophers, not neuroscientists or psychiatrists. "I took that as a challenge." Jeste grew up in a world steeped in reverence for wisdom. "It's cultural, growing up in India," he said. "We read the Gita, the Hindu Bible, as it were. But the Gita really is a document about what a wise person should do." In recent years, Western psychiatry has generated a very small but scientifically legitimate body of research literature on wisdom. Surveying both modern research and ancient texts, Jeste found that the concept of wisdom has stayed "surprisingly similar" across centuries and across geographic regions: "All across the world, we have an implicit notion of what a wise person is." The traits of the wise tend to include compassion and empathy, good social reasoning and decision making, equanimity, tolerance of divergent values, comfort with uncertainty and ambiguity. And the whole package is more than the sum of the parts, because these traits work together to improve life not only for the wise but also for their communities. Wisdom is pro-social. (Has any society ever wanted less of it?) Humans, Jeste says, live for an unusually long time after their fertile years; perhaps wisdom provides benefits to our children or our social groups that make older people worth keeping around, from an evolutionary perspective.

"Wisdom is useful at any age," he says. "But from an evolutionary point of view, younger people are fertile, so even if they're not wise, they're okay. But older people need to find some other way that they can contribute to the survival of the species." It's also possible, he says, that "competitiveness may be more favored in the young, and more emotional regulation, more tolerance of diversity, more insight, in older people." In any case, the very universality of the concept of wisdom, Jeste believes, suggests some biological basis. Which is why he's seeking wisdom's roots in the brain.

"The peak of emotional life may not occur until well into the seventh decade."

In San Diego this summer, I watched as Jeste and Lisa Eyler, a clinical psychologist at UCSD, conducted brain-imaging experiments to learn how older people process tasks related to compassion-an element of wisdom. They greeted J., a 71-year-old business coach, and outfitted her with earplugs, a head-mounted optical device that let her see projected images, a "button box" that let her respond to what she saw, and a panic button to stop the experiment. Then she was swallowed by a massive and impressively noisy functional-MRI scanning machine. She spent an hour performing tasks designed to stimulate both cognitive and emotional centers-remembering letters, matching facial expressions-while computers recorded images of her brain at work. This was followed by half an hour in front of a laptop as a postdoctoral researcher conducted a standardized empathy test, showing J. photos-some images benign, some upsetting-and recording her reactions. Finally came an interview with a clinician. Did J. consider herself a wise person? Sometimes-more so when she had time to reflect than when she was in a crisis. Had her wisdom increased with age? Yes, definitely. Had that made a difference? Yes again; she had learned not to act so precipitously, and she was better at seeing the best in others, even if it didn't show on the surface. All of this information would be collated with results from dozens of other subjects and combed for insights into the neurology of compassion in older people; those results, in turn, will add a tile to the wisdom mosaic.

The science of wisdom is in its infancy, and as of now there is no evidence, Jeste says, that people get wiser as a result of aging per se (as opposed to learning from experience over time-also, of course, an element of wisdom). And there is no "wisdom organ" in the brain. Wisdom is an inherently multifarious trait, an emergent property of many other functions. (A psychological screening test for wisdom contains 39 quite diverse questions, although psychologists at UCSD are working on reducing the number to a more manageable dozen or so.)

But it does look likely that some elements of aging are conducive to wisdom, and to greater life satisfaction. In a 2012 paper evocatively titled "Don't Look Back in Anger! Responsiveness to Missed Chances in Successful and Nonsuccessful Aging," a group of German neuroscientists, using brain scans and other physical tests of mental and emotional activity, found that healthy older people (average age: 66) have "a reduced regret responsiveness" compared with younger people (average age: 25). That is, older people are less prone to feel unhappy about things they can't change-an attitude consistent, of course, with ancient traditions that see stoicism and calm as part of wisdom. In fact, it is well established that older people's brains react less strongly to negative stimuli than younger people's brains do. "Young people just have more negative feelings," Elaine Wethington, the Cornell professor, told me. Older brains may thus be less susceptible to the furies that buffet us earlier in life. Also, as Laura Carstensen, the Stanford psychologist, told me (summarizing a good deal of evidence), "Young people are miserable at regulating their emotions." Years ago, my father made much the same point when I asked him why in his 50s he stopped having rages, which had shadowed his younger years and disrupted our family: "I realized I didn't need to have five-dollar reactions to nickel provocations."

Other studies find that social reasoning and long-term decision making improve with age; that spirituality increases (especially among women); that older adults feel more comfortable coping with uncertainty and ambiguity. Particularly intriguing are findings by Jeste and his colleagues suggesting that older people compensate for deterioration in specific regions of the brain by recruiting additional neural networks in other regions-an increase in so-called neuroplasticity that compensates for cognitive decline and perhaps brings other benefits. Jeste also notes that the brain circuits linked to rewards lose some sensitivity with age, possibly reducing impulsivity and addictive tendencies.

None of this, again, proves that people automatically get wiser with age (or more satisfied, or more calm, or more grateful). Many young people are wise, and many old people are not. It does hint, however, that aging changes us in ways that make it easier to be wise (and satisfied, and calm, and grateful). And I believe it suggests the need to rethink the meaning of midlife.

In the 1990s and early 2000s, when David Blanchflower and Andrew Oswald and Carol Graham and others began investigating the U-curve, almost no one seemed interested. And now? "It's ridiculous," Graham told me. "I can't keep up with it." In a few years, science will know a great deal more about the relationship between aging and life satisfaction, and it may even be able to apply some of that knowledge in ways that help us get through the hard patches and be, or become, wise. I believe, though, that the larger significance of the U-curve is not scientific or medical at all, but cultural. The U-curve offers an opportunity for society to tell a different and better story about life in middle age and beyond: a story that is more accurate and more forgiving and much less embarrassing and lonely.

The dominant story now, of course, is the narrative of midlife crisis. Although the idea of middle age as a distinct time of life dates back to the 19th century (according to Patricia Cohen, the author of In Our Prime: The Invention of Middle Age), the idea of a midlife crisis as such is quite recent, first appearing in 1965, in an article by the late psychologist Elliott Jaques. In 1974, in her best-selling book Passages: Predictable Crises of Adult Life, Gail Sheehy depicted midlife crisis with the example of a 40-year-old man who

has reached his professional goal but feels depressed and unappreciated. He blames his job or his wife or his physical surroundings for imprisoning him in this rut. Fantasies of breaking out begin to dominate his thoughts. An interesting woman he has met, another field of work, an Elysian part of the country-any or all of these become magnets for his wishes of deliverance. But once these objects of desire become accessible, the picture often begins to reverse itself. The new situation appears to be the dangerous trap from which he longs to take flight by returning to his old home base and the wife and children whose loss suddenly makes them dear.

No wonder many wives stand aghast.

This is not a bad description of how I felt in my 40s. All praise to Sheehy for her insight. Note, however, the element of disapproval that creeps in as "wives stand aghast." Society stands aghast, too. Almost as soon as it was born, the social narrative of midlife crisis took on connotations of irresponsibility, escapism, self-indulgence, antisocial behavior. Wethington, the Cornell psychologist, found in research she published in 2000 that about a quarter of Americans reported experiencing a midlife crisis, and that many who disclaimed the notion regarded midlife crisis as a lame excuse for behaving immaturely. The term crisis also contributes to the stigma, because it suggests a shock or disruption or loss of control, when the evidence points to something much more like an extended and unpleasant but manageable downturn.

The story of the U-curve, I think, tells an emotionally fairer and more accurate tale. It is a story not of chaos or disruption but of a difficult yet natural transition to a new equilibrium. And I find that when I tell troubled middle-aged people about it, their reaction is one of relief. Just knowing that the phenomenon is common can be therapeutic. Hannes Schwandt, of Princeton, notes what he calls a feedback effect: "Part of your disappointment is driven by the disappointment itself." If more people understood how common the U-shaped pattern is, they might be less inclined to make the forecasting errors that contribute to disappointment-and also less inclined to judge themselves harshly for feeling disappointed.

"When I give lectures, I say we're stuck with this," Andrew Oswald told me, "but at least you know it's completely normal if you're feeling low in your 40s." He adds: "And when you're low, you blame the wrong things." People thrash around for explanations, which can lead to attribution errors and bad decisions. And those, of course, can bring on what really is a stereotypical midlife crisis, complete with lurching change and ill-judged behavior. In my late 40s, my own nameless dissatisfaction, like a parasitic wasp searching for a host, fixed upon my career and pestered me with an unbidden and unwelcome but insistent urge to quit my magazine column- today, right now, what was I waiting for? Fortunately my better judgment and my friends stopped me from acting on what would have been a useless and self-destructive whim. Still, in hindsight, I wish I had been forewarned that the U-curve, not my column, was the likely source of my discontent, and that a lot of other people, and possibly also a lot of other primates, were in the same boat.

Science has a great deal to learn about the intersection of aging and happiness, but I don't think it is too early to begin spreading the word about the U-curve. And so I tell people in their 30s and 40s that nothing is written in stone, and that they may sail through midlife in grand emotional style-but if not, they aren't alone, and usually it gets better, so march through it and don't do anything stupid. When George Orwell was 40 (he died at only 46), he wrote: "Any life when viewed from the inside is simply a series of defeats." He was wrong, thank goodness-as perhaps I am gaining the wisdom to see.

The Happiness U-Curve

An analysis by the Brookings scholars Carol Graham and Milena Nikolova, drawing on Gallup polls, shows a clear relationship between age and well-being in the United States. Respondents rated their life satisfaction relative to the "best possible life" for them, with 0 being worst and 10 being best.

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What a growing body of research reveals about the biology of human happiness-and how to navigate the (temporary) slump in middle age This summer, a friend called in a state of unhappy perplexity. At age 47, after years of struggling to find security in academia, he had received tenure.

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Each day, as they discussed sports (Johnny Unitas and Wilt Chamberlain) or "current" events (the first U.S. satellite launch) or dissected the movie they just watched ( "Anatomy of a Murder," with Jimmy Stewart), they spoke about these late-'50s artifacts and events in the present tense - one of Langer's chief priming strategies. Nothing - no mirrors, no modern-day clothing, no photos except portraits of their much younger selves - spoiled the illusion that they had shaken off 22 years.

At the end of their stay, the men were tested again. On several measures, they outperformed a control group that came earlier to the monastery but didn't imagine themselves back into the skin of their younger selves, though they were encouraged to reminisce. They were suppler, showed greater manual dexterity and sat taller - just as Langer had guessed. Perhaps most improbable, their sight improved. Independent judges said they looked younger. The experimental subjects, Langer told me, had "put their mind in an earlier time," and their bodies went along for the ride.

The results were almost too good. They beggared belief. "It sounded like Lourdes," Langer said. Though she and her students would write up the experiment for a chapter in a book for Oxford University Press called "Higher Stages of Human Development," they left out a lot of the tantalizing color - like the spontaneous touch-football game that erupted between heretofore creaky seniors as they waited for the bus back to Cambridge. And Langer never sent it out to the journals. She suspected it would be rejected.

After all, it was a small-sample study, conducted over a mere five days, with plenty of potentially confounding variables in the design. (Perhaps the stimulating novelty of the whole setup or wanting to try extra hard to please the testers explained some of the great improvement.) But more fundamental, the unconventionality of the study made Langer self-conscious about showing it around. "It was just too different from anything that was being done in the field as I understood it," she said. "You have to appreciate, people weren't talking about mind-body medicine," she said.

Langer did not try to replicate the study - mostly because it was so complicated and expensive; every time she thought about trying it again, she talked herself out of it. Then in 2010, the BBC broadcast a recreation, which Langer consulted on, called "The Young Ones," with six aging former celebrities as guinea pigs.

The stars were squired via period cars to a country house meticulously retrofitted to 1975, right down to the kitschy wall art. They emerged after a week as apparently rejuvenated as Langer's septuagenarians in New Hampshire, showing marked improvement on the test measures. One, who had rolled up in a wheelchair, walked out with a cane. Another, who couldn't even put his socks on unassisted at the start, hosted the final evening's dinner party, gliding around with purpose and vim. The others walked taller and indeed seemed to look younger. They had been pulled out of mothballs and made to feel important again, and perhaps, Langer later mused, that rekindling of their egos was central to the reclamation of their bodies.

The program, which was shown in four parts and nominated for a Bafta Award (a British Emmy), brought new attention to Langer's work. Jeffrey Rediger, a psychiatrist and the medical and clinical director of McLean SouthEast, a program of Harvard's McLean Hospital, was invited by a friend of Langer's to watch it with some colleagues last year. Rediger was aware of Langer's original New Hampshire study, but the made-for-TV version brought its tantalizing implications to life.

"She's one of the people at Harvard who really gets it," Rediger told me. "That health and illness are much more rooted in our minds and in our hearts and how we experience ourselves in the world than our models even begin to understand."

Langer's house in Cambridge was as chilly as a meat locker when we arrived together, having walked from campus, last winter. The back door had been left open all day so that her aging, coddled Westie, Gus, could relieve himself in the yard. (Langer's partner, Nancy Hemenway, who normally would be at home, was away.) Gus has a brain tumor. "He was supposed to be dead over a year ago," Langer said. "But I think he might outlive us all."

In the kitchen, Langer began laying out wide noodles for a lasagna she was making for an end-of-term party. It was the last time she would meet with her students for a while; they were about to scatter for the winter break, and she was leaving for a sabbatical in Puerto Vallarta, Mexico, where she and Nancy have another home. (Langer planned to Skype into weekly lab meetings.)

"Family recipe?" I asked of the dinner.

"I don't follow recipes - you should know that," she said. She piled on an immoderate amount of cheese. "Besides, if I blow it, what's going to be the cost?" Langer said. "Is it anyone's last meal?" She added, "My students aren't going to love me if my lasagna's no good?"

Langer was born in the Bronx and went to N.Y.U., becoming a chemistry major with her eye on med school. That all changed after she took Psych 101. Her professor was Philip Zimbardo, who would later go to Stanford and investigate the effects of authority and obedience in his well-known prison experiment. Human behavior, as Zimbardo presented it, was more interesting than what she'd been studying, and Langer soon switched tracks.

She went on to graduate work at Yale, where a poker game led to her doctoral dissertation on the magical thinking of otherwise logical people. Even smart people fall prey to an "illusion of control" over chance events, Langer concluded. We aren't really very rational creatures. Our cognitive biases routinely steer us wrong. Langer's notion that people are trained not to think and are thus extremely vulnerable to right-sounding but actually wrong notions prefigured many of the tenets of "behavioral economics" and the work of people like Daniel Kahneman, who won a Nobel Prize in economic sciences. But unlike many researchers who systematically work out one concept until they own it, Langer's peripatetic mind quickly moved on to other areas of inquiry. "I was never - and maybe this is a character flaw - the type of person who is going to take one idea and beat it to death," she said. "Part of that is that I have so many ideas. If whatever it is I'm excited about now doesn't happen, it doesn't matter, because there's always the next possibility."

By the 1970s, Langer had become convinced that not only are most people led astray by their biases, but they are also spectacularly inattentive to what's going on around them. "They're just not there," as she puts it. When you're not there, Langer reasoned, you're very likely to end up where you're led. She set up a number of studies to show how people's thinking and behavior can easily be manipulated with subtle primes.

In one, she and her colleagues found that office workers were far more likely to comply with a ridiculous interdepartmental memo if it looked like other official memos. In another, created with her Yale mentor, Robert Abelson, they asked behavioral and traditional therapists to watch a video of a person being interviewed, who was labeled either "patient" or "job applicant," and then evaluate the person. The behavioral therapists regarded the interviewee as well adjusted regardless of whether they were told the person was a patient or an applicant. But the traditional therapists found the interviewee labeled "patient" significantly more disturbed. Even trained observers "were mindlessly led by the label," Langer says.

If people could learn to be mindful and always perceive the choices available to them, Langer says, they would fulfill their potential and improve their health. Langer's technique of achieving a state of mindfulness is different from the one often utilized in Eastern "mindfulness meditation" - nonjudgmental awareness of the thoughts and feelings drifting through your mind - that is everywhere today. Her emphasis is on noticing moment-to-moment changes around you, from the differences in the face of your spouse across the breakfast table to the variability of your asthma symptoms. When we are "actively making new distinctions, rather than relying on habitual" categorizations, we're alive; and when we're alive, we can improve. Indeed, "well-being and enhanced performance" were Langer's goals from the beginning of her career.

Martin Seligman in the past two decades has come to be recognized as the father of positive psychology. Tal Ben-Shahar, who taught a popular undergraduate course at Harvard on the subject until 2008, calls Langer "the mother of positive psychology," by virtue of her early work that anticipated the field.

Langer came to believe that one way to enhance well-being was to use all sorts of placebos. Placebos aren't just sugar pills disguised as medicine, though that's the literal definition; they are any intervention, benign but believed by the recipient to be potent, that produces measurable physiological changes. Placebo effects are a striking phenomenon and still not all that well understood. Entire fields like psychoneuroimmunology and psychoendocrinology have emerged to investigate the relationship between psychological and physiological processes. Neuroscientists are charting what's going on in the brain when expectations alone reduce pain or relieve Parkinson's symptoms. More traditionally minded health researchers acknowledge the role of placebo effects and account for them in their experiments. But Langer goes well beyond that. She thinks they're huge - so huge that in many cases they may actually be the main factor producing the results.

As an example, she points to a study she conducted in a hair salon in 2009. She got the idea from a study undertaken nearly a decade earlier by three scientists who looked at more than 4,000 subjects over two decades and found that men who were bald when they joined the study were more likely to develop prostate cancer than men who kept their hair. The researchers couldn't be sure what explained the link, though they suspected that androgens (male hormones including testosterone) could be affecting both scalp and prostate. Langer had another theory: " Baldness is a cue for old age," she says. "Therefore, men who go bald early in life may perceive themselves as older and may consequently be expected to age more quickly." And those expectations may actually lead them to experience the effects of aging. To explore this relationship between expectations of aging and physiological signs of health, Langer and her colleagues designed the hair-salon study. They had research assistants approach 47 women, ranging in age from 27 to 83, who were about to have their hair cut, colored or both. They took blood-pressure readings. After the subjects' hair was done, they filled out a questionnaire about how they felt they looked, and their blood pressure was taken again. In a paper published in 2010 in the journal Perspectives on Psychological Science, they reported that the subjects who perceived themselves as looking younger after the makeover experienced a drop in blood pressure.

A few years earlier, Langer and one of her students, Alia Crum, conducted a study, published in the journal Psychological Science, involving 84 hotel chambermaids. The maids had mostly reported that they didn't get much exercise in a typical week. The researchers primed the experimental group to think differently about their work by informing them that cleaning rooms was fairly serious exercise - as much if not more than the surgeon general recommends. Once their expectations were shifted, those maids lost weight, relative to a control group (and also improved on other measures like body mass index and hip-to-waist ratio). All other factors were held constant. The only difference was the change in mind-set.

Critics hunted for other explanations - statistical errors or subtle behavior changes in the weight-loss group that Langer hadn't accounted for. Otherwise the outcome seemed to defy physics. "To which I would say, 'There's no discipline that is complete,' " Langer responds. "If current-day physics can't explain these things, maybe there are changes that need to be made in physics."

In the course of her career, Langer says, she has written or co-written more than 200 studies, and she continues to churn out research at a striking pace. Just before winter break, in her final meeting with two dozen or so students and postdocs, Langer went around the table checking the progress of nearly 30 experiments, all of which manipulated subjects' perceptions. Some used a special clock that could be set to run at half-speed or double-speed. In one study, sleeping subjects were fooled, upon awakening, into thinking they had more or less sleep than they actually did. She posits that the scores on measures of short-term memory and reaction time will vary accordingly, regardless of how long the subjects actually slept. In a yet-to-be-published diabetes study, Langer wondered whether the biochemistry of Type 2 diabetics could be manipulated by the same psychological intervention - the subjects' perception of how much time had passed. Her theory was that the diabetics' blood-glucose levels would follow perceived time rather than actual time; in other words, they would spike and dip when the subjects expected them to. And that's what her data revealed. When a student emailed her with the results this fall, she could barely contain her excitement. "This is the beginning of a psychological cure for diabetes!" she told me.

Some of the new experiments rely on variables that change self-perception. In a study using avatars, scheduled to take place at the popular gaming facility Second Life, subjects will watch a digital version of themselves playing tennis and gradually getting thinner from the exertion. Langer is exploring whether watching an avatar will have a physiological effect on the real person. "You see yourself, you're playing tennis," Langer said. "The question is: Will people lose weight? We'll see."

Some of Langer's colleagues in the academy see her as a valuable force in psychology, praising her eccentric intelligence and ingenious study designs. Steven Pinker, the writer and Harvard professor, told me that she filled an important niche within the school's department, which has often harbored "mavericks with nontraditional projects," including "B. F. Skinner's utopian novels and manifestoes and Herb Kelman's encounter groups between Arab and Israeli activists - not to mention Timothy Leary and Richard Alpert," who would become Ram Dass.

But Langer's sensibility can feel at odds with the rigors of contemporary academia. Sometimes she will give equal weight to casually hatched ideas and peer-reviewed studies. She spoke loosely to me of her New Hampshire counterclockwise study as having been "replicated" three times - in Britain, the Netherlands and South Korea. But none of these were lab experiments. They were events made for television. The study that arguably made Langer's name - the plant study with nursing-home patients - wouldn't have "much credibility today, nor would it meet the tightened standards of rigor," says James Coyne, professor emeritus of psychology at the University of Pennsylvania medical school and a widely published bird dog of pseudoscience. (Though, as Coyne also acknowledges, "that is true of much of the work of the '70s, including my own concerning depressed persons depressing others.") Langer's long-term contributions, Coyne says, "will be seen in terms of the thinking and experimenting they encouraged."

Four years ago, Langer and her colleagues published in Psychological Science a study that came closest in spirit to the original counterclockwise study in New Hampshire. Here, too, the placebo was a health prime, a situational nudge. They had two groups of subjects go into a flight simulator. One group was told to think of themselves as Air Force pilots and given flight suits to wear while guiding a simulated flight. The other group was told that the simulator was broken and that they should just pretend to fly a plane. Afterward, they gave each group an eyesight test. The group that piloted the flight performed 40 percent better than the other group. Clearly "mind-set manipulation can counteract presumed physiological limits," Langer said. If a certain kind of prompt could change vision, Langer thought, there was no reason, that you couldn't try almost anything. The endgame, she has said many times since, is to "return the control of our health back to ourselves."

Last spring, Langer and a postdoctoral researcher, Deborah Phillips, were chatting when the subject of the counterclockwise study came up. Over the more than 30 intervening years, Langer had explored many dimensions of health psychology and tested the power of the mind to ease various afflictions. Perhaps it was finally time to run the counterclockwise study again. But if they did, she wanted to raise the stakes: Could they shrink the tumors of cancer patients? Langer often says she has no clue where her ideas come from - but in this case it was crystal clear: Metastatic breast cancer killed her mother at 56, when Langer was 29.

Phillips suggested that perhaps they should start with early-stage cancers, ones perceived as more curable, but Langer was firm: It had to be a big, common killer that traditional Western medicine had no answer for. She settled on Stage 4 metastatic breast cancer. Treatment of such cases is usually framed in terms of so-called comfort care. "The medical world has given up on these people," Langer says.

The study, which is planned for the spring, is designed to include three groups of 24 women with Stage 4 breast cancer who are in stable condition and undergoing hormonal therapy. Two groups will gather at resorts in San Miguel de Allende, Mexico, under the supervision of Langer and her staff. The experimental group will live for a week in surroundings that evoke 2003, a date when all the women were healthy and hopeful, living without a mortal threat hanging over them. They will be told to try to inhabit their former selves. Few clues of the present day will be visible inside the resorts or, for that matter, outside them. In the living areas, turn-of-the-millennium magazines will be lying around, as will DVDs of films like "Titanic" and "The Big Lebowski." San Miguel de Allende, which has historically been a place known for its nearby healing mineral springs, is a Unesco World Heritage Site, and many of its buildings look as they did a few hundred years ago. "The whole town is a time capsule," Langer says. (The other group at San Miguel will have the support of fellow cancer patients but will not live in the past; a third group will not experience any research intervention.)

As with the original counterclockwise experiment, subjects will be tested before and after on relevant measures - in this case the size of their tumors and the levels of circulating proteins in their blood known to be made by cancer cells - in addition to variables like mood and energy and pain levels. The experimental group will bring with them the same kinds of primes that the New Hampshire men did, like photographs of their younger selves. "We won't make them haul their bags up the stairs," Langer says. But otherwise they will be nudged to do all they can for themselves.

The staff will encourage the women to think anew about their circumstances in an attempt to purge any negative messages they have absorbed during their passage through in the medical system. This is crucial, Langer says, because just as the mind can make things better, it can also make things worse. The nocebo effect is the flip side of the more positive placebo effect, and she says that one of the most pernicious nocebo effects can occur when a patient is informed by her doctor that she is ill. The diagnosis itself, Langer says, primes the symptoms the patient expects to feel. "You change a word here or there, and you get vastly different results," Langer says. She told me about a yet-to-be-published study she did in 2010 that found that breast-cancer survivors who described themselves as "in remission" were less functional and showed poorer general health and more pain than subjects who considered themselves "cured."

So there will be no talk of cancer "victims," nor anyone "fighting" a "chronic" disease. "When you're saying 'fighting,' you're already acknowledging the adversary is very powerful," Langer says. " 'Chronic' is understood as 'uncontrollable' - and that's not something anyone can know."

Of course, the subjects hope to get better, and everything about the setup is nudging them in that direction. So the study becomes a kind of open placebo experiment. Langer has long believed it's possible to get people to gin up positive effects in their own body - in effect, to decide to get well. Last fall, she tested that proposition, but in reverse: She recruited a number of healthy test subjects and gave them the mission to make themselves unwell. The subjects watched videos of people coughing and sneezing. There were tissues around and those in the experimental group were encouraged to act as if they had a cold. No deception was involved: The subjects weren't misled, for example, into thinking they were being put into a germ chamber or anything like that. This was explicitly a test to see if they could voluntarily change their immune systems in measurable ways.

In the study, which is ongoing, 40 percent of the experimental group reported cold symptoms following the experiment, while 10 percent of those in control group did. Buoyed, Langer ordered further analysis, looking for more concrete proof that they actually caught colds by testing their saliva for the IgA antibody, a sign of elevated immune-system response. In February, the results came in. All of the experimental subjects who had reported cold symptoms showed high levels of the IgA antibody.

Placebo effects have already been proven to work on the immune system. But this study could show for the first time that they work in a different way - that is, through an act of will. "As far as we know today, the placebo responses in the immune system are attributable to unconscious classical conditioning," says the Italian neuroscientist Fabrizio Benedetti, a leading expert in placebo effects. In Benedetti's experiments, a suggestion planted in the minds of test subjects produced physiological changes directly, the way a dinner bell might goose the salivary glands of a dog. (In one study, healthy volunteers given a placebo - a suggestion that any pain they experienced was actually beneficial to their bodies - were found to produce higher levels of natural painkillers.) "There's no evidence that expectations play a role as well," Benedetti says. Langer plans to further analyze the subjects' saliva to see whether they actually have the rhinovirus and not just elevated IgA.

The implications of the open placebo - that is, we know the sugar pill is just a sugar pill, but it still works as medicine - are tantalizing. If placebo effects can be harnessed without deception, it would remove many of the ethical issues that surround placebo work. In a study published in the journal Plos One in 2010, Ted Kaptchuk, a professor of medicine at Harvard Medical School, and his colleagues administered a placebo labeled "placebo" to a test group of patients suffering from irritable bowel syndrome. Their symptoms declined significantly as compared with a no-treatment control group. "At some level everybody realizes they themselves are the placebo," Langer says.

Langer's cancer study has had to clear the hurdles of three human-subjects ethics boards - one from Mexico, one from Harvard's psychology department and, for a time, one from the University of Southern California's medical school, where until recently Debu Tripathy, an oncologist who is recruiting subjects for Langer's study, was a professor of medicine. In June, progress stalled when the board at U.S.C. asked that the language be tweaked. "There's so much stuff that's totally outrageous in this world," Langer told me at the time. "They want me to add a consent form for the people to sign saying there's no known benefit to them. But that just introduces a nocebo effect!" (The study now has to clear the ethics board at the University of Texas M.D. Anderson Cancer Center in Houston, where Tripathy presently works.)

Like the men in New Hampshire, Langer's cancer patients in San Miguel will pass a richly diverting week. In this case, art classes, cooking classes and writing classes will help distract them from the brute dread of their circumstances and re-engage them in life. The terror of late-stage cancer can be as debilitating as the physical reality, Tripathy says. Some sufferers, he says, show symptoms akin to PTSD. There's strong evidence that the support of other people boosts the quality of life for cancer patients. There's less evidence that it improves their health prospects.

I asked Tripathy whether there's any precedent for what Langer is trying to do. "Well, there are many examples in medicine where improvement in the emotional state seems also to bring about some improvement in the disease state," he said. "We know, for example, that Tibetan monks can meditate and lower their blood pressure. People with hypertension, they embark on behavioral changes, and you can see the improvement in the medical indexes, like fewer heart attacks. But cancer? That's a harder thing to fathom."

Positive psychology doesn't have a great track record as a way to fight cancer. Indeed, when James Coyne and colleagues followed 1,093 people with advanced head-and-neck cancer over nine years, they found even the most optimistic subjects lived no longer than the most pessimistic ones.

Some cancer patients respond to interventions better than others, Tripathy notes. "But even with high-dose chemotherapy, you rarely see 'complete response,' which is total disappearance" of advanced breast cancer. "So if we saw anything like that, boy, that would hit the medical journals in a hurry."

One day in Puerto Vallarta in February, Langer sat on the patio of her hillside home. An iguana the length of a celery rib scooted across a high railing, and the dogs went bananas. "That's Ada," Langer said. "Or is it Ida? There are two - it's hard to tell them apart." When the iguanas first appeared and began devouring the hibiscus, Langer was startled. Now she and Nancy feed them petals for lunch. "That's the way it is," she said. "You can be scared. You give it a name, and then it's a pet."

Langer peered out over the deep blue sea, in the direction of a lagoon, where early in her career she conducted experiments on whether dolphins were more likely to want to swim with mindful people. In the last few days, she had been exchanging emails with a writer who wanted to come stay with her for a couple of weeks, taking notes for a screenplay for a Hollywood biopic.

Langer told me that she chose San Miguel for her new counterclockwise study primarily because the town had made "an offer I couldn't refuse." A group of local businesspeople, convinced of the value of having Langer's name attached to San Miguel, arranged for lodging to be made available free to Langer. They also encouraged her to build a Langer Mindfulness Institute, which will take part in research and run retreats. (A local developer donated a beautiful casa, next to his Nick Faldo-designed golf course, to serve as staff quarters for the institute.) Starting sometime next year, adults will be able to sign up for a paid, weeklong counterclockwise experience, presumably with a chance at some of the same rejuvenative benefits the New Hampshire test subjects enjoyed.

Langer says she is in conversation with health and business organizations in Australia about establishing another research facility that would also accept paying customers, who will learn to become more mindful through a variety of cognitive-behavioral techniques and exercises. She has already opened a mindfulness institute in Bangalore, India, where researchers are undertaking a study to look at whether mindfulness can stem the spread of prostate cancer.

Langer makes no apologies for the paid retreats, nor for what will be their steep price. (This, too, is calculated: In the absence of other cues, people tend to place disproportionate value on things that cost more. Dan Ariely, a psychologist at Duke, and his colleagues found that pricier placebos were more effective than cheap ones.) To my question of whether such a nakedly commercial venture will undermine her academic credibility, Langer rolled her eyes a bit. "Look, I'm not 40 years old. I've paid my dues, and there's nothing wrong with making this more widely available to people, since I deeply believe it."

Medical colleagues have asked Langer if she is setting herself up to fail with the cancer study - and perhaps underappreciating the potential setbacks to her work. It's also possible that subjects who don't improve could feel more demoralized by the experience. In her memoir, "Bright-sided," the journalist Barbara Ehrenreich wrote scorchingly about the sunshine brigade that bombarded her with "positive thinking" as she suffered through breast cancer. Under those conditions, patients who don't get better might feel as if they themselves were somehow to blame.

After a lecture in 2010, in which she'd discussed how when we talk about "fighting" cancer we actually give the disease power, a man buttonholed Langer and laid into her. His wife had died of breast cancer. "He said she had fought it, and I made it seem that it was her fault," Langer told me.

Langer apologized to the man. "Those are good points, and I'm sorry I didn't address them," she said. "But let me explain to you that it's the culture that teaches us that we have no control. I'm not blaming your wife; I'm blaming the culture." Langer imagines a day when blame isn't the first thing people reach for when things go awry. Instead, we will simply bring to bear the power of our own minds - which she believes will turn out to be far greater than we imagined.

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Each day, as they discussed sports (Johnny Unitas and Wilt Chamberlain) or "current" events (the first U.S. satellite launch) or dissected the movie they just watched ( "Anatomy of a Murder," with Jimmy Stewart), they spoke about these late-'50s artifacts and events in the present tense - one of Langer's chief priming strategies.

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One fine May morning not long ago my oldest son, 17 at the time, phoned to tell me that he had just spent a couple hours at the state police barracks. Apparently he had been driving "a little fast." What, I asked, was "a little fast"? Turns out this product of my genes and loving care, the boy-man I had swaddled, coddled, cooed at, and then pushed and pulled to the brink of manhood, had been flying down the highway at 113 miles an hour.

"That's more than a little fast," I said.

He agreed. In fact, he sounded somber and contrite. He did not object when I told him he'd have to pay the fines and probably for a lawyer. He did not argue when I pointed out that if anything happens at that speed-a dog in the road, a blown tire, a sneeze-he dies. He was in fact almost irritatingly reasonable. He even proffered that the cop did the right thing in stopping him, for, as he put it, "We can't all go around doing 113."

He did, however, object to one thing. He didn't like it that one of the several citations he received was for reckless driving.

"Well," I huffed, sensing an opportunity to finally yell at him, "what would you call it?"

"It's just not accurate," he said calmly. " 'Reckless' sounds like you're not paying attention. But I was. I made a deliberate point of doing this on an empty stretch of dry interstate, in broad daylight, with good sight lines and no traffic. I mean, I wasn't just gunning the thing. I was driving.

"I guess that's what I want you to know. If it makes you feel any better, I was really focused."

Actually, it did make me feel better. That bothered me, for I didn't understand why. Now I do.

My son's high-speed adventure raised the question long asked by people who have pondered the class of humans we call teenagers: What on Earth was he doing? Parents often phrase this question more colorfully. Scientists put it more coolly. They ask, What can explain this behavior? But even that is just another way of wondering, What is wrong with these kids? Why do they act this way? The question passes judgment even as it inquires.

Through the ages, most answers have cited dark forces that uniquely affect the teen. Aristotle concluded more than 2,300 years ago that "the young are heated by Nature as drunken men by wine." A shepherd in William Shakespeare's The Winter's Tale wishes "there were no age between ten and three-and-twenty, or that youth would sleep out the rest; for there is nothing in the between but getting wenches with child, wronging the ancientry, stealing, fighting." His lament colors most modern scientific inquiries as well. G. Stanley Hall, who formalized adolescent studies with his 1904 Adolescence: Its Psychology and Its Relations to Physiology, Anthropology, Sociology, Sex, Crime, Religion and Education, believed this period of "storm and stress" replicated earlier, less civilized stages of human development. Freud saw adolescence as an expression of torturous psychosexual conflict; Erik Erikson, as the most tumultuous of life's several identity crises. Adolescence: always a problem.

Such thinking carried into the late 20th century, when researchers developed brain-imaging technology that enabled them to see the teen brain in enough detail to track both its physical development and its patterns of activity. These imaging tools offered a new way to ask the same question-What's wrong with these kids?-and revealed an answer that surprised almost everyone. Our brains, it turned out, take much longer to develop than we had thought. This revelation suggested both a simplistic, unflattering explanation for teens' maddening behavior-and a more complex, affirmative explanation as well.

The first full series of scans of the developing adolescent brain-a National Institutes of Health (NIH) project that studied over a hundred young people as they grew up during the 1990s-showed that our brains undergo a massive reorganization between our 12th and 25th years. The brain doesn't actually grow very much during this period. It has already reached 90 percent of its full size by the time a person is six, and a thickening skull accounts for most head growth afterward. But as we move through adolescence, the brain undergoes extensive remodeling, resembling a network and wiring upgrade.

For starters, the brain's axons-the long nerve fibers that neurons use to send signals to other neurons-become gradually more insulated with a fatty substance called myelin (the brain's white matter), eventually boosting the axons' transmission speed up to a hundred times. Meanwhile, dendrites, the branchlike extensions that neurons use to receive signals from nearby axons, grow twiggier, and the most heavily used synapses-the little chemical junctures across which axons and dendrites pass notes-grow richer and stronger. At the same time, synapses that see little use begin to wither. This synaptic pruning, as it is called, causes the brain's cortex-the outer layer of gray matter where we do much of our conscious and complicated thinking-to become thinner but more efficient. Taken together, these changes make the entire brain a much faster and more sophisticated organ.

This process of maturation, once thought to be largely finished by elementary school, continues throughout adolescence. Imaging work done since the 1990s shows that these physical changes move in a slow wave from the brain's rear to its front, from areas close to the brain stem that look after older and more behaviorally basic functions, such as vision, movement, and fundamental processing, to the evolutionarily newer and more complicated thinking areas up front. The corpus callosum, which connects the brain's left and right hemispheres and carries traffic essential to many advanced brain functions, steadily thickens. Stronger links also develop between the hippocampus, a sort of memory directory, and frontal areas that set goals and weigh different agendas; as a result, we get better at integrating memory and experience into our decisions. At the same time, the frontal areas develop greater speed and richer connections, allowing us to generate and weigh far more variables and agendas than before.

When this development proceeds normally, we get better at balancing impulse, desire, goals, self-interest, rules, ethics, and even altruism, generating behavior that is more complex and, sometimes at least, more sensible. But at times, and especially at first, the brain does this work clumsily. It's hard to get all those new cogs to mesh.

Beatriz Luna, a University of Pittsburgh professor of psychiatry who uses neuroimaging to study the teen brain, used a simple test that illustrates this learning curve. Luna scanned the brains of children, teens, and twentysomethings while they performed an antisaccade task, a sort of eyes-only video game where you have to stop yourself from looking at a suddenly appearing light. You view a screen on which the red crosshairs at the center occasionally disappear just as a light flickers elsewhere on the screen. Your instructions are to not look at the light and instead to look in the opposite direction. A sensor detects any eye movement. It's a tough assignment, since flickering lights naturally draw our attention. To succeed, you must override both a normal impulse to attend to new information and curiosity about something forbidden. Brain geeks call this response inhibition.

Ten-year-olds stink at it, failing about 45 percent of the time. Teens do much better. In fact, by age 15 they can score as well as adults if they're motivated, resisting temptation about 70 to 80 percent of the time. What Luna found most interesting, however, was not those scores. It was the brain scans she took while people took the test. Compared with adults, teens tended to make less use of brain regions that monitor performance, spot errors, plan, and stay focused-areas the adults seemed to bring online automatically. This let the adults use a variety of brain resources and better resist temptation, while the teens used those areas less often and more readily gave in to the impulse to look at the flickering light-just as they're more likely to look away from the road to read a text message.

If offered an extra reward, however, teens showed they could push those executive regions to work harder, improving their scores. And by age 20, their brains respond to this task much as the adults' do. Luna suspects the improvement comes as richer networks and faster connections make the executive region more effective.

These studies help explain why teens behave with such vexing inconsistency: beguiling at breakfast, disgusting at dinner; masterful on Monday, sleepwalking on Saturday. Along with lacking experience generally, they're still learning to use their brain's new networks. Stress, fatigue, or challenges can cause a misfire. Abigail Baird, a Vassar psychologist who studies teens, calls this neural gawkiness-an equivalent to the physical awkwardness teens sometimes display while mastering their growing bodies.

The slow and uneven developmental arc revealed by these imaging studies offers an alluringly pithy explanation for why teens may do stupid things like drive at 113 miles an hour, aggrieve their ancientry, and get people (or get gotten) with child: They act that way because their brains aren't done! You can see it right there in the scans!

This view, as titles from the explosion of scientific papers and popular articles about the "teen brain" put it, presents adolescents as "works in progress" whose "immature brains" lead some to question whether they are in a state "akin to mental retardation."

The story you're reading right now, however, tells a different scientific tale about the teen brain. Over the past five years or so, even as the work-in-progress story spread into our culture, the discipline of adolescent brain studies learned to do some more-complex thinking of its own. A few researchers began to view recent brain and genetic findings in a brighter, more flattering light, one distinctly colored by evolutionary theory. The resulting account of the adolescent brain-call it the adaptive-adolescent story-casts the teen less as a rough draft than as an exquisitely sensitive, highly adaptable creature wired almost perfectly for the job of moving from the safety of home into the complicated world outside.

This view will likely sit better with teens. More important, it sits better with biology's most fundamental principle, that of natural selection. Selection is hell on dysfunctional traits. If adolescence is essentially a collection of them-angst, idiocy, and haste; impulsiveness, selfishness, and reckless bumbling-then how did those traits survive selection? They couldn't-not if they were the period's most fundamental or consequential features.

The answer is that those troublesome traits don't really characterize adolescence; they're just what we notice most because they annoy us or put our children in danger. As B. J. Casey, a neuroscientist at Weill Cornell Medical College who has spent nearly a decade applying brain and genetic studies to our understanding of adolescence, puts it, "We're so used to seeing adolescence as a problem. But the more we learn about what really makes this period unique, the more adolescence starts to seem like a highly functional, even adaptive period. It's exactly what you'd need to do the things you have to do then."

To see past the distracting, dopey teenager and glimpse the adaptive adolescent within, we should look not at specific, sometimes startling, behaviors, such as skateboarding down stairways or dating fast company, but at the broader traits that underlie those acts.

Let's start with the teen's love of the thrill. We all like new and exciting things, but we never value them more highly than we do during adolescence. Here we hit a high in what behavioral scientists call sensation seeking: the hunt for the neural buzz, the jolt of the unusual or unexpected.

Seeking sensation isn't necessarily impulsive. You might plan a sensation-seeking experience-a skydive or a fast drive-quite deliberately, as my son did. Impulsivity generally drops throughout life, starting at about age 10, but this love of the thrill peaks at around age 15. And although sensation seeking can lead to dangerous behaviors, it can also generate positive ones: The urge to meet more people, for instance, can create a wider circle of friends, which generally makes us healthier, happier, safer, and more successful.

This upside probably explains why an openness to the new, though it can sometimes kill the cat, remains a highlight of adolescent development. A love of novelty leads directly to useful experience. More broadly, the hunt for sensation provides the inspiration needed to "get you out of the house" and into new terrain, as Jay Giedd, a pioneering researcher in teen brain development at NIH, puts it.

Also peaking during adolescence (and perhaps aggrieving the ancientry the most) is risk-taking. We court risk more avidly as teens than at any other time. This shows reliably in the lab, where teens take more chances in controlled experiments involving everything from card games to simulated driving. And it shows in real life, where the period from roughly 15 to 25 brings peaks in all sorts of risky ventures and ugly outcomes. This age group dies of accidents of almost every sort (other than work accidents) at high rates. Most long-term drug or alcohol abuse starts during adolescence, and even people who later drink responsibly often drink too much as teens. Especially in cultures where teenage driving is common, this takes a gory toll: In the U.S., one in three teen deaths is from car crashes, many involving alcohol.

Are these kids just being stupid? That's the conventional explanation: They're not thinking, or by the work-in-progress model, their puny developing brains fail them.

Yet these explanations don't hold up. As Laurence Steinberg, a developmental psychologist specializing in adolescence at Temple University, points out, even 14- to 17-year-olds-the biggest risk takers-use the same basic cognitive strategies that adults do, and they usually reason their way through problems just as well as adults. Contrary to popular belief, they also fully recognize they're mortal. And, like adults, says Steinberg, "teens actually overestimate risk."

So if teens think as well as adults do and recognize risk just as well, why do they take more chances? Here, as elsewhere, the problem lies less in what teens lack compared with adults than in what they have more of. Teens take more risks not because they don't understand the dangers but because they weigh risk versus reward differently: In situations where risk can get them something they want, they value the reward more heavily than adults do.

A video game Steinberg uses draws this out nicely. In the game, you try to drive across town in as little time as possible. Along the way you encounter several traffic lights. As in real life, the traffic lights sometimes turn from green to yellow as you approach them, forcing a quick go-or-stop decision. You save time-and score more points-if you drive through before the light turns red. But if you try to drive through the red and don't beat it, you lose even more time than you would have if you had stopped for it. Thus the game rewards you for taking a certain amount of risk but punishes you for taking too much.

When teens drive the course alone, in what Steinberg calls the emotionally "cool" situation of an empty room, they take risks at about the same rates that adults do. Add stakes that the teen cares about, however, and the situation changes. In this case Steinberg added friends: When he brought a teen's friends into the room to watch, the teen would take twice as many risks, trying to gun it through lights he'd stopped for before. The adults, meanwhile, drove no differently with a friend watching.

To Steinberg, this shows clearly that risk-taking rises not from puny thinking but from a higher regard for reward.

"They didn't take more chances because they suddenly downgraded the risk," says Steinberg. "They did so because they gave more weight to the payoff."

Researchers such as Steinberg and Casey believe this risk-friendly weighing of cost versus reward has been selected for because, over the course of human evolution, the willingness to take risks during this period of life has granted an adaptive edge. Succeeding often requires moving out of the home and into less secure situations. "The more you seek novelty and take risks," says Baird, "the better you do." This responsiveness to reward thus works like the desire for new sensation: It gets you out of the house and into new turf.

As Steinberg's driving game suggests, teens respond strongly to social rewards. Physiology and evolutionary theory alike offer explanations for this tendency. Physiologically, adolescence brings a peak in the brain's sensitivity to dopamine, a neurotransmitter that appears to prime and fire reward circuits and aids in learning patterns and making decisions. This helps explain the teen's quickness of learning and extraordinary receptivity to reward-and his keen, sometimes melodramatic reaction to success as well as defeat.

The teen brain is similarly attuned to oxytocin, another neural hormone, which (among other things) makes social connections in particular more rewarding. The neural networks and dynamics associated with general reward and social interactions overlap heavily. Engage one, and you often engage the other. Engage them during adolescence, and you light a fire.

This helps explain another trait that marks adolescence: Teens prefer the company of those their own age more than ever before or after. At one level, this passion for same-age peers merely expresses in the social realm the teen's general attraction to novelty: Teens offer teens far more novelty than familiar old family does.

Yet teens gravitate toward peers for another, more powerful reason: to invest in the future rather than the past. We enter a world made by our parents. But we will live most of our lives, and prosper (or not) in a world run and remade by our peers. Knowing, understanding, and building relationships with them bears critically on success. Socially savvy rats or monkeys, for instance, generally get the best nesting areas or territories, the most food and water, more allies, and more sex with better and fitter mates. And no species is more intricately and deeply social than humans are.

This supremely human characteristic makes peer relations not a sideshow but the main show. Some brain-scan studies, in fact, suggest that our brains react to peer exclusion much as they respond to threats to physical health or food supply. At a neural level, in other words, we perceive social rejection as a threat to existence. Knowing this might make it easier to abide the hysteria of a 13-year-old deceived by a friend or the gloom of a 15-year-old not invited to a party. These people! we lament. They react to social ups and downs as if their fates depended upon them! They're right. They do.

Excitement, novelty, risk, the company of peers. These traits may seem to add up to nothing more than doing foolish new stuff with friends. Look deeper, however, and you see that these traits that define adolescence make us more adaptive, both as individuals and as a species. That's doubtless why these traits, broadly defined, seem to show themselves in virtually all human cultures, modern or tribal. They may concentrate and express themselves more starkly in modern Western cultures, in which teens spend so much time with each other. But anthropologists have found that virtually all the world's cultures recognize adolescence as a distinct period in which adolescents prefer novelty, excitement, and peers. This near-universal recognition sinks the notion that it's a cultural construct.

Culture clearly shapes adolescence. It influences its expression and possibly its length. It can magnify its manifestations. Yet culture does not create adolescence. The period's uniqueness rises from genes and developmental processes that have been selected for over thousands of generations because they play an amplified role during this key transitional period: producing a creature optimally primed to leave a safe home and move into unfamiliar territory.

The move outward from home is the most difficult thing that humans do, as well as the most critical-not just for individuals but for a species that has shown an unmatched ability to master challenging new environments. In scientific terms, teenagers can be a pain in the ass. But they are quite possibly the most fully, crucially adaptive human beings around. Without them, humanity might not have so readily spread across the globe.

This adaptive-adolescence view, however accurate, can be tricky to come to terms with-the more so for parents dealing with teens in their most trying, contrary, or flat-out scary moments. It's reassuring to recast worrisome aspects as signs of an organism learning how to negotiate its surroundings. But natural selection swings a sharp edge, and the teen's sloppier moments can bring unbearable consequences. We may not run the risk of being killed in ritualistic battles or being eaten by leopards, but drugs, drinking, driving, and crime take a mighty toll. My son lives, and thrives, sans car, at college. Some of his high school friends, however, died during their driving experiments. Our children wield their adaptive plasticity amid small but horrific risks.

We parents, of course, often stumble too, as we try to walk the blurry line between helping and hindering our kids as they adapt to adulthood. The United States spends about a billion dollars a year on programs to counsel adolescents on violence, gangs, suicide, sex, substance abuse, and other potential pitfalls. Few of them work.

Yet we can and do help. We can ward off some of the world's worst hazards and nudge adolescents toward appropriate responses to the rest. Studies show that when parents engage and guide their teens with a light but steady hand, staying connected but allowing independence, their kids generally do much better in life. Adolescents want to learn primarily, but not entirely, from their friends. At some level and at some times (and it's the parent's job to spot when), the teen recognizes that the parent can offer certain kernels of wisdom-knowledge valued not because it comes from parental authority but because it comes from the parent's own struggles to learn how the world turns. The teen rightly perceives that she must understand not just her parents' world but also the one she is entering. Yet if allowed to, she can appreciate that her parents once faced the same problems and may remember a few things worth knowing.

Meanwhile, in times of doubt, take inspiration in one last distinction of the teen brain-a final key to both its clumsiness and its remarkable adaptability. This is the prolonged plasticity of those late-developing frontal areas as they slowly mature. As noted earlier, these areas are the last to lay down the fatty myelin insulation-the brain's white matter-that speeds transmission. And at first glance this seems like bad news: If we need these areas for the complex task of entering the world, why aren't they running at full speed when the challenges are most daunting?

The answer is that speed comes at the price of flexibility. While a myelin coating greatly accelerates an axon's bandwidth, it also inhibits the growth of new branches from the axon. According to Douglas Fields, an NIH neuroscientist who has spent years studying myelin, "This makes the period when a brain area lays down myelin a sort of crucial period of learning-the wiring is getting upgraded, but once that's done, it's harder to change."

The window in which experience can best rewire those connections is highly specific to each brain area. Thus the brain's language centers acquire their insulation most heavily in the first 13 years, when a child is learning language. The completed insulation consolidates those gains-but makes further gains, such as second languages, far harder to come by.

So it is with the forebrain's myelination during the late teens and early 20s. This delayed completion-a withholding of readiness-heightens flexibility just as we confront and enter the world that we will face as adults.

This long, slow, back-to-front developmental wave, completed only in the mid-20s, appears to be a uniquely human adaptation. It may be one of our most consequential. It can seem a bit crazy that we humans don't wise up a bit earlier in life. But if we smartened up sooner, we'd end up dumber.

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One fine May morning not long ago my oldest son, 17 at the time, phoned to tell me that he had just spent a couple hours at the state police barracks. Apparently he had been driving "a little fast." What, I asked, was "a little fast"?

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Her voice trails off. She wants to make a difference, she says, and worries about whether she will. "I can't stop thinking about that."

Watching this video again makes Kagan fairly vibrate with the thrill of rediscovery: here on camera is the young girl who, as an infant, first embodied for him what it meant to be wired to worry. He went on to find many more such children, and would watch a big chunk of them run into trouble with anxiety or other problems as they grew up.

The tenuousness of modern life can make anyone feel overwrought. And in societal moments like the one we are in - thousands losing jobs and homes, our futures threatened by everything from diminishing retirement funds to global warming - it often feels as if ours is the Age of Anxiety. But some people, no matter how robust their stock portfolios or how healthy their children, are always mentally preparing for doom. They are just born worriers, their brains forever anticipating the dropping of some dreaded other shoe. For the past 20 years, Kagan and his colleagues have been following hundreds of such people, beginning in infancy, to see what happens to those who start out primed to fret. Now that these infants are young adults, the studies are yielding new information about the anxious brain.

These psychologists have put the assumptions about innate temperament on firmer footing, and they have also demonstrated that some of us, like Baby 19, are born anxious - or, more accurately, born predisposed to be anxious. Four significant long-term longitudinal studies are now under way: two at Harvard that Kagan initiated, two more at the University of Maryland under the direction of Nathan Fox, a former graduate student of Kagan's. With slight variations, they all have reached similar conclusions: that babies differ according to inborn temperament; that 15 to 20 percent of them will react strongly to novel people or situations; and that strongly reactive babies are more likely to grow up to be anxious.

They have also shown that while temperament persists, the behavior associated with it doesn't always. Kagan often talks about the three ways to identify an emotion: the physiological brain state, the way an individual describes the feeling and the behavior the feeling leads to. Not every brain state sparks the same subjective experience; one person might describe a hyperaroused brain in a negative way, as feeling anxious or tense, while another might enjoy the sensation and instead uses a positive word like "alert." Nor does every brain state spark the same behavior: some might repress the bad feelings and act normally; others might withdraw. But while the behavior and the subjective experience associated with an emotion like anxiety might be in a person's conscious control, physiology usually is not. This is what Kagan calls "the long shadow of temperament." The oldest high-reactive subjects in Kagan's and Fox's studies, like Baby 19, are in their 20s now, and for many of them, no matter how much they manage to avoid looking anxious to an outsider, fears still rattle in their skulls at 3 o'clock in the morning. They remain anxious just below the surface, their subconscious brains still twitchy, still hypervigilant, still unable to shift attention away from perceived threats that aren't really there.

ANXIETY IS NOT fear, exactly, because fear is focused on something right in front of you, a real and objective danger. It is instead a kind of fear gone wild, a generalized sense of dread about something out there that seems menacing - but that in truth is not menacing, and may not even be out there. If you're anxious, you find it difficult to talk yourself out of this foreboding; you become trapped in an endless loop of what-ifs.

"I was flesh bereft of spirit," wrote the journalist Patricia Pearson in "A Brief History of Anxiety (Yours and Mine)," in a pitch-perfect description of this emotional morass, "a friable self, grotesque... I got an AIDS test. I had my moles checked. I grew suspicious of pains in my back. If I was nauseous, I worried about cancer and started reading up obsessively on symptoms. I lay in bed whenever I could, trying to shut up the clamor of terror with sleep."

When the "clamor of terror" starts to interfere with functioning, as it did for Pearson when she was a crime reporter in her early 30s, worrying turns into a clinical anxiety disorder, of which there are several forms: panic, social anxiety, phobia, obsessive-compulsive, post-traumatic stress and a catch-all called generalized anxiety disorder. Taken together, they make anxiety the most common mental illness in America, affecting an estimated 40 million adults, according to the National Institute of Mental Health. And that figure doesn't even count the far greater swath who are garden-variety worriers, people who fret when a child is late, who worry when they hear a siren headed toward home, who are sure that a phone call in the middle of the night means someone is dead.

In the brain, these thoughts can often be traced to overreactivity in the amygdala, a small site in the middle of the brain that, among its many other functions, responds to novelty and threat. When the amygdala works as it should, it orchestrates a physiological response to changes in the environment. That response includes heightened memory for emotional experiences and the familiar chest pounding of fight or flight. But in people born with a particular brain circuitry, the kind seen in Kagan's high-reactive study subjects, the amygdala is hyperreactive, prickly as a haywire motion-detector light that turns on when nothing's moving but the rain. Other physiological changes exist in children with this temperament, many of them also related to hyperreactivity in the amygdala. They have a tendency to more activity in the right hemisphere, the half of the brain associated with negative mood and anxiety; greater increases in heart rate and pupil dilation in response to stress; and on occasion higher levels of the stress hormones cortisol and norepinephrine.

But having all the earmarks of anxiety in the brain does not always translate into a subjective experience of anxiety. "The brain state does not make it a disorder," Kagan told me. "The brain state exists, and the statement 'I'm anxious,' exists, and the correlation is imperfect." Two people can experience the same level of anxiety, he said, but one who has interesting work to distract her from the jittery feelings might do fine, while another who has just lost his job spends all day at home fretting and might be quicker to reach a point where the thrum becomes overwhelming. It's all in the context, the interpretation, the ability to divert your attention from the knot in your gut. These variations also happen when someone grows up from an anxious infant to someone either fretful or tranquil. One aim of Kagan's and Fox's longitudinal studies is to watch how the life stories of these high-strung babies unfold.

The quintessential longitudinal study, the one often mentioned because it set the standard, is the Framingham Heart Study, which enshrined the idea of risk factors. It was through Framingham, for instance, that scientists learned that high blood pressure was a risk factor for cardiovascular disease, since it followed its subjects for long enough to detect that those who had high blood pressure in their 30s and 40s were more likely to have heart disease later in life.

But such studies draw conclusions about trends, not destinies. If someone with high blood pressure treats it early, the risk of heart disease can be reduced significantly. Similarly, if someone with an anxiety-prone temperament grows up in the right surroundings, he or she might never develop a full-blown anxiety disorder.

Kagan's first exposure to longitudinal studies came shortly after he received his Ph.D. from Yale in 1954. He was working at the Fels Research Institute on the campus of Antioch College in Ohio, where a longitudinal study of middle-class children had been going on for nearly 30 years. He stumbled upon a gigantic room "loaded with prose summaries of what these children were like from the age of 1 month on," he told me recently. He knew a treasure trove when he saw one.

Among these prose summaries, which ultimately Kagan and a colleague, Howard Moss, turned into the book "Birth to Maturity," were descriptions indicating that babies had different innate temperaments. Kagan studiously ignored this finding; it didn't fit with his left-leaning politics, which saw all individuals as born inherently the same - blank slates, to use the old terminology - and capable of achieving anything if afforded the right social, economic and educational opportunities. "I was so resistant to awarding biology much influence, I didn't follow up on the inhibited temperaments I was seeing," he told me. It took another 20 years of listening to arguments about nature versus nurture for Kagan finally to entertain the possibility that some behavior might be attributed to genes.

BY THE TIME Kagan moved to Harvard in 1964, the notion of an inborn temperament was on the ascent, in part because of the findings of Stella Chess and Alexander Thomas of New York University, who divided children into three categories: easy children, difficult children and those who were slow to warm up. Remembering the Fels data, Kagan embarked on his own longitudinal study of temperament. In 1979, he screened about 400 preschoolers, exposing them to new toys and new people in a laboratory playroom, videotaping them and coding their behavior. About 15 percent ended up in the group Kagan called "behaviorally inhibited": wary, subdued, tending to hover near their mothers. Another 15 percent were "behaviorally uninhibited." They were the fearless ones, who ran around trying to play with every new toy and chatting happily with the examiner. When Kagan talks about such children, he uses one of his favorite words: "ebullient."

Over the next five years, 107 of these children - half of them timid, half bold - came back to the lab for more testing. (To keep environmental differences to a minimum, Kagan restricted his sample to children who were white, middle class and healthy at birth.) Their behavior was again recorded and again coded. Temperament, it turned out, tended to be stable over those five years, at least in children who started out at the extremes. There was a shift toward the middle between ages 2 and 7, but only 3 of the 107 changed categories completely from uninhibited to inhibited or vice versa. In addition, the most inhibited 7-year-olds showed some physiological differences that indicated an exaggerated response to stress.

Kagan and his colleagues, Nancy Snidman and J. Steven Reznick, published their results in Science in 1988. The physiological measurements led them to believe something biological was at work. Their hypothesis: the inhibited children were "born with a lower threshold" for arousal of various brain regions, in particular the amygdala, the hypothalamus and the hypothalamic-pituitary-adrenal axis, the circuit responsible for the stress hormone cortisol.

Though its findings seem almost self-evident today, the Science paper made a splash at the time. "There are two kinds of great research," Susan Engel, a developmental psychologist at Williams College, told me when I discussed Kagan's study with her. "There's research that is counterintuitive, that shows you something you'd never guess on your own, and there's research that shows you irrefutably what you had an intuition about, something you thought was true but didn't have evidence to support." Kagan's research was of the second type, she says: "a beautiful, elegant experimental demonstration of an old intuition."

But these subjects were preschoolers when Kagan first met them, already too old for him to know how much to attribute to nature rather than nurture. Couldn't the inhibited children somehow have been raised to be wary instead of born that way? So the following year, Kagan began a new study he said he hoped would minimize the effects of the environment. He recruited infants who were just 4 months old, planning to categorize them according to temperament and to follow them as they grew to see whether temperament in infancy predicted anything about subsequent personality.

How to measure temperament in babies so young, at an age when some parents are still wondering whether a smile means happiness or gas? Kagan couldn't measure the amygdala directly, so he looked for signs of its rampant firing that would be meaningful - and measurable - in infants. Since projections from the amygdala connect it to brain regions that control motor activity and the autonomic nervous system (heartbeat, breathing and other involuntary actions), he reasoned that if the amygdala was highly reactive, it would show up as increased motor activity, fretting and crying, as well as increases in heart rate, respiration and blood pressure.

Showing that a few physical measurements could offer insight into a baby's psyche was one of Kagan's real contributions. "Where his work had so much depth was not only in the longitudinal follow-up," says Joan Kaufman, a Yale psychologist who was a research assistant at Harvard when the study began, "but in thinking about the behavioral phenotype of an inborn temperament and really assessing it with such rigor."

Kagan brought about 500 babies - as before, all white, middle class and healthy - into the laboratory, placed them in infant seats in front of a video camera and exposed them to a series of novel stimuli. He showed them a schematic face that emitted words in a synthetic voice designed to be what he called "discrepant but not terrifying." He dangled a dancing mobile with plastic Winnie the Pooh characters - again, nothing scary, but something new. He brought to their noses a cotton swab that had been dipped in diluted alcohol. The battery of novel stimuli took 45 minutes. Some of the babies gazed contentedly throughout. Others were in constant motion, kicking and moving their arms fitfully, furrowing their brows, arching their backs or crying if they were really upset.

Kagan and his research assistants again looked at videotapes and coded movements and cries. Based on the final tally, each infant was categorized as either low-reactive, high-reactive or somewhere in between. The low-reactives were the classic easy babies, the ones who take unfamiliarity in stride. The high-reactives, among them Baby 19, thrashed and whimpered when exposed to the same unfamiliar things. It was clear, as they twisted about in their infant seats, that these babies were high-maintenance, difficult to comfort.

About 40 percent were low-reactive, and about 20 percent were high-reactive. Kagan brought most of them, as well as those with intermediate temperament, back for testing at ages 1 and 2. About half of them - primarily those at each extreme - returned for further testing at ages 4, 7, 11 and 15. That pattern continues to this day, even after Kagan retired in 2000 and handed over his records to a collaborator, Carl Schwartz, an adolescent psychiatrist at Harvard and Massachusetts General Hospital, who tested some of Kagan's subjects when they were 18 or 21.

By the earliest assessments, certain patterns had already emerged. At age 4, children who had been high-reactive were four times as likely to be behaviorally inhibited as those who had been low-reactive. By age 7, almost half of the jittery babies had developed symptoms of anxiety - fear of thunder or dogs or darkness, extreme shyness in the classroom or playground - compared with just 10 percent of the more easygoing ones. About one in five of the high-reactive babies were consistently inhibited and fearful at every visit up to the age of 7.

"Fear is an incredibly heterogeneous construct," says Daniel Pine, a child psychiatrist at the National Institute of Mental Health. Pine collaborates on the two longitudinal studies at the University of Maryland, conducting psychiatric interviews and functional M.R.I. scans on subjects at several stages. "Fear of social things is different from fear of physical things." The same brain circuitry is probably involved in both, he said, but different fears tend to show up at different points in development: fear of things like clowns, balloons or spiders emerging early in life; fear of things like social situations with peers emerging later. In addition, it's relatively easy to avoid the physical things that frighten you; if you're afraid of dogs, you can just take a different route to school to keep from passing that bull terrier down the street. It's much harder to avoid social fears - you can avoid the dog on the way to school, but you still have to go to school.

The children tended to get a better grip on their fearfulness as they got older. By adolescence, the rate of anxiety in Kagan's study subjects declined overall, including in the high-risk group. At 15, about two-thirds of those who had been high-reactors in infancy behaved pretty much like everybody else.

One such person was Mary, now a 21-year-old junior at Harvard, who was in the high-reactive group as a baby and was moderately fearful at ages 1 and 2. She didn't think of herself as anxious, just dutiful. "I don't stray from the rules too much," she said when we spoke by telephone not long ago. "But it's natural for me - I never felt troubled about it. I was definitely the kid who worked really hard to get good grades, who got all my homework done before I watched TV." Mary also was an accomplished ballet dancer as a child, which gave her a way to work off energy and to find a niche in which she excelled. That talent, plus being raised in what Kagan called a "benevolent home environment," might have helped shift Mary's innate inhibition to something more constructive. If Mary's high-reactive temperament is evident now, it comes out in the form of conscientiousness and self-control.

PEOPLE WITH A nervous temperament don't usually get off so easily, Kagan and his colleagues have found. There exists a kind of sub-rosa anxiety, a secret stash of worries that continue to plague a subset of high-reactive people no matter how well they function outwardly. They cannot quite outrun their own natures: consciously or unconsciously, they remain the same uneasy people they were when they were little.

Most of the high-reactive kids in Kagan's study did well in adolescence, getting good grades, going to parties, making friends. Scratch the surface, though, and many of them - probably most of them - were buckets of nerves. "It's only the high-reactives who say, 'I'm tense in school,' 'I vomit before examinations,' 'If we're going on a class trip to D.C., I can't sleep the night before,' " Kagan told me. "They don't like it, but they've accepted the fact that they're just tense people." Invoking Jungian terminology, he called it the difference between persona (the outer-directed personality) and anima (the inner-directed thoughts and feelings). The persona can be controlled, but the anima often cannot.

Nathan Fox of the University of Maryland says that when the anima erupts in high-risk children, it often takes the form of excessive vigilance and misdirected attention. In the first of his two longitudinal studies of temperament, begun in 1989, he followed 180 children from the age of 4 months and gave them a set of neuropsychological tests when they were between 13 and 15. One test, called the spatial-cuing task, measures vigilance and the ability to disengage attention from a perceived threat. It shows two faces briefly on a computer screen, one on each side - the same face looking threatening on one side and pleasant on the other. The faces fade away, and an arrow appears on one side of the screen, sometimes on the side the threatening face had been on, sometimes on the other. The subject must notice the arrow and press a button to indicate whether the arrow points up or down.

Adults with clinical anxiety consistently are faster at pressing the correct button if the arrow is on the side of the screen where the threatening face had been, and slower if the arrow is on the other side. (Non-anxious adults show no such subconscious preference.) In the kids in Fox's study, those who were born anxiety-prone - even the outwardly calm, well-adjusted ones - tended to perform this task like anxious adults, paying more attention to the threatening face whether or not they meant to.

A similar result came from another test Fox gave his subjects, called the potentiated startle response. In this test, teenagers are placed in front of a screen and told that when the screen is blue, there is a chance a puff of air will be blasted at their throats - a sensation that, Fox assured me, is surprising and uncomfortable but not painful. When the screen is green, they're safe; they are told that no puff of air will ever come when the green screen is on. Then, to evoke a startle, the experimenter plays a loud noise and measures the teenager's response (an involuntary eye blink). All subjects have a robust startle response when the blue screen is on, which reflects the fact that they are tensing up in anticipation of that uncomfortable air puff. But anxiety-prone kids startle just as much with the green, supposedly safe screen. They stay on guard, anxious and wired, even when the situation is not threatening. Again, this finding held no matter how the subjects behaved in real life - and no matter how they were feeling while the test was taking place.

Fox's collaborator, Daniel Pine of the N.I.M.H., conducted functional M.R.I. scans on 27 of these study subjects when they were adolescents. While they were in the scanner, Pine showed them pictures of fearful faces. Sometimes he told them to try to measure how wide the nose was - in other words, to focus on a detail that is emotionally neutral. Other times he told them to think about how afraid they felt looking at the person in the picture.

Teenagers who were in the group at low risk for anxiety showed no increase in activity in the amygdala when they looked at the face, even if they had been told to focus on their own fear. But those in the high-risk group showed increased activity in the amygdala when they were thinking about their own feelings (though not when they were thinking about the nose). Once again, this pattern was seen in anxiety-prone youngsters quite apart from whether they had problems with anxiety in their daily lives. In the high-risk kids, even those who were apparently calm in most settings, their amygdalas lighted up more than the others' did.

Temperamental type tends to reveal itself not only in functional M.R.I. scans but also in structural M.R.I.'s, which look at brain anatomy rather than activity. In 2007 Carl Schwartz, the Harvard psychiatrist who has taken over the follow-up work on Kagan's two longitudinal studies, put 76 of Kagan's study subjects in an M.R.I. machine. At the time, they were 18 years old. (Baby 19 was part of the sample; Mary was asked to participate, but she declined.) He found that the subjects who were high-reactors at 4 months tended to show significant thickening in the prefrontal cortex compared to those who were low-reactors. "This was amazing," Schwartz told me. "The temperament they exhibited as infants still seemed to leave a fingerprint in the brain 18 years later."

He is still trying to work out the exact meaning of this fingerprint; he cannot yet tell, for instance, whether a thicker cortex is a cause of a high-reactive temperament, or an effect, or something else entirely. One job of the prefrontal cortex is inhibitory, putting a damper on signals that come from the amygdala. Could it be that the cortex thickens more in the anxiety-prone as it is busy tamping down the overactive amygdala and growing new neural connections? Or does a thicker cortex come first, and contribute to a tendency to be anxious in the first place?

One way Schwartz tried to untangle his uncertainties was by winnowing from his sample the 14 subjects who had ever been given a diagnosis of social-anxiety disorder. What was left, presumably, were 62 young people who all functioned just fine, at least in the sense of never having suffered from social anxiety. Schwartz reviewed their brain images, and the difference between the cortical thickening in the high-reactive group and the low-reactives not only remained; it also became more pronounced. One explanation of this could be that a thicker cortex is protective in the anxiety-prone. He surmises that those 14 subjects who developed problems did so in part because their cortex was thinner, and the high-reactives who had avoided social anxiety had the thickest cortexes of all.

So what do these brain-anxious young people report about their state of mind? Anxiety, remember, can occur at three levels: brain, behavior and subjective experience. Were the ones whose brains looked anxious on the M.R.I. scans actually experiencing the sensation of being anxious?

This is a question the scientists struggle with, hampered as they are by peoples' inability to report their own feelings accurately. Pine told me that his subjects often admit, after the fact, that they had been more afraid during the experiment than they said at the time - leaving him unsure what conclusions to draw. According to Kagan, the high-reactive temperament is characterized by a tendency to be supersensitive to your own body's signals. Wouldn't you expect, then, that anxiety-prone kids would have some insight into their own brains? Yet even in the high-risk subjects, objective brain state and subjective experience of anxiety still don't always track.

It is also difficult to say whether high-reactive people are aware, more generally, that their brains are more tightly coiled than other people's. "What people say about what they're feeling is significant, but it is hardly the whole story," Schwartz says. "Some of those kids probably do have a subjective awareness of their brain state; others who have equally large amygdala signals - depending on how they have adapted, how they've been brought up and supported - might have little awareness of it." In some cases, he says, people might even have "reframed" certain physical sensations that could be considered symptoms of anxiety - like feeling jazzed up or having your pulse quicken - as "vaguely exhilarating or exciting."

Studies like Pine's and Schwartz's might actually be revealing not an anxious brain at all but an experimental artifact, says the developmental psychologist Robert Plomin. Plomin, who runs a longitudinal twin study of genes and behavior at King's College, London, agrees that anxiety does have a neurological fingerprint, but he worries about a disconnect between anxiety in the lab and anxiety as a quotidian experience. "Let's say that in your real life you learn to manage your temperamental dispositions so you don't freak out," he said. "Let's say you learn to take a deep breath, learn tricks to make yourself function better in life. But in the lab you're not dealing with social situations you've learned to control. You're just shown - boom! - some horrible picture of a bloody accident." If your response to a brutal image is milliseconds faster than the response of someone who is more sanguine, Plomin asked, what does that really tell you about how your brain would respond in the real world to a worrisome situation?

To make the anxiety-provoking lab challenge more authentic and emotionally charged, Pine and his colleagues at the N.I.M.H., Eric Nelson and Amanda Guyer, concocted an elaborate experimental setup to persuade teenagers in a functional M.R.I. machine that their social status really is on the line: a fake Internet chat room. They created a set of potential chat-room partners for their subjects: smiley, fictitious teenagers, complete with sham MySpace pages. The setup was that the other kids would eventually tell the subjects in the scanner whether they did or did not want to chat with them. The scans were taken, then, while the subjects were lying still, awaiting the verdict. In a handful of pilot experiments, this has proved to be an emotionally significant challenge for teenagers with social anxiety. The anxious youngsters, while waiting to hear from one of the pretend teenagers they wanted to avoid, showed more reactivity in the amygdala and prefrontal cortex. Pine has conducted this same experiment on 40 of Fox's longitudinal-study subjects and is currently analyzing the results.

Still, tracking the anxious mind, even with a more realistic experimental setup, means having the subject lie in an M.R.I. scanner, which is inherently not only artificial but also stressful. So Plomin's point is interesting. Brain scans and other lab findings might reflect something deep and persistent going on in the anxious mind. But if you have learned to control your behavior, to structure your life so you can limit triggers and cope with your emotional skittishness, how much does it really matter?

THE BEHAVIORAL STRAND of the brain-behavior-experience triad is the one that seems most amenable to intervention, and scientists are now investigating how it is that two-thirds of those with a high-reactive temperament manage to avoid trouble. Many environmental factors no doubt come into play - some of them malleable, some less so. In Kagan's first study, for instance, he found that birth order seemed relevant. Behaviorally inhibited children were much more likely to have older siblings: two-thirds of them did, compared with just one-third of the uninhibited children. Could having older siblings, he and his co-authors wondered, mean being teased and pushed, which becomes a source of chronic stress, which in turn amplifies a biological predisposition to inhibition? Kagan never replicated this finding, as intriguing as it was - which shows how difficult it can be to tease out which environmental factors are relevant, and which turn out to be incidental. Fox, meanwhile, noted that the high-reactive babies who went to day care when they were young were significantly less fearful at age 4 than were the high-reactives who stayed home with their mothers.

Attempts to see what kind of parenting works best with an anxiety-prone temperament leave almost as many questions asked as answered. Which is better for a fearful, high-strung child - a parent who coddles the child and says everything will be all right, or a parent who sets firm, strict limits and has no tolerance for skittishness? You could picture it as going either way, really. On the one hand, it might be good to shield children from the things that worry them. On the other hand, it might be better to urge them, maybe even force them, to confront the things they dread.

Scientists from both Kagan's and Fox's labs have looked at this question in a systematic way, and they have come up with two somewhat different findings. Both studies involved a series of home visits and hours of videotapes of mother-baby interactions. But one study, by Kagan's graduate student Doreen Arcus in the early 1990s, found that what seemed to be best for high-reactive babies were mothers who set firm limits and did not rush too quickly to comfort them when they cried. And the other, by Fox's postdoctoral fellow Amie Ashley Hane a decade later, found something slightly different: that the best fit for high-strung babies were sensitive mothers, who met their fearful children on their own terms and interacted with them in a way that was accepting and supportive without being intrusive. Sometimes, of course, there's a fine line between firm and hardhearted, and a fine line between supportive and intrusive. This makes it especially tough to turn research findings like Arcus's and Hane's into clear guidance on how best to care for a fretful child.

The best outcome, however it happens, is to rear a child who learns to wrestle his demons on his own. Some children figure out themselves what works best. "Inner struggles pulled at me for years until I was able to just let go and calm myself," wrote one of Kagan's high-reactive study subjects in an essay, revealing a wisdom far beyond his 13 years. "For example, when I first heard about the anthrax in Washington, I began to have an upset stomach. I realized it was simply because of my anxiety that I was feeling sick. As soon as I realized that, the stomachache went away. Because I now understand my predisposition toward anxiety, I can talk myself out of simple fears." There are many adults, anxious or not, who can't control their own interior monologues as well as this boy can.

For the children who need help grappling with their fears, some psychologists try to intervene early, with programs that give worried children tools for quieting the scary thoughts in their heads. Kids are often taught the same skills that anxious adults are, a variation on cognitive behavior therapy, designed to stop the endless recursive loop of rumination, replacing it with a smart, rational interior voice. In a way, it's teaching anxious people to do what non-anxious people do naturally.

"I joke a lot about my anxiety," wrote a young woman named Brittany on the group blog We Worry, part of a thriving community of anxiety blogs. "And there are times I do find it funny. I can do this because there is that voice in my head that tells me what I'm worrying about is irrational. But then I worry about worrying about irrational things. It is a never-ending cycle." She might laugh at herself, she wrote, but life can get "overwhelming to me sometimes. Things that don't even register to most people are uphill battles for me."

Even those with normal, run-of-the-mill fretfulness - not a clinical anxiety disorder like Brittany's - struggle to outsmart their brooding. "I have a friend who's a clinical psychologist, and we talk about this a lot - what people do on their own to make themselves less anxious," said Engel of Williams College, who is writing a book about temperament called "Red Flags and Red Herrings." Engel said she is by nature very anxious, as is the eldest of her three sons. "The way we deal with it is that we both get everything done in lots of time. We can't stand the anxiety of a looming deadline; we're so worried about being late that we do it five days early." This is one way to alleviate anxiety, she said. "There are other things we could do. We could drink, we could procrastinate, we could pretend we don't have the deadline. I guess we both happen to be lucky that our method is adaptive."

This kind of adapting might have something to do with intelligence, says Steven Pinker, a psychologist at Harvard and author of "The Blank Slate: The Modern Denial of Human Nature." He says he believes, based on pure conjecture, that people with higher intelligence are better at overcoming their anxious temperament and more likely to "see their own worry list as a problem to be solved, minimizing unnecessary anxiety while still being anxious enough to get things done." At least one study lends support to Pinker's impression. In a 2004 article called "Can Worriers Be Winners?" two British scientists gave personality questionnaires to a group of financial services managers and found that those who reported themselves as scoring high on anxiety traits, like being nervous about performing well on the job, turned out to be better employees, but only if their worrying was accompanied by high cognitive ability.

Fox said that what distinguishes the high-reactives who learn to adapt from those who don't often comes down to something simple, like finding one or two supportive friends - or, like Mary and her ballet, finding something they're good at and can feel self-confident about. But there could be some physiological differences between the adapters and the nonadapters, too. Baby 19, for instance, ran into some problems as she grew up. At a year old, she was one of the most fearful children in Kagan's study, and she had an episode of depression in middle school and a diagnosis of social anxiety disorder as a teenager. While these could have been related to any of a number of environmental factors, including a broken home, they could be related too to something curious that turned up in the brain scan Schwartz did on Baby 19 when she was 18 years old.

When Baby 19 was in the functional M.R.I. scanner and shown a series of unfamiliar faces, Schwartz said, her amygdala was highly reactive - about three times as much as that of a typical low-reactor. This was what Schwartz expected in someone with her temperament and psychiatric history. More surprising, though, was how her prefrontal cortex appeared on the structural M.R.I. scan. Rather than the thickened cortex that so many young adults with her temperament had, Baby 19's was relatively thin.

"This is the brain area implicated in emotional regulation," Schwartz told me. Could it be that in her case, her thin cortex was unable to regulate excessive activity in the amygdala, leading to more problems than someone with a thicker cortex would encounter? "At the level of an individual, it's always a bit dangerous to draw conclusions," he said. "In fact, it's pretty much impossible. But maybe one thing that affects outcome is whether the genes that contribute to these two areas, the amygdala and the cortex, travel together or separately." Maybe a high-reactive person with a jumpy amygdala can manage to avoid the behavioral and subjective experience of anxiety because of a strong cortex that can quiet the overactive brain. But in Baby 19's case, the jumpy amygdala might instead have been accompanied by a cortex less able to mount an inhibitory response. "Maybe when those things occur together," Schwartz said, "your outcome is that you have a little bit more trouble."

LOOKING AT THE neurology of anxiety raises the inevitable question of why a trait that causes so much mental anguish would have evolved in the first place. For the species as a whole, it is most likely an advantage to have some group members who are hypervigilant and who see everything as a threat, always ready to sound an alarm and leap into action. For the individual, though, being inhibited can mean having fewer mating opportunities, not to mention the psychic burden, wearing yourself ragged with a brain that's always on high alert.

In the modern world, the anxious temperament does offer certain benefits: caution, introspection, the capacity to work alone. These can be adaptive qualities. Kagan has observed that the high-reactives in his sample tend to avoid the traditional hazards of adolescence. Because they are more restrained than their wilder peers, he says, high-reactive kids are less likely to experiment with drugs, to get pregnant or to drive recklessly. They grow up to be the Felix Ungers of the world, he says, clearing a safe, neat path for the Oscar Madisons.

People with a high-reactive temperament - as long as it doesn't show itself as a clinical disorder - are generally conscientious and almost obsessively well-prepared. Worriers are likely to be the most thorough workers and the most attentive friends. Someone who worries about being late will plan to get to places early. Someone anxious about giving a public lecture will work harder to prepare for it. Test-taking anxiety can lead to better studying; fear of traveling can lead to careful mapping of transit routes.

Kagan told me that in the 40 years he worked at Harvard, he hired at least 200 research assistants, "and I always looked for high-reactives. They're compulsive, they don't make errors, they're careful when they're coding data." He said he would bet that when the United States sends people up in space, the steely, brave astronauts were low-reactive as infants, and the mission-control people down on the ground, doing the detail work that keeps the craft aloft, were high-reactive.

An anxious temperament might serve a more exalted function too. "Our culture has this illusion that anxiety is toxic," Kagan said. But without inner-directed people who prefer solitude, where would we get the writers and artists and scientists and computer programmers who make society hum? Kagan likes to point out that T. S. Eliot suffered from anxiety, and that biographies indicate that he was a typical high-reactive baby. "That line 'I will show you fear in a handful of dust' - he couldn't have written that without feeling the tension and dysphoria he did," Kagan said.

These are overgeneralizations, of course. And they're easy to shoot down with exceptions. But all the exceptions mean, really, is that the link between neurology and behavior is complicated. There may well be hundreds of different temperaments, and these studies have investigated only two - the most stable and most amenable to measurement, but still just two. If it were as simple as saying that a high-reactive infant will become a behaviorally inhibited child who will become an anxious adult, all the scientific work on temperament would amount to little more than charting horoscopes.

The predictive power of an anxiety-prone temperament, such as it is, essentially works in just one direction: not by predicting what these children will become but by predicting what they will not. In the longitudinal studies of anxiety, all you can say with confidence is that the high-reactive infants will not grow up to be exuberant, outgoing, bubbly or bold. Still, while a Sylvia Plath almost certainly won't grow up to be a Bill Clinton, she can either grow up to be anxious and suicidal, or simply a poet. Temperament is important, but life intervenes.

As for Baby 19, she has not yet gone against type, and odds are she never will. She is in college and doing pretty well, Kagan told me. But her temperament still comes through in her personality. Kagan said Baby 19 tends to be "dour" and "melancholy." And she is still, and probably always will be, a worrier.

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Her voice trails off. She wants to make a difference, she says, and worries about whether she will. "I can't stop thinking about that." Watching this video again makes Kagan fairly vibrate with the thrill of rediscovery: here on camera is the young girl who, as an infant, first embodied for him what it meant to be wired to worry.

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I'm the youngest by far of five children. My mother was 35 when she conceived me in 1951, so chagrined by this chronological indiscretion that she tried to hide the pregnancy from her sister. My mortified oldest brother didn't want to tell his high-school friends that a new baby was on the way, but it was a small town. Word spread.

My mother's age and my late arrival in the family felt burdensome to me too, especially when I started school in 1957 and met my classmates' mothers. They were still having babies! Still piling their children into cars and heading off to picnics at the river or hikes into the lava-capped, wild flower-rampant plateau outside town. They still had to mediate hair-pulling and toy-snatching. But by the time I started first grade, my siblings were gone, the oldest three to college and the youngest to a residential school four hours away, and we went from a very noisy household to a very quiet one.

My family has told me stories about those years before everything changed. How my oldest brother nicknamed me 'Ubangi' because my hair grew in tight fat curls close to my head. How my other brother liked to ambush me around corners with a toy crocodile because it never failed to make me shriek in terror. How my oldest sister carried me around like a kangaroo with her joey. But I can offer very few stories of my own from those early years.

My strongest recollection is a constant straining to be with my brothers and sisters. I remember having to go to bed when it was still light out, kicking at the sheets as I listened for their voices coming down the hall or through the windows from the back yard. Sometimes I could smell popcorn. The next morning, I'd search the living room rug for their leftovers and roll the unpopped kernels around in my mouth. I do remember that, probably because it was something that played out night after night - our father loved popcorn.

Several years ago, I thought I might have the chance to recover that lost past when we were all tightly clustered together in one house. My brothers had driven to Bucks Lake up in the Sierras of northeastern California where, until I was around three years old, our family had leased a house every summer to escape the Sacramento Valley heat. They found our old cabin unchanged. Even a table built by a local sawmill was still in the living room. They knocked on the door and, weirdly enough, my younger brother knew the current lessee. He invited them in and then invited the rest of us back for a look.

With our father, we set off a few months later, up highways that narrowed into dusty roads through dark pines and past bright stony summits. When we got to the cabin, my siblings scattered to claim their favourite outdoor spots, but I was rooted near the car, struck by how much this place differed from what I thought I remembered.

I recalled that the water was a long walk across a sandy beach from the house; I had an image of my mother standing on that wide beach, her dress whipped by the wind, her hand cupped near her mouth. But the pebbled shoreline was just a few feet away. I recalled the spine of a dam jutting from the water not far from the house, a perilous and sudden cliff at the edge of the lake that my siblings had once ventured too close to. But even though the lake is a man-made one, the dam wasn't visible from the house. I followed my father inside, where the tininess of the kitchen fascinated him. He kept opening cabinet doors and laughing as they banged each other in the narrow aisle. 'Mother just hated this kitchen!' he said. 'She always made big breakfasts - eggs and sausage and pancakes - and as soon as she finished cleaning up, you kids would come running back in the house wanting lunch.'

I didn't remember that. I didn't remember the table. I didn't remember anything about the place. My siblings tugged me through the house, pointing out where everyone had slept - they said I had been in a little alcove in the hallway, though I recalled staying in my parents' room and watching them sleep in the early morning light. They pointed out other features tied to the life that we all lived in the cabin, eager for me to remember, but there was nothing. I even dropped to my knees and circled the living room at toddler level, peering at dusty windowsills and sniffing at the knotholes in the pine walls and running my fingers over the floorboards. Nothing.

I now know that it would have been unusual for me to remember anything from that time. Hardly any adult does. There is even a term for this - childhood amnesia, coined by Sigmund Freud in 1910 - to describe the lack of recall adults have of their first three or four years and our paucity of solid memories until around the age of seven. There has been some back and forth over a century of research about whether memories of these early years are tucked away in some part of our brains and need only a cue to be recovered. That's what I was hoping when I revisited our old cabin with my siblings. I intended to jostle out a recalcitrant memory with the sights, sounds, smells and touch of the place. But research suggests that the memories we form in these early years simply disappear.

Freud argued that we repress our earliest memories because of sexual trauma but, until the 1980s, most researchers assumed that we retained no memories of early childhood because we created no memories - that events took place and passed without leaving a lasting imprint on our baby brains. Then in 1987, a study by the Emory University psychologist Robyn Fivush and her colleagues dispelled that misconception for good, showing that children who were just 2.5 years old could describe events from as far as six months into their past.

But what happens to those memories? Most of us assume that we can't recall them as adults because they're just too far back in our past to tug into the present, but this is not the case. We lose them when we're still children.

The psychologist Carole Peterson of Memorial University of Newfoundland has conducted a series of studies to pinpoint the age at which these memories vanish. First, she and her colleagues assembled a group of children between the ages of four and 13 to describe their three earliest memories. The children's parents stood by to verify that the memories were, indeed, true, and even the very youngest of the children could recall events from when they were around two years old.

if the memory was a very emotional one, children were three times more likely to retain it two years later

Then the children were interviewed again two years later to see if anything had changed. More than a third of those age 10 and older retained the memories they had offered up for the first study. But the younger children - especially the very youngest who had been four years old in the first study - had gone largely blank. 'Even when we prompted them about their earlier memories, they said: "No, that never happened to me,"' Peterson told me. 'We were watching childhood amnesia in action.'

In both children and adults, memory is bizarrely selective about what adheres and what falls away. In one of her papers, Peterson trots out a story about her own son and a childhood memory gone missing. She had taken him to Greece when he was 20 months old, and, while there, he became very excited about some donkeys. There was family discussion of those donkeys for at least a year. But by the time he went to school, he had completely forgotten about them. He was queried when he was a teenager about his earliest childhood memory and, instead of the remarkable Greek donkeys, he recalled a moment not long after the trip to Greece when a woman gave him lots of cookies while her husband showed the boy's parents around a house they planned to buy.

Peterson has no idea why he would remember that - it was a completely unremarkable moment and one that the family hadn't reinforced with domestic chitchat. To try to get a handle on why some memories endure over others, she and her colleagues studied the children's memories again. They concluded that if the memory was a very emotional one, children were three times more likely to retain it two years later. Dense memories - if they understood the who, what, when, where and why - were five times more likely to be retained than disconnected fragments. Still, oddball and inconsequential memories such as the bounty of cookies will hang on, frustrating the person who wants a more penetrating look at their early past.

To form long-term memories, an array of biological and psychological stars must align, and most children lack the machinery for this alignment. The raw material of memory - the sights, sounds, smells, tastes and tactile sensations of our life experiences - arrive and register across the cerebral cortex, the seat of cognition. For these to become memory, they must undergo bundling in the hippocampus, a brain structure named for its supposed resemblance to a sea horse, located under the cerebral cortex. The hippocampus not only bundles multiple input from our senses together into a single new memory, it also links these sights, sounds, smells, tastes, and tactile sensations to similar ones already stored in the brain. But some parts of the hippocampus aren't fully developed until we're adolescents, making it hard for a child's brain to complete this process.

'So much has to happen biologically to store a memory,' the psychologist Patricia Bauer of Emory University told me. There's 'a race to get it stabilised and consolidated before you forget it. It's like making Jell-O: you mix the stuff up, you put it in a mould, and you put it in the refrigerator to set, but your mould has a tiny hole in it. You just hope your Jell-O - your memory - gets set before it leaks out through that tiny hole.'

In addition, young children have a tenuous grip on chronology. They are years from mastering clocks and calendars, and thus have a hard time nailing an event to a specific time and place. They also don't have the vocabulary to describe an event, and without that vocabulary, they can't create the kind of causal narrative that Peterson found at the root of a solid memory. And they don't have a greatly elaborated sense of self, which would encourage them to hoard and reconsider chunks of experience as part of a growing life-narrative.

Frail as they are, children's memories are then susceptible to a process called shredding. In our early years, we create a storm of new neurons in a part of the hippocampus called the dentate gyrus and continue to form them throughout the rest of our lives, although not at nearly the same rate. A recent study by the neuroscientists Paul Frankland and Sheena Josselyn of the Hospital for Sick Children in Toronto suggests that this process, called neurogenesis, can actually create forgetting by disrupting the circuits for existing memories.

the mother engages the child in a lively conversation about events, always passing the baton of remembering back to the child

Our memories can become distorted by other people's memories of the same event or by new information, especially when that new information is so similar to information already in storage. For instance, you meet someone and remember their name, but later meet a second person with a similar name, and become confused about the name of the first person. We can also lose our memories when the synapses that connect neurons decay from disuse. 'If you never use that memory, those synapses can be recruited for something different,' Bauer told me.

Memories are less vulnerable to shredding and disruptions as the child grows up. Most of the solid memories that we carry into the rest of our lives are formed during what's called 'the reminiscence bump', from ages 15 to 30, when we invest a lot of energy in examining everything to try to figure out who we are. The events, culture and people of that time remain with us and can even overshadow the features of our ageing present, according to Bauer. The movies were the best back then, and so was the music, and the fashion, and the political leaders, and the friendships, and the romances. And so on.

Of course, some people have more memories from early childhood than others do. It appears that remembering is partly influenced by the culture of family engagement. A 2009 study conducted by Peterson together with Qi Wang of Cornell and Yubo Hou of Peking University found that children in China have fewer of these memories than children in Canada. The finding, they suggest, might be explained by culture: Chinese people prize individuality less than North Americans and thus may be less likely to spend as much time drawing attention to the moments of an individual's life. Canadians, by contrast, reinforce recollection and keep the synapses that underlie early personal memories vibrant. Another study, by the psychologist Federica Artioli and colleagues at the University of Otago in New Zealand in 2012, found that young adults from Italian extended families had earlier and denser memories than those from Italian nuclear families, presumably as a result of more intense family reminiscence.

But it doesn't necessarily take a crowd of on-site relatives to enhance a child's recollection. Bauer's research also points to 'maternal deflections of conversation', meaning that the mother (or another adult) engages the child in a lively conversation about events, always passing the baton of remembering back to the child and inviting him or her to contribute to the story. 'That kind of interaction contributes to the richness of memory over a long period of time,' Bauer told me. 'It doesn't predict whether a given event will be remembered, but it builds a muscle. The child learns how to have memories and understands what part to share. Over the course of these conversations, the child learns how to tell the story.'

Borrowing Bauer's Jello-O analogy, I've always suspected that my mother had a tinier hole in her Jell-O mould than mine, which allowed her to retain information until it was set into memory. She seemed to remember everything from my childhood, from my siblings' childhoods, and from her own first six years. Intensely, she recalled the fight between her mother and father, when her mother wound up getting knocked out cold and her father forced her to tell visiting neighbours that his wife was sleeping. The day my grandmother packed up my mother and her sister and moved them from Nebraska to Nevada, with their unwanted household goods strewn across their lawn for the townspeople to pick through and haggle over. The day the doctor took out my mother's appendix on the kitchen table. The day she wet her pants at school and the nuns made her walk home in weather so cold that her underwear froze. I wondered if her memories were so sharp because these were all terrible events, especially compared with my presumably bland early years.

I now suspect that my mother's ability to tell the story of her early life also came from the constellation of people clustered at the centre of it. Her young mother, bolting from a marriage she was pressured into and retreating to her brother's crowded house, her two girls held close. And her sister, three years older, always the point and counterpoint, the question and response. My mother and her sister talked their lives over to such an extent that it must have seemed as if things didn't really happen unless they had confided them to each other. Thus, 'Don't tell Aunt Helen!' was whispered in our house when something went wrong, echoed by 'Don't tell Aunt Kathleen!' in our cousins' house when something went amiss there.

I might have a very large hole in my Jell-O mould, but I also wonder if our family's storytelling and memory-setting apparatus had broken down by the time I came along. My brothers and sisters doted on me - I'm told this and I believe it - but it was their job to be out in the world riding horses and playing football and winning spelling bees and getting into various kinds of trouble, not talking to the baby. And sometime between my being born and my siblings leaving, our mother suffered a breakdown that plunged her into 20 years of depression and agoraphobia. She could go to the grocery store only with my father close to her side, steering the cart, list in hand. Even when she went to the beauty salon to have her hair cut and styled and sprayed into submission, my father sat next to her reading his Wall Street Journal as she cured under one of those bullet-head dryers. When we were home, she spent a lot of time in her room. No one really knows when my mother's sadness and retreat from the world began - and she's not around to tell us now - but it might have started when I was very young. What I remember is silence.

Our first three to four years are the maddeningly, mysteriously blank opening pages to our story of self. As Freud said, childhood amnesia 'veils our earliest youth from us and makes us strangers to it'. During that time, we transition from what my brother-in-law calls 'a loaf of bread with a nervous system' to sentient humans. If we can't remember much of anything from those years - whether abuse or exuberant cherishing - does it matter what actually happened? If a tree fell in the forest of our early development and we didn't have the brains and cognitive tools to stash the event in memory, did it still help shape who we are?

I don't remember, but I can choose to imagine myself on my siblings' laps as they read me stories or sang me songs

Bauer says yes. Even if we don't remember early events, they leave an imprint on the way we understand and feel about ourselves, other people, and the greater world, for better or worse. We have elaborate concepts about birds, dogs, lakes and mountains, for example, even if we can't recall the experiences that created those concepts. 'You can't remember going ice-skating with Uncle Henry, but you understand that skating and visiting relatives are fun,' Bauer explained. 'You have a feeling for how nice people are, how reliable they are. You might never be able to pinpoint how you learnt that, but it's just something you know.'

And we are not the sum of our memories, or at least, not entirely. We are also the story we construct about ourselves, our personal narrative that interprets and assigns meaning to the things we do remember and the things other people tell us about ourselves. Research by the Northwestern University psychologist Dan McAdams, author of The Redemptive Self (2005), suggests that these narratives guide our behaviour and help chart our path into the future. Especially lucky are those of us with redemptive stories, in which we find good fortune even in past adversity.

So our stories are not bald facts etched on stone tablets. They are narratives that move and morph, and that's the underpinning to much of talk therapy. And here is one uplifting aspect of ageing: our stories of self get better. 'For whatever reason, we tend to accentuate the positive things more as we age,' McAdams told me. 'We have a greater willingness or motivation to see the world in brighter terms. We develop a positivity bias regarding our memories.'

I can't make myself remember my early life with my siblings nearby and my mother before her breakdown, even if I revisit the mountain idyll where the summers of that life unfolded. But I can employ the kinder lens of ageing and the research by these memory scientists to limn a story on those blank pages that is not stained with loss.

I am by nature trusting and optimistic, traits that I've sometimes worried are signs of intellectual weakness, but I can choose to interpret them as approaches to the world developed by myriad, if unrecalled, experiences with a loving family in those early years. I don't remember, but I can choose to imagine myself on my siblings' laps as they read me stories or sang me songs or showed me the waving arms of a crawdad from that mountain lake. I can imagine myself on their shoulders, fingers twined in their curly Ohlson hair.

I can imagine them patiently feeding me the lines to The Night Before Christmas, over and over, hour after hour, day after day, because someone had to have done it - my mother told me that I could recite the whole poem when I was two years old. Not that they remember doing this, because most of them were teenagers by then and off having the kinds of encounters with people and culture that would define their sense of self for years to come. But I'll imagine and reconstruct it, both for me and for them. Because our pasts had to have had a lot of that kind of sweetness, given our lucky loving bonds today. We've just forgotten the details.

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Where do children's earliest memories go? | Aeon Essays

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Our first three years are usually a blur and we don't remember much before age seven. What are we hiding from ourselves?

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It seems that Americans are in the midst of a raging epidemic of mental illness, at least as judged by the increase in the numbers treated for it. The tally of those who are so disabled by mental disorders that they qualify for Supplemental Security Income (SSI) or Social Security Disability Insurance (SSDI) increased nearly two and a half times between 1987 and 2007-from one in 184 Americans to one in seventy-six. For children, the rise is even more startling-a thirty-five-fold increase in the same two decades. Mental illness is now the leading cause of disability in children, well ahead of physical disabilities like cerebral palsy or Down syndrome, for which the federal programs were created.

A large survey of randomly selected adults, sponsored by the National Institute of Mental Health (NIMH) and conducted between 2001 and 2003, found that an astonishing 46 percent met criteria established by the American Psychiatric Association (APA) for having had at least one mental illness within four broad categories at some time in their lives. The categories were "anxiety disorders," including, among other subcategories, phobias and post-traumatic stress disorder (PTSD); "mood disorders," including major depression and bipolar disorders; "impulse-control disorders," including various behavioral problems and attention-deficit/hyperactivity disorder (ADHD); and "substance use disorders," including alcohol and drug abuse. Most met criteria for more than one diagnosis. Of a subgroup affected within the previous year, a third were under treatment-up from a fifth in a similar survey ten years earlier.

Nowadays treatment by medical doctors nearly always means psychoactive drugs, that is, drugs that affect the mental state. In fact, most psychiatrists treat only with drugs, and refer patients to psychologists or social workers if they believe psychotherapy is also warranted. The shift from "talk therapy" to drugs as the dominant mode of treatment coincides with the emergence over the past four decades of the theory that mental illness is caused primarily by chemical imbalances in the brain that can be corrected by specific drugs. That theory became broadly accepted, by the media and the public as well as by the medical profession, after Prozac came to market in 1987 and was intensively promoted as a corrective for a deficiency of serotonin in the brain. The number of people treated for depression tripled in the following ten years, and about 10 percent of Americans over age six now take antidepressants. The increased use of drugs to treat psychosis is even more dramatic. The new generation of antipsychotics, such as Risperdal, Zyprexa, and Seroquel, has replaced cholesterol-lowering agents as the top-selling class of drugs in the US.

What is going on here? Is the prevalence of mental illness really that high and still climbing? Particularly if these disorders are biologically determined and not a result of environmental influences, is it plausible to suppose that such an increase is real? Or are we learning to recognize and diagnose mental disorders that were always there? On the other hand, are we simply expanding the criteria for mental illness so that nearly everyone has one? And what about the drugs that are now the mainstay of treatment? Do they work? If they do, shouldn't we expect the prevalence of mental illness to be declining, not rising?

These are the questions, among others, that concern the authors of the three provocative books under review here. They come at the questions from different backgrounds-Irving Kirsch is a psychologist at the University of Hull in the UK, Robert Whitaker a journalist and previously the author of a history of the treatment of mental illness called Mad in America (2001), and Daniel Carlat a psychiatrist who practices in a Boston suburb and publishes a newsletter and blog about his profession.

The authors emphasize different aspects of the epidemic of mental illness. Kirsch is concerned with whether antidepressants work. Whitaker, who has written an angrier book, takes on the entire spectrum of mental illness and asks whether psychoactive drugs create worse problems than they solve. Carlat, who writes more in sorrow than in anger, looks mainly at how his profession has allied itself with, and is manipulated by, the pharmaceutical industry. But despite their differences, all three are in remarkable agreement on some important matters, and they have documented their views well.

First, they agree on the disturbing extent to which the companies that sell psychoactive drugs-through various forms of marketing, both legal and illegal, and what many people would describe as bribery-have come to determine what constitutes a mental illness and how the disorders should be diagnosed and treated. This is a subject to which I'll return.

Second, none of the three authors subscribes to the popular theory that mental illness is caused by a chemical imbalance in the brain. As Whitaker tells the story, that theory had its genesis shortly after psychoactive drugs were introduced in the 1950s. The first was Thorazine (chlorpromazine), which was launched in 1954 as a "major tranquilizer" and quickly found widespread use in mental hospitals to calm psychotic patients, mainly those with schizophrenia. Thorazine was followed the next year by Miltown (meprobamate), sold as a "minor tranquilizer" to treat anxiety in outpatients. And in 1957, Marsilid (iproniazid) came on the market as a "psychic energizer" to treat depression.

In the space of three short years, then, drugs had become available to treat what at that time were regarded as the three major categories of mental illness-psychosis, anxiety, and depression-and the face of psychiatry was totally transformed. These drugs, however, had not initially been developed to treat mental illness. They had been derived from drugs meant to treat infections, and were found only serendipitously to alter the mental state. At first, no one had any idea how they worked. They simply blunted disturbing mental symptoms. But over the next decade, researchers found that these drugs, and the newer psychoactive drugs that quickly followed, affected the levels of certain chemicals in the brain.

Some brief-and necessarily quite simplified-background: the brain contains billions of nerve cells, called neurons, arrayed in immensely complicated networks and communicating with one another constantly. The typical neuron has multiple filamentous extensions, one called an axon and the others called dendrites, through which it sends and receives signals from other neurons. For one neuron to communicate with another, however, the signal must be transmitted across the tiny space separating them, called a synapse. To accomplish that, the axon of the sending neuron releases a chemical, called a neurotransmitter, into the synapse. The neurotransmitter crosses the synapse and attaches to receptors on the second neuron, often a dendrite, thereby activating or inhibiting the receiving cell. Axons have multiple terminals, so each neuron has multiple synapses. Afterward, the neurotransmitter is either reabsorbed by the first neuron or metabolized by enzymes so that the status quo ante is restored. There are exceptions and variations to this story, but that is the usual way neurons communicate with one another.

When it was found that psychoactive drugs affect neurotransmitter levels in the brain, as evidenced mainly by the levels of their breakdown products in the spinal fluid, the theory arose that the cause of mental illness is an abnormality in the brain's concentration of these chemicals that is specifically countered by the appropriate drug. For example, because Thorazine was found to lower dopamine levels in the brain, it was postulated that psychoses like schizophrenia are caused by too much dopamine. Or later, because certain antidepressants increase levels of the neurotransmitter serotonin in the brain, it was postulated that depression is caused by too little serotonin. (These antidepressants, like Prozac or Celexa, are called selective serotonin reuptake inhibitors (SSRIs) because they prevent the reabsorption of serotonin by the neurons that release it, so that more remains in the synapses to activate other neurons.) Thus, instead of developing a drug to treat an abnormality, an abnormality was postulated to fit a drug.

That was a great leap in logic, as all three authors point out. It was entirely possible that drugs that affected neurotransmitter levels could relieve symptoms even if neurotransmitters had nothing to do with the illness in the first place (and even possible that they relieved symptoms through some other mode of action entirely). As Carlat puts it, "By this same logic one could argue that the cause of all pain conditions is a deficiency of opiates, since narcotic pain medications activate opiate receptors in the brain." Or similarly, one could argue that fevers are caused by too little aspirin.

But the main problem with the theory is that after decades of trying to prove it, researchers have still come up empty-handed. All three authors document the failure of scientists to find good evidence in its favor. Neurotransmitter function seems to be normal in people with mental illness before treatment. In Whitaker's words:

Prior to treatment, patients diagnosed with schizophrenia, depression, and other psychiatric disorders do not suffer from any known "chemical imbalance." However, once a person is put on a psychiatric medication, which, in one manner or another, throws a wrench into the usual mechanics of a neuronal pathway, his or her brain begins to function... abnormally.

Carlat refers to the chemical imbalance theory as a "myth" (which he calls "convenient" because it destigmatizes mental illness), and Kirsch, whose book focuses on depression, sums up this way: "It now seems beyond question that the traditional account of depression as a chemical imbalance in the brain is simply wrong." Why the theory persists despite the lack of evidence is a subject I'll come to.

Do the drugs work? After all, regardless of the theory, that is the practical question. In his spare, remarkably engrossing book, The Emperor's New Drugs, Kirsch describes his fifteen-year scientific quest to answer that question about antidepressants. When he began his work in 1995, his main interest was in the effects of placebos. To study them, he and a colleague reviewed thirty-eight published clinical trials that compared various treatments for depression with placebos, or compared psychotherapy with no treatment. Most such trials last for six to eight weeks, and during that time, patients tend to improve somewhat even without any treatment. But Kirsch found that placebos were three times as effective as no treatment. That didn't particularly surprise him. What did surprise him was the fact that antidepressants were only marginally better than placebos. As judged by scales used to measure depression, placebos were 75 percent as effective as antidepressants. Kirsch then decided to repeat his study by examining a more complete and standardized data set.

The data he used were obtained from the US Food and Drug Administration (FDA) instead of the published literature. When drug companies seek approval from the FDA to market a new drug, they must submit to the agency all clinical trials they have sponsored. The trials are usually double-blind and placebo-controlled, that is, the participating patients are randomly assigned to either drug or placebo, and neither they nor their doctors know which they have been assigned. The patients are told only that they will receive an active drug or a placebo, and they are also told of any side effects they might experience. If two trials show that the drug is more effective than a placebo, the drug is generally approved. But companies may sponsor as many trials as they like, most of which could be negative-that is, fail to show effectiveness. All they need is two positive ones. (The results of trials of the same drug can differ for many reasons, including the way the trial is designed and conducted, its size, and the types of patients studied.)

Edward Gorey Charitable Trust

For obvious reasons, drug companies make very sure that their positive studies are published in medical journals and doctors know about them, while the negative ones often languish unseen within the FDA, which regards them as proprietary and therefore confidential. This practice greatly biases the medical literature, medical education, and treatment decisions.

Kirsch and his colleagues used the Freedom of Information Act to obtain FDA reviews of all placebo-controlled clinical trials, whether positive or negative, submitted for the initial approval of the six most widely used antidepressant drugs approved between 1987 and 1999-Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor. This was a better data set than the one used in his previous study, not only because it included negative studies but because the FDA sets uniform quality standards for the trials it reviews and not all of the published research in Kirsch's earlier study had been submitted to the FDA as part of a drug approval application.

Altogether, there were forty-two trials of the six drugs. Most of them were negative. Overall, placebos were 82 percent as effective as the drugs, as measured by the Hamilton Depression Scale (HAM-D), a widely used score of symptoms of depression. The average difference between drug and placebo was only 1.8 points on the HAM-D, a difference that, while statistically significant, was clinically meaningless. The results were much the same for all six drugs: they were all equally unimpressive. Yet because the positive studies were extensively publicized, while the negative ones were hidden, the public and the medical profession came to believe that these drugs were highly effective antidepressants.

Kirsch was also struck by another unexpected finding. In his earlier study and in work by others, he observed that even treatments that were not considered to be antidepressants-such as synthetic thyroid hormone, opiates, sedatives, stimulants, and some herbal remedies-were as effective as antidepressants in alleviating the symptoms of depression. Kirsch writes, "When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree." What all these "effective" drugs had in common was that they produced side effects, which participating patients had been told they might experience.

It is important that clinical trials, particularly those dealing with subjective conditions like depression, remain double-blind, with neither patients nor doctors knowing whether or not they are getting a placebo. That prevents both patients and doctors from imagining improvements that are not there, something that is more likely if they believe the agent being administered is an active drug instead of a placebo. Faced with his findings that nearly any pill with side effects was slightly more effective in treating depression than an inert placebo, Kirsch speculated that the presence of side effects in individuals receiving drugs enabled them to guess correctly that they were getting active treatment-and this was borne out by interviews with patients and doctors-which made them more likely to report improvement. He suggests that the reason antidepressants appear to work better in relieving severe depression than in less severe cases is that patients with severe symptoms are likely to be on higher doses and therefore experience more side effects.

To further investigate whether side effects bias responses, Kirsch looked at some trials that employed "active" placebos instead of inert ones. An active placebo is one that itself produces side effects, such as atropine-a drug that selectively blocks the action of certain types of nerve fibers. Although not an antidepressant, atropine causes, among other things, a noticeably dry mouth. In trials using atropine as the placebo, there was no difference between the antidepressant and the active placebo. Everyone had side effects of one type or another, and everyone reported the same level of improvement. Kirsch reported a number of other odd findings in clinical trials of antidepressants, including the fact that there is no dose-response curve-that is, high doses worked no better than low ones-which is extremely unlikely for truly effective drugs. "Putting all this together," writes Kirsch,

leads to the conclusion that the relatively small difference between drugs and placebos might not be a real drug effect at all. Instead, it might be an enhanced placebo effect, produced by the fact that some patients have broken [the] blind and have come to realize whether they were given drug or placebo. If this is the case, then there is no real antidepressant drug effect at all. Rather than comparing placebo to drug, we have been comparing "regular" placebos to "extra-strength" placebos.

That is a startling conclusion that flies in the face of widely accepted medical opinion, but Kirsch reaches it in a careful, logical way. Psychiatrists who use antidepressants-and that's most of them-and patients who take them might insist that they know from clinical experience that the drugs work. But anecdotes are known to be a treacherous way to evaluate medical treatments, since they are so subject to bias; they can suggest hypotheses to be studied, but they cannot prove them. That is why the development of the double-blind, randomized, placebo-controlled clinical trial in the middle of the past century was such an important advance in medical science. Anecdotes about leeches or laetrile or megadoses of vitamin C, or any number of other popular treatments, could not stand up to the scrutiny of well-designed trials. Kirsch is a faithful proponent of the scientific method, and his voice therefore brings a welcome objectivity to a subject often swayed by anecdotes, emotions, or, as we will see, self-interest.

Whitaker's book is broader and more polemical. He considers all mental illness, not just depression. Whereas Kirsch concludes that antidepressants are probably no more effective than placebos, Whitaker concludes that they and most of the other psychoactive drugs are not only ineffective but harmful. He begins by observing that even as drug treatment for mental illness has skyrocketed, so has the prevalence of the conditions treated:

The number of disabled mentally ill has risen dramatically since 1955, and during the past two decades, a period when the prescribing of psychiatric medications has exploded, the number of adults and children disabled by mental illness has risen at a mind-boggling rate. Thus we arrive at an obvious question, even though it is heretical in kind: Could our drug-based paradigm of care, in some unforeseen way, be fueling this modern-day plague?

Moreover, Whitaker contends, the natural history of mental illness has changed. Whereas conditions such as schizophrenia and depression were once mainly self-limited or episodic, with each episode usually lasting no more than six months and interspersed with long periods of normalcy, the conditions are now chronic and lifelong. Whitaker believes that this might be because drugs, even those that relieve symptoms in the short term, cause long-term mental harms that continue after the underlying illness would have naturally resolved.

The evidence he marshals for this theory varies in quality. He doesn't sufficiently acknowledge the difficulty of studying the natural history of any illness over a fifty-some-year time span during which many circumstances have changed, in addition to drug use. It is even more difficult to compare long-term outcomes in treated versus untreated patients, since treatment may be more likely in those with more severe disease at the outset. Nevertheless, Whitaker's evidence is suggestive, if not conclusive.

If psychoactive drugs do cause harm, as Whitaker contends, what is the mechanism? The answer, he believes, lies in their effects on neurotransmitters. It is well understood that psychoactive drugs disturb neurotransmitter function, even if that was not the cause of the illness in the first place. Whitaker describes a chain of effects. When, for example, an SSRI antidepressant like Celexa increases serotonin levels in synapses, it stimulates compensatory changes through a process called negative feedback. In response to the high levels of serotonin, the neurons that secrete it (presynaptic neurons) release less of it, and the postsynaptic neurons become desensitized to it. In effect, the brain is trying to nullify the drug's effects. The same is true for drugs that block neurotransmitters, except in reverse. For example, most antipsychotic drugs block dopamine, but the presynaptic neurons compensate by releasing more of it, and the postsynaptic neurons take it up more avidly. (This explanation is necessarily oversimplified, since many psychoactive drugs affect more than one of the many neurotransmitters.)

With long-term use of psychoactive drugs, the result is, in the words of Steve Hyman, a former director of the NIMH and until recently provost of Harvard University, "substantial and long-lasting alterations in neural function." As quoted by Whitaker, the brain, Hyman wrote, begins to function in a manner "qualitatively as well as quantitatively different from the normal state." After several weeks on psychoactive drugs, the brain's compensatory efforts begin to fail, and side effects emerge that reflect the mechanism of action of the drugs. For example, the SSRIs may cause episodes of mania, because of the excess of serotonin. Antipsychotics cause side effects that resemble Parkinson's disease, because of the depletion of dopamine (which is also depleted in Parkinson's disease). As side effects emerge, they are often treated by other drugs, and many patients end up on a cocktail of psychoactive drugs prescribed for a cocktail of diagnoses. The episodes of mania caused by antidepressants may lead to a new diagnosis of "bipolar disorder" and treatment with a "mood stabilizer," such as Depokote (an anticonvulsant) plus one of the newer antipsychotic drugs. And so on.

Some patients take as many as six psychoactive drugs daily. One well- respected researcher, Nancy Andreasen, and her colleagues published evidence that the use of antipsychotic drugs is associated with shrinkage of the brain, and that the effect is directly related to the dose and duration of treatment. As Andreasen explained to The New York Times, "The prefrontal cortex doesn't get the input it needs and is being shut down by drugs. That reduces the psychotic symptoms. It also causes the prefrontal cortex to slowly atrophy."*

Getting off the drugs is exceedingly difficult, according to Whitaker, because when they are withdrawn the compensatory mechanisms are left unopposed. When Celexa is withdrawn, serotonin levels fall precipitously because the presynaptic neurons are not releasing normal amounts and the postsynaptic neurons no longer have enough receptors for it. Similarly, when an antipsychotic is withdrawn, dopamine levels may skyrocket. The symptoms produced by withdrawing psychoactive drugs are often confused with relapses of the original disorder, which can lead psychiatrists to resume drug treatment, perhaps at higher doses.

Unlike the cool Kirsch, Whitaker is outraged by what he sees as an iatrogenic (i.e., inadvertent and medically introduced) epidemic of brain dysfunction, particularly that caused by the widespread use of the newer ("atypical") antipsychotics, such as Zyprexa, which cause serious side effects. Here is what he calls his "quick thought experiment":

Imagine that a virus suddenly appears in our society that makes people sleep twelve, fourteen hours a day. Those infected with it move about somewhat slowly and seem emotionally disengaged. Many gain huge amounts of weight-twenty, forty, sixty, and even one hundred pounds. Often their blood sugar levels soar, and so do their cholesterol levels. A number of those struck by the mysterious illness-including young children and teenagers-become diabetic in fairly short order.... The federal government gives hundreds of millions of dollars to scientists at the best universities to decipher the inner workings of this virus, and they report that the reason it causes such global dysfunction is that it blocks a multitude of neurotransmitter receptors in the brain-dopaminergic, serotonergic, muscarinic, adrenergic, and histaminergic. All of those neuronal pathways in the brain are compromised. Meanwhile, MRI studies find that over a period of several years, the virus shrinks the cerebral cortex, and this shrinkage is tied to cognitive decline. A terrified public clamors for a cure.

Now such an illness has in fact hit millions of American children and adults. We have just described the effects of Eli Lilly's best-selling antipsychotic, Zyprexa.

If psychoactive drugs are useless, as Kirsch believes about antidepressants, or worse than useless, as Whitaker believes, why are they so widely prescribed by psychiatrists and regarded by the public and the profession as something akin to wonder drugs? Why is the current against which Kirsch and Whitaker and, as we will see, Carlat are swimming so powerful? I discuss these questions in Part II of this review.
-This is the first part of a two-part article.

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It seems that Americans are in the midst of a raging epidemic of mental illness, at least as judged by the increase in the numbers treated for it. Are we learning to recognize and diagnose mental disorders that were always there?

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There is a widely held belief in this country (and many others) that if we start teaching children to read, write, and spell in preschool and kindergarten that they will be ahead of the game (and their peers) by first grade. We think that pushing our kids to start early will make them better and give them the edge.

But it doesn't work that way, in fact it can be detrimental.

Here's why...

Children's neurological pathways for reading, writing, and spelling are not formed yet at these young ages, therefore they are not equipped. In child development you can not miss, shortcut, or rush steps, it just doesn't work.

Between 3 and 7 years old, predominantly the right side of the brain is developing. The right side of the brain is not where word reading takes place. The right side sees pictures and shapes and uses mental imagery to create the movie in their mind to understand the story. The left side of the brain is where we read words, it is responsible for decoding words into letters and phonetically sounding them out. This is true word reading. It is not until about age 7 that the corpus callosum fully connects the left and right hemispheres of the brain to make reading complete for kids.

By making children read when they really only have access to the right side of their brain, they are forced to memorize what words look like by shape and guess, opposed to being able to sound them out. Not true reading. Also, when kids are focused on memorizing what the words look like by shape, they are not using their right brain to create the movie in their mind, leading to low comprehension.

What you might not know is that developing a strong sense of balance and proprioception (knowing where your body is), is a mandatory precursors to being a strong learner and student. Balance and proprioception are achieved through play, movement, and experiencing your surroundings, not through sitting still reading.

Don't get me wrong, I think being a good reader and spending lots of time reading is . Reading ability is probably the most important learned skill in our society. But the path to learning to read is counter-intuitive, the earlier we start them the harder it may be for them to achieve the skill of effortless reading needed to excel in school.

Slow down. Let them use their body, play lots of games that require balance, help your child develop their balance and a sense of where their body starts and stops. Also, spend lots of time reading to them . Read to them so they can practice mental imagery in a relaxed environment. By reading to them, especially nursery rhymes, they train their ears to hear the slight differences in words, which is very important later when they are phonetically learning letters, sounding out words, and decoding words for spelling. (TV and videos can't give this to them.)

Until you have worked on this, your efforts for mastery in reading, writing, and spelling will be in frustration.

Cheers,

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There is a widely held belief in this country (and many others) that if we start teaching children to read, write, and spell in preschool and kindergarten that they will be ahead of the game (and their peers) by first grade. We think that pushing our kids to start early will make them better and give them the edge.