One way to distinguish the effects of nature from nurture would be to look at brain regions believed by neuro-anatomists to be fully formed at birth and impervious to subsequent environmental effects, both physical and psychological. Focusing on such brain regions, a research team at the Karolinska Institute in Stockholm, Sweden, headed by neuroscientist Ivanka Savic, obtained MRIs for 90 adult volunteers — 25 straight men, 25 straight women, 20 gay men and 20 lesbians. Using the latest quantitative techniques for assessing cerebral symmetry and functional connections between various areas of brain, Savic was able to demonstrate highly statistically significant differences between straight and gay brains. Gay and lesbian brains more closely resembled the brains of straight volunteers of the opposite sex than the brains of heterosexual members of the same sex.

In their study, reported in the June 16, 2008, issue of the Proceedings of the National Academy of Sciences, Savic said, “This is the most robust measure so far of cerebral differences between homosexual and heterosexual subjects.” Although Savic admits that her study cannot distinguish between genetic or prenatal intrauterine environmental changes, such as relative differences in sex hormone levels, her studies do suggest that our sexual preferences are, at least in large part, determined by the time of birth.

Not long after reading the study, I got a call from neurologist Jerome Goldstein, M.D., 67, once a fellow resident in the UCSF neurology training program. This fall, Goldstein, an internationally respected headache researcher and sometimes controversial gay activist, is giving a series of lectures on the innate biology of gayness. He was phoning to ask if I had seen the study and if I might write about the latest scientific evidence supporting the biology of gayness. I decided to interview him instead. Goldstein is compact, rapid-talking and constantly on the verge of impatience. Yet during our conversations he was subdued, confessional in tone, with frequent pauses to gather his thoughts; the seriousness of his concerns was palpable.

Jerry, you’ve been an outspoken gay activist for 40-plus years. Why the sudden interest in the biology of sexual orientation?

I was aware that I was attracted to men by age 8, even though I did not have any gay sexual experiences until I was 19. Meanwhile, despite having no sex or even a clear understanding of what homosexuality meant, virtually everyone that I encountered, including my dear parents, made a point of telling me that homosexuality was dirty, sinful and a phase that would pass.

Beginning my sophomore year in college, and before my first gay experience, I began the endless rounds of psychiatrists and counselors. I even tried to modify my behavior to make it acceptable. Sadly, even though I now know better, and am fully aware of the overwhelming evidence as to the underlying neurobiologic predisposition to gayness, I have never been able to entirely shake this feeling of guilt and wrongdoing. Future generations should be spared. Right now, I’m interested in seeing that good science prevails over outdated, misguided psychology and false-headed thinking that homosexuality is a conscious choice.

Do you think people accept that homosexuality arises out of biological predispositions?

Only on the surface. Down deep, there’s a lingering suspicion that, even if the cause is biological, there is something intrinsically wrong with being gay. It has been 35 years since homosexuality was removed from a psychiatric diagnostic category and we [still] don’t see the changes in the way people think. Sadly, even our major neurological societies haven’t taken a serious look at the biology of sexual orientation. For example, when was the last time that you saw the American Academy of Neurology even address the subject? And the general public? Just listen to right-wing talk show hosts offering to pray for my sins. Or look at the damage caused by the religious right and its “conversion therapy,” which attempts to alter an inborn characteristic of human behavior. I don’t want pity and sympathy, I want scientific understanding based on logic and reason.

Could you give me a brief rundown of what you think is the most compelling evidence supporting the biology of gayness?

Keep in mind that sexual orientation is exceedingly complex and not reducible to a single gene or hormonal aberration, or explained by demonstrable anatomic brain differences. But by examining multiple lines of evidence, you can begin to connect the dots as to how biology influences sexual preferences. With these caveats in mind, let’s look at the history leading up to the present functional imaging studies.

In 1991, Simon LeVay, formerly a professor of neuroscience at Harvard and the Salk Biological Institute, claimed to have discovered specific anatomic differences between gay and straight brains, primarily in a region of the hypothalamus believed to have a major influence on sexual behavior. By the way, this region’s fetal development is greatly influenced by the levels of intrauterine testosterone, a major reason why intrauterine shifts of sex hormone levels are thought by some researchers to contribute to sexual preference.

But LeVay’s work was considered controversial, nonreproducible, and part of a gay political agenda. The real take-away was the promise that neuroscience might one day offer better insights into the origins of homosexuality.

At the same time, there were a variety of quasi-scientific studies claiming to uncover markers for “gay tendencies.” One suggested that you could tell whether or not you’re gay by whether your hair whorl — that patch of hair on the crown of your head — curled clockwise or counterclockwise. Another suggested that you could tell by the relative symmetry of your second and fourth digits. Those studies weren’t exactly good science and certainly didn’t make the biology of sexual orientation an attractive area for basic research funding.

Early genetic studies also ran into major criticisms. In the early ’90s, Dean Hamer of the National Cancer Institute raised the possibility of “a gay gene.” His studies met the same criticisms asserting that that single genes don’t cause complex behavior. On a YouTube video, Hamer denies the idea of a single gene for gayness.

But what has emerged from the genetic approach is incontrovertible evidence that sexual preference runs in families. Several independent large-scale studies show that a man with a gay identical twin brother will have between a 33 and 52 percent chance of being gay — a rate far higher than is seen in the general population. But even here, one could argue that half to two-thirds of genetically similar twins will not have the same sexual orientation. Naysayers have used this fact as evidence that, even in the face of similar genetics, each of us retains the ability to consciously choose and control our sexual preferences.

Of course, this is a ridiculous argument. Genes can be variably expressed, depending upon environmental factors. And no one is saying that genes are the sole cause of sexual behavior; nongenetic factors are likely to also play a major role. It’s entirely conceivable that identical twins with a similar genetic predisposition for homosexuality but exposed to different intrauterine testosterone levels will end up with different sexual orientations.

Let’s talk about your take on the new brain-imaging studies.

Begin with Dr. Savic’s work on pheromones. It’s fairly common knowledge that, throughout the animal kingdom, sniffing chemicals secreted by other members of the same species — pheromones — can invoke innate behaviors such as a flight response in aphids, aggression in bees, trail marking in ants. We forgive our pet cat for marking our favorite couch as “her territory.” All of these are basic survival techniques with clear evolutionary benefits. Ditto for chemicals involved in “being in heat.”

What’s fascinating about Savic and her colleagues’ study was their ability to test the role of pheromones in identifying human sexual orientation. Functional imaging studies or PET scans of heterosexual controls were compared with a group of gay and lesbian volunteers. All subjects were asked to sniff gender-specific sex-hormone-like compounds: AND for the androgen-like pheromones secreted by males and EST for the estrogen-like pheromones secreted by females.

To enhance normal reproduction, you’d expect that males would be attracted to EST and females to AND. But Savic found that these self-declared gays and lesbians process these pheromones differently than their heterosexual counterparts. When exposed to the male pheromone AND, homosexual men tended to respond similarly to heterosexual women, both in brain location and degree of activation. On the other hand, gay women responded to EST similarly to straight men. In short, it looks as though straight men and gay women processed similarly while the converse is true for straight women and gay men.

But her pheromone study still doesn’t answer the nature-nurture question. These PET scan differences could reflect the consequences of a behavior rather than necessarily being indicative of the cause of the behavior.

But that’s what makes her study so important, and allows her to draw the most important conclusion — that sexual orientation is determined prior to exposure to life’s environmental influences. Savic has assured me that these findings aren’t “learned” but rather reflect either genetic or intrauterine developmental differences. And, unlike some of the early researchers, Savic can’t be accused of having a gay political agenda or bias. Her field was originally epilepsy research. She inadvertently stumbled onto the pheromone sex differences while studying how smells might trigger temporal lobe epilepsy.

You’ve seen the studies. How impressive are the differences?

There are obvious-to-the-naked-eye differences in cerebral symmetry and in the functional connections in various portions of the limbic system, including the differing degrees of connectivity between amygdala and other brain regions critical for emotional responsiveness. It’s as though you can actually see the brain changes that most gays have always suspected; and, believe me, it’s a great relief to realize that these findings are clearly present at birth and aren’t anyone’s “fault.” They simply are [present] in the same way that one has blue eyes or red hair. No more and no less.

As with all functional-brain-imaging studies, there is the very real problem of interpretation. Is it possible that the Savic studies are less than conclusive?

I’ve read some of the critiques. But to me, the statistical significance of her studies is beyond question. As to absolute proof, only time will tell.

In thinking about sexual orientation as a choice, isn’t there also the problem of how unconscious biological traits affect conscious decisions?

Of course. In a way, choosing a sex partner is like choosing what you eat; it might feel like a choice, but biology plays a major, though unconscious, role.

I presume that you are alluding to the recent studies of the genetics of taste?

Yes. Take our ability to taste bitterness. A single gene, isolated in 2003, determines whether or not foods such as Brussels sprouts are experienced as bitter. Remember how our parents insisted that we could learn to like Brussels sprouts; if we didn’t, we were accused of being finicky eaters, or worse. Now, we would be sent for genetic testing.

Are you equating homosexuality with a taste for Brussels sprouts?

Very interesting and funny. But sex is much more complex and emotionally charged as a point of discussion than taste. But yes, in a larger sense, genetics helps determine the shape of desire.

Are you suggesting that outside influences — parental, peer group and general cultural — aren’t important in determining our sexual preferences?

Not entirely. I’m saying that these influences are far less potent than the biological. Certainly there are a variety of strictly environmental circumstances, such as long-term prison incarceration, that might trigger homosexual behavior. But then you run into the reverse argument. Given that lots of men are confined to prison, only some end up with homosexual behavior. Perhaps these circumstances still reflect a combination of biology and environment. Right now, all bets are off.

There is the additional problem that you discussed at length in your recent book, “On Being Certain,” namely, how conscious decisions can be affected by unconscious biological mechanisms. The same biology that affects our sexual desires may also affect how we consciously think about these desires.

In a separate study (PDF), Savic has shown that differential responses to pheromones even affect how we determine the relative masculinity or femininity of facial images. Savic presented male volunteers with a series of facial images and asked them to rate the faces on a scale of masculine to feminine. When inhaling a masculine pheromone, the volunteers perceived the faces to be more masculine than when they were exposed to estrogen-like pheromones.

What’s so intriguing about this study is that it shows how simple chemicals can actually affect our visual perception of gender. It’s not a great leap of imagination to see how these same chemicals might influence whether an adolescent male chooses to read a muscle magazine or Playboy.

Do you think these studies can help counter fundamentalist arguments that homosexuality is evil?

Accepting sexual preference as an innate characteristic is an essential first step. But this sidesteps the more deep-seated gut sense that homosexuality isn’t natural and goes against the laws of nature. This argument can be partially defused by recognizing how ubiquitous homosexual behavior is in the animal kingdom — starting with the lowliest fruit fly. I’m sure you’re aware that there is a single gene, which, in the fruit fly, can turn on and off homosexual behavior.

But in the end, I suspect that real acceptance will only come about when we have a much more comprehensive view of how the mind works, including how we make conscious choices versus how much of our apparent willfulness arises out of involuntary biological mechanisms.

The popular glucosamine is only a tip of the complementary and alternative medicine (CAM) iceberg. Health-conscious consumers now spend more than $30 billion a year on CAM therapies. But as a growing body of medical research and the convincing recent book, “Snake-Oil Science: The Truth About Complementary and Alternative Medicine,” by R. Barker Bausell, former research director of the National Institutes of Health-funded National Center for Complementary and Alternative Medicine, point out, the primary benefit of CAM therapies is a result of placebo.

Before jumping to the conclusion that I’m on the anti-CAM bandwagon, be assured that the placebo effect is equally prominent in conventional medical therapy. Consider the previously well-accepted surgical procedure for incapacitating wear-and-tear osteoarthritis of the knee — removal of the bony spurs and degenerated cartilage.

In a landmark 2002 study of 180 patients with demonstrable knee osteoarthritis, patients who had “sham” arthroscopic surgery (general anesthesia was given and superficial incisions were made in the skin, but no actual surgical repair was performed) reported as much pain relief and improved mobility as patients who underwent the actual procedure. At the time of the study, more than 650,000 knee operations had been performed annually at a cost of $5,000 each.

In other words, billions were spent on a surgical procedure that hadn’t undergone a decent controlled study against placebo — the same criticism often leveled by CAM skeptics. At least glucosamine doesn’t have the known serious side effects associated with unnecessary surgery.

The placebo effect has maddened the medical world for generations. But recent advances in brain imaging emphasize for me that “placebo” should not be regarded a dirty word. In fact, it is time to give placebo a new image and update its beneficial role in our modern medical armamentarium.

Folk psychology tells us that the placebo effect is, in large part, a function of patient suggestibility and that some of us are clearly more suggestible than others. For centuries, physicians have handed out inert colored water and sugar pills with the full knowledge that approximately a third of their patients will report feeling better. We assume that the degree of response is somehow a reflection of the psychological state of the patient — the greater the degree of gullibility, the more likely he or she is to believe that a sugar pill will relieve aches and pains. But there’s an unanticipated side effect of this assumption.

Attributing the placebo effect to gullibility is a subtle accusation of a patient’s weakness and lack of sophistication. I suspect that many of us consciously or unconsciously look down upon those who are good placebo responders, as though you have to be a real dummy to believe everything the doctor tells or gives you.

But placebo serves a very real evolutionary function. At a time when there were no medicines, the placebo effect was all that stood between primitive humans and the agonies of injuries and illnesses. A look at the functional imaging scans shows how truly robust are the involved brain systems. These systems are here to stay. Even given our advanced state of medical knowledge, much of routine medical care — from treating backaches to the common cold — relies primarily upon reassurance and hope, not disease-specific treatments.

Given the choice, we’d all prefer to be placebo responders, though none of us want to be categorized as rubes. We complain about not getting enough quality time with our doctors, yet would never dream of directly asking for a prescription for a placebo. Instead, if we believe in conventional (allopathic) medicine, we might ask for an antibiotic for the common cold, with the rationale that, yes, it’s only a virus, but perhaps the antibiotic will help. If we are inclined toward alternative medical treatments, we will plunk down a few bucks for a bottle of echinacea or a pack of zinc lozenges. To the extent that we feel better, we have invoked the placebo effect.

Keep in mind that whenever there is no specific well-substantiated treatment for a condition, the only alternative to glum acceptance and the proverbial stiff upper lip is to seek out a placebo. But don’t tell us it’s a placebo. Don’t even hint that we are self-deluded suckers who might spring for a case of snake oil or a six-pack of eye of newt. Just as religion softens the blow of facing death, placebo softens the blow of facing life.

It’s no wonder that CAM is so popular. In her recent book, “The Cure Within: A History of Mind-Body Medicine,” Harvard chairwoman of history of science Anne Harrington outlines the various narratives that have historically contributed to the placebo response’s role in CAM. She points out that the belief in positive thinking and maintaining personal self-control push us into making our own health choices, irrespective of their scientific validity.

She also emphasizes another increasingly popular Western narrative — the “broken by modern life” tale of woe, anger and rebellion. It cannot be overstated that a medical system that feels and appears unfriendly will be abandoned in favor of one that does not, even if the supporting evidence isn’t there. The urge for comfort is greater than an insistence upon objectivity. Even if glucosamine isn’t demonstrably helpful for garden-variety arthritis, it will be a bestseller until a real treatment is found.

Again and again, the same problem applies to conventional medicine. Even some of the best-designed trials run headlong into the hidden power of the placebo. Consider the data from a 2002 review of trials on the six leading antidepressants, including Prozac, Zoloft and Effexor. Of the 47 trials, 27 showed the antidepressants to have no greater benefit than the placebo control group. According to the lead author, Irving Kirsch of the University of Connecticut, the remaining 20 showed improvements of dubious clinical significance.

In fact, evaluating any new treatment for a condition that must be subjectively evaluated — pain, mood change, quality of life — runs into the same problem. Whether looking at drugs for attention-deficit hyperactivity disorder or for mental illnesses such as bipolar disorder and schizophrenia, or simply determining if a drug can modify the behavioral manifestations of Alzheimer’s disease, we are at the mercy of how to adequately contain and measure the placebo effect — an impossibly complex task with serious ethical implications.

To get a sense of how far off-base our ideas about placebo often are, consider the latest deliciously amusing if it weren’t so serious controversy. Not long ago, a chewable, cherry-flavored dextrose tablet, Obecalp (placebo spelled backward), went on sale online; bottles of 50 tablets sell for $5.95. The manufacturer clearly explains that the pills are inert. The rationale of the developer for offering commercial placebo tablets for children is “to empower parents to do something tangible for minor ills and reduce the unnecessary use of antibiotics and other medicines,” as the New York Times reported. Needless to say, there has been a great deal of concern about the ethics of marketing medical deception to children, including teaching children that pills can be the solution for whatever ails them.

No matter how you feel about such products, you have to tip your hat to the utter ingenuity of the marketers who are knowingly pushing an inert pill that has an already-proven effect. The truth is, many of the standard ailments of childhood, such as the cough associated with the common cold, have a decent placebo response rate. In attempting to boycott the sale of placebos for children, the opposition has, inadvertently, with tortured logic worthy of Alice in Wonderland, revealed how poorly understood the placebo effect can be.

For instance, according to Daniel Fabricant, science and regulatory affairs vice-president at the Washington, D.C.-based Natural Products Association, “This is not a lawfully marketed product, and it shouldn’t be on the shelves at all. By calling a product a placebo you are indicating that you’re treating something. It is consumer fraud.”

But ask the approximately 30 percent of those who will respond to the sugar pills if the treatment is a fraud or a “real” benefit. At the heart of the widely held misunderstanding of the placebo effect is that the benefits are “imaginary,” as opposed to “real.” I’ve put imaginary and real in quotes to indicate the folly of discussing subjective benefits as though they don’t count if they can’t be objectively observed. Subjective improvement is still real improvement.

To clarify this point, let’s look at a couple of studies on the biological effects of inert substances. To date, the most robust and best-studied placebo effect is its ability to reduce pain. In a classic study from University of California at San Francisco dental school in the late ’70s, postoperative dental surgery patients were given either I.V. saline or morphine for pain relief. Those receiving saline after being told that the injection was a new, powerful analgesic achieved the same level of relief as those receiving morphine. The tentative conclusion was that the placebo effect worked by triggering the release of the brain’s own (endogenous) opiatelike hormones (endorphins) that reduce pain levels.

Recent functional brain imaging by University of Michigan researchers, headed by neuroscientist Jon-Kar Zubieta, has confirmed this finding. Their model is straightforward. Healthy young volunteers agreed to receive a painful injection into a jaw muscle. Prior to the injection, the volunteers were asked to gauge how much pain reduction they would experience if they were also administered a painkiller. Would they feel a 20 percent reduction in pain? Fifty percent? Then, simultaneously, they received the painful jaw muscle injection and a painkiller injection — only the “painkiller” was a placebo — an inert saline solution.

In patients reporting pain relief, PET scans showed an activation of their opioid receptors, where both narcotics and endorphins ply their trade, and a decrease in activity in several brain regions vital for feeling pain. The scans also showed that the placebo effect isn’t confined to endorphin release; the neurotransmitter dopamine receptor sites critical for the brain’s primary reward system also lighted up.

In an elegant follow-up study, Zubieta and colleagues looked at how subject expectation of pain relief was associated with a more generalized expectation of good results. The volunteers were invited to play a game; if they won, they’d get a small monetary reward. Before playing the game, they were asked to estimate their chances of winning. The study showed that those who felt they were most likely to win were the same folks who predicted the greatest relief from their “painkiller” injection. Scans confirmed that the activation of brain reward regions correlated with both general anticipation of winning and degree of expectation of pain relief.

As a result of such imaging studies, the placebo effect is presently thought to involve several distinct but overlapping mechanisms: expectation of pain relief, direct modification of pain perception and a differential degree in reporting the actual experience of pain. In short, the placebo response is complex, with multiple brain systems and neurotransmitters orchestrating the effect.

The University of Michigan researchers conclude: “There is substantial evidence that the placebo effect has strong biological underpinnings, and that some individuals are more likely than others to demonstrate this effect.” Just watching the dopamine receptors light up in those expecting positive results raises the impossibly complex question of how much of a placebo response is related to cultural and personal narratives and how much might be due to one’s individual biology.

Already, genetic variations in dopamine receptor responsiveness have been associated with a wide variety of behaviors, such as ADHD, risk-taking behavior, even pathological gambling. If so, how one responds to the site of a needle containing a placebo injection will itself be modified by genetic differences. Just as we are beginning to understand how certain genetic populations respond differentially to various drugs, it’s likely that we will see placebo response in the same light.

Ultimately, we need a more level-headed, scientific and empathetic view of placebo. After all, we are built to seek out placebo in the same way that we try to avoid touching a hot stove or are biologically primed for lust and greed. Ironically, CAM is so hugely popular in large part because its advocates vehemently deny that CAM’s primary benefit is pure placebo effect. It is their noncritical insistence upon the specificity of their herbs, supplements, devices and manipulations that provides believers with real benefits (and real risks, ranging from cost and potential side effects to delay in the diagnosis and treatment of serious conditions). The same goes for many conventional medical therapies. Keep in mind that sham surgery made a significant percentage of arthritis sufferers feel better and that the majority of the benefits of major antidepressants can be duplicated with sugar pills augmented by the cultural belief in antidepressants as effective specific treatments.

As a matter of public policy, we should seriously debate what it means to spend such huge sums on inert conventional and alternative treatments that provide real relief. Ideally, we would have perfect specific treatments for whatever ails us. Until then, we need to reconsider how to facilitate the placebo effect with minimal risk and cost, and without deception — a paradoxical set of conditions that is unlikely to satisfy anyone. No explanation will be entirely sugarcoated, but perhaps that’s not necessary if the real sweetness is magically tucked away inside our own deviously evolved minds.

Wait a minute. Prevent Alzheimer’s disease? Is he kidding? But Sherwood is already holding up Amen’s package of DVDs on learning your risk factors for A.D., as well as his book with a section titled “Preventing Alzheimer’s.” Then, as though offering a landmark insight into a tragic disease — and encouraging viewers to pledge money to the station — Sherwood beams and says, “This is the kind of program that you’ve come to expect from PBS.”

If so, that’s a shame. One of the messages of Amen’s PBS special and his book on Alzheimer’s is that early detection of A.D. can lead to methods that both slow the progression of the disease and prevent it. But this opinion isn’t shared by the vast majority of the medical community. Despite decades of studies, there are at present no definitive long-term treatments for A.D. or its prevention, as Amen would have viewers and readers believe.

At the core of Amen’s crusade — both in print and on TV — is a type of functional brain imaging known as SPECT (single photon emission computed tomography), a radioisotope-enhanced CAT scan that measures blood flow in certain regions of the brain. Amen relies heavily on SPECT to make an early diagnosis of Alzheimer’s so that it can be prevented. But medical science does not support his view.

“SPECT scans are not sufficiently sensitive or specific to be useful in the diagnosis of A.D.,” neurologist Michael Greicius , who runs the Stanford University memory clinic, and has a special interest in the use of functional brain imaging in the diagnosis of A.D., tells me. “The PBS airing of Amen’s program provides a stamp of scientific validity to work which has no scientific validity.”

Throughout March and April this year, “Change Your Brain, Change Your Life” aired nearly 1,300 times on PBS stations across the country, reaching more than 75 percent of U.S. television households. As I was to learn after several frustrating phone calls and e-mails with PBS spokespersons, the nation’s public broadcasting system did not vet “Change Your Brain, Change Your Life” for scientific validity. As a result, it broadcast what amounts to an unregulated infomercial for Amen’s unproven treatments.

When I come across a controversial medical opinion, I try to look at how it might have arisen. Amen, who appears as a medical expert on TV news and talk shows, including CNN and Fox News, the “Today” show and “Oprah,” has not followed a traditional scientific path. He received a biology degree from Southern California College, a Pentecostal school, now Vanguard University (“We believe The Bible to be the inspired and only infallible and authoritative Word of God”), and earned his medical degree from Oral Roberts University School of Medicine, defunct as of 1989.

“One of the sustaining factors in my work has been my own personal faith,” he declared in his 2002 book, “Healing the Hardware of the Soul: How Making the Brain-Soul Connection Can Optimize Your Life, Love, and Spiritual Growth.” “From the first month that I started to order these (SPECT) scans, I felt that they had a special place in science and that I was led by God to pursue this work.”

It’s hard to dismiss the religious undertones of Amen’s work. On his Web site in 2003, he stated, “How your brain and soul work together determines how happy you feel, how successful you become, and how well you connect with others. The brain-soul connection is vastly more powerful than your conscious will. Will power falters when the physical functioning of the brain and the health of your soul fail to support your desires, as seen by illogical behaviors like overeating, smoking, drug and alcohol abuse, and compulsive spending.”

And yet Amen’s sense of calling hasn’t led him to undertake the high-quality clinical investigations that would lend scientific credence to his claims. He is a board-certified psychiatrist and assistant clinical professor at University of California at Irvine School of Medicine, as his current Web site claims. But as U.C. Irvine assistant director of health sciences communications Tom Vasich explains, the title “assistant clinical professor” is the name for an untenured volunteer faculty member, of which the U.C. Irvine School of Medicine has more than 1,000. Amen is not affiliated with the university’s Brain Imaging Center; all of his studies on SPECT scanning have been privately performed at his proprietary Amen Clinics.

To understand my concerns regarding Amen’s claims, we first need to take a quick look at A.D. and why unsubstantiated promises of prevention and treatment raise real ethical and health considerations. A.D. affects about 5 million Americans; the number will rise as our population ages. Although the disease isn’t sufficiently well-understood to assign specific causes, it’s clear that there are multiple risk factors, ranging from age to genetics, coexisting heart disease to prior serious brain injury. So far, addressing such risk factors either isn’t possible (we can’t change our genes or stop getting older), hasn’t been prospectively demonstrated to prevent A.D., or is simply part of any common-sense medical practice.

The problem remains: We have abundant information about the underlying abnormalities in A.D., but don’t know exactly how the pathology creates the illness. The brain of a patient with A.D. will show clumps of protein fragments (plaques) as well as disruption of the normal architecture of the neurons — neurofibrillary tangles. From a biochemical standpoint, there is a diminution of function of various neurotransmitters, especially acetylcholine.

To date, the mainstay of symptomatic treatment has been a class of drugs that prevents the breakdown of acetylcholine — cholinesterase inhibitors. Although they do not slow or alter the course of the disease, they can provide modest but temporary improvement in cognition and behavior, usually on the order of months to a couple years. Importantly, the American Academy of Neurology states that available medications “do not reverse or change the progression of the disease.” The NIH National Institute on Aging also warns: “It is important to understand that none of these medications stops the disease itself.”

Amen, however, claims that he can arrest the progression of the disease. In his 2004 co-authored book, “Preventing Alzheimer’s,” he writes: “Contrary to popular belief, with current medical and scientific knowledge, the onset of Alzheimer’s Disease can be delayed by six years.” He makes a more expansive claim: “Through prevention strategies, you may be able to delay the onset of Alzheimer’s long enough so that you will never have symptoms.”

Faced with the prospect of overlooking a preventable disaster, the public is a sitting duck for Amen’s medical sales pitch. And what exactly is he offering that the rest of the medical community has overlooked? He reiterates the usual common-sense recommendations: mental and physical exercise, good nutrition, avoidance of excess alcohol, not smoking and stress reduction. All of these are modestly helpful in preventing general cognitive decline. But none of them has a specific anti-Alzheimer’s effect.

The rest of his recommendations, including those gathered from his Web site and other published writings, aren’t specific evidence-based treatments for A.D., but rather a potpourri of unproven treatments, such as antioxidants and proprietary nutraceuticals.

For example, on his Web site, Amen touts NeuroMemory, a non-FDA-approved combination of folic acid and various plant extracts, including Huperzine A, a moss extract that has some anti-cholinesterase properties. The Alzheimer’s Foundation warns that such drugs are “unregulated and manufactured with no uniform standards.” Even the manufacturer issues (in small print) the following warning: “These products are not intended to diagnose, treat, cure, or prevent any diseases.” With NeuroMemory, you will be paying out-of-pocket for a non-regulated product that, at best, might turn out to have a similar temporary effect as the more rigorously controlled cholinesterase inhibitors already on the market, and routinely covered by most health insurance policies.

Other proprietary nutraceuticals for sale on his Web site also suffer from lack of good control studies. For example, Amen refers to omega-3 essential fatty acids (found in high concentrations in certain fish oils) as “brain food.” He writes that you can purchase NeuroGuppies — “ideal for children to support healthy brain development and vision” — and NeurOmega. In “Preventing Alzheimer’s,” Amen’s lead supporting evidence for the efficacy of nutraceuticals like NeuroGuppies is a 2002 British Medical Journal study in which “French researchers reported that there is a significantly lower risk of developing Alzheimer’s disease among older people who eat fish at least once a week.”

But the whole study from the British Medical Journal in 2002 reads quite differently. The lowered incidence of A.D. in those study participants who ate fish or seafood at least once a week was described as having “borderline significance.” Borderline means possibly significant, not significant, especially when you factor in that fish or seafood consumption was higher in those participants with higher education. Higher levels of education have been shown to be associated with a lower statistical risk of A.D. When the authors added the level of education to their risk model, the results “indicated that the ‘protective’ effect of weekly fish or seafood consumption was partially explained by higher education of regular consumers.” The study’s conclusion — fish consumption provided a borderline significant effect partially explained by other factors — is a far cry from proof that fish oils can help prevent A.D.

Amen makes other medically questionable recommendations, such as the use of estrogen replacement in post-menopausal women. The role of estrogen in the prevention of A.D. remains hypothetically possible but as yet unproven; clinical trials are in progress, but to date there is no definitive evidence that taking estrogen will reduce the chances of getting A.D.

In “Preventing Alzheimer’s,” Amen states that post-menopausal women “should avoid Premarin and other forms of estrogen that are not made by the human ovary. However, a severe reduction in female estrogen hormones is equally harmful and should be treated.” Amen suggests that taking the smallest amount of human estrogen that will keep estrogen (estradiol) levels from falling too low “is reasonably safe.” But how can we know that estrogen replacement, no matter how small a dose, is safe, when safety standards for estrogen replacement haven’t been established in clinical trials, and so remain controversial? Also, note Amen’s use of vague language: “smallest amount” (unspecified), “falling too low” (unspecified), “reasonably safe” (unsupported by evidence).

By cleverly wording his claims and cherry-picking his evidence, Amen has created the false impression that an earlier diagnosis of A.D. can ultimately slow down or prevent its devastating effects. The implications and potential risks of such unsubstantiated claims are very real.

If Amen were correct, consider how negligent the rest of the medical community must be in withholding such treatments. And imagine how you’d feel if you were the spouse or child of a patient devastated by A.D., and you were told by an “expert” that an earlier diagnosis might have delayed or prevented your family member’s catastrophic condition.

Even the well-standardized genetic testing for risk factors for A.D. isn’t used to diagnose A.D. in the absence of symptoms. The markers only serve as information for calculating the odds, not for making the diagnosis. Yet Amen believes that with SPECT, he can accurately identify persons with “early stage Alzheimer’s Disease up to four years before the first symptoms appear.”

However, a multi-institutional task force of neurologists and neuro-radiologists — the Neuroimaging Work Group of the Alzheimer’s Association — disagrees. Based upon their evidence-based literature review, they have concluded: “Current clinical neuro-imaging techniques are poor at predicting which non-demented individuals will develop AD or other dementias.” They also concur that the practical value of such determinations is limited in the absence of preventive therapies for A.D.

Amen’s published response is that he doesn’t rely solely upon a SPECT scan to make the diagnosis of A.D.; he also relies on clinical judgment, including memory testing. This somewhat circular argument raises the serious question of the value of a screening test that can’t stand on its own predictive merits. How are we to interpret an abnormal scan in an asymptomatic patient? At least with genetic testing, we can tell the patient the likelihood of eventually getting A.D. without resorting to subjective clinical judgment.

Amen states that he has read more than 40,000 SPECT scans and holds himself up as a world expert. But a brief quote from his TV special quickly reveals a very peculiar method of determining what constitutes a normal SPECT scan. “You know, it took us almost 3,000 people screening to find about 90 healthy brains.” He then added, “So, if your brain is struggling, welcome to normal. Normal is not healthy.”

If, by normal, Amen is referring to the idealized brain and mind, none of us is normal. We all have quirks and asymmetries; no two brains are identical, not even those of identical twins. But if we are to use normal in the conventional medical sense of meaning biological values shared by a major percentage of a population, we have a serious problem. Using Amen’s figures from his TV program, only 3 percent of those he has studied have been interpreted by himself and his staff as being normal. Put another way, 97 percent of patients who attend Amen’s clinic can expect to be told that their SPECT brain scan is abnormal.

Compounding the problems generated by his idiosyncratic definition of normal is his failure to adequately address several major ethical concerns. Amen skirts the well-recognized potential for profound psychological consequences of a healthy asymptomatic patient learning that he or she will develop a devastating illness, particularly in the absence of definitive treatments. A second serious oversight is the potentially devastating consequence of falsely receiving the diagnosis of A.D. Every attempt should be made to minimize any false-positive diagnoses; any test used to predict the likelihood of A.D. should first have undergone strict peer-reviewed scrutiny, including reproduction of the data by independent scientific studies.

As might be anticipated, Amen is not a stranger to controversy. In 2005, on Quackwatch.org, a nonprofit that investigates health-related frauds, myths, fads and fallacies, Dr. Harriet Hall, a retired family physician, outlined concerns regarding Amen’s practices. In addition to those I’ve mentioned, Hall was critical of Amen’s unsupported claims that SPECT scanning provides “guidance in the application of specific medications or other treatments such as supplements, neurofeedback, transcranial magnetic stimulation, and hyperbaric oxygen therapy.”

In a recent phone call, Hall tells me, “Amen’s recommendations defy science, common sense and logic. I feel much worse about him now than I did when I wrote the piece because I went back and looked at his Web site again, and I’m just appalled by some of the things that are on it now. He’s selling vitamin supplements and he’s selling his own line of products. He’s turned into big business.” According to its Web site, Amen Clinics charges $3,250 for a “comprehensive evaluation,” which includes the patient’s history, two SPECT scans, a physician consultation, and a 30-minute treatment follow-up appointment. Follow-up scans after treatment are $795 each.

In trying to divine PBS’ role and obligations in airing such an obviously controversial figure as Amen, I got the proverbial runaround. I first e-mailed my local PBS station, KQED. The station’s executive director of communications, Scott Walton, responded that “KQED only aired the program and was not involved in any decision concerning content.” He pointed out that KQED isn’t staffed to review 60,000 hours of programming per year and relied upon other PBS stations that offer shows to do proper vetting. KQED, Walton added, took into consideration “a copy of the press kit, which … contains profiles and articles about Dr. Amen from Newsweek, Men’s Health and other well-known publications as well as information about his appearances on Oprah, CNN and more.”

Did a local PBS station, or PBS headquarters, do proper vetting? Michael Getler, the PBS ombudsman, didn’t have an answer for me and forwarded my message to “the top people.” I then got a note from Joseph Campbell, PBS vice president of fundraising programming, who said, “PBS is not responsible for the content of those programs obtained from outside sources (other than PBS); it is up to each individual station to decide on the merits of such non-PBS produced programs.”

In fact, “Change Your Brain, Change Your Life” was neither produced nor distributed by PBS headquarters. It was co-produced by Amen and High Five Entertainment, a production company in Nashville, Tenn., which has produced live award shows and videos for, among others, Wynonna Judd. It was distributed by Executive Program Services, a regional PBS distributor, which places programs on the PBS satellite, where local PBS affiliates can find and select them for their stations. Alan Foster, co-principal of Executive Program Services, explains that’s how stations acquired “Change Your Brain, Change Your Life.” He stresses that Executive Program Services “programming is unrelated to the programming that comes from PBS programming, and vice versa.”

Foster, who says he consulted with Amen to make the program “better suited for public television,” is not troubled by its content. “I look at it in the sense of, ‘Are there any problems with this?’ I can’t verify or say in a medical sense whether the information is accurate. PBS doesn’t do that either. But if I felt there was any reason for alarm, then we wouldn’t be involved with it. But I didn’t find that.”

In a recent Slate article, critical of the Los Angeles Times for publishing an Op-Ed by Amen, in which Amen argued that all presidential candidates should be given brain scans, Daniel Engber wrote, “Perhaps the paper’s editors assumed Amen was credible because of all his appearances in other publications. In that case, they’ve only exacerbated the problem, further padding his resume as an ‘expert’ on the brain.”

The same criticism surely applies to those PBS stations that aired “Change Your Brain, Change Your Life” without internal review or audience notification that no program review had been performed. At the least, the stations should simultaneously display a disclaimer indicating that the program’s contents haven’t been specifically vetted by PBS. Without such a disclaimer, anyone watching a PBS-aired program must assume a caveat emptor default position.

According to the PBS mission statement, “as a non-commercial enterprise, we can maintain our commitment to delivering quality, innovative and distinctive media content as our utmost priority. By guaranteeing our programs treat complex social issues with journalistic integrity and compassion, our audiences know they can rely on us to provide accurate, impartial information.” In the case of Amen, that is simply not true.

Reporting assistance by Erin Renzas

(Daniel Amen responds here.)

It’s certainly true that good health practices, physical and mental exercise, and stress reduction are associated with lower rates of mental decline. But do brain fitness programs add any additional specific benefits? The optimistic answer is they might. The realistic answer is that it’s hard to know. Despite what the makers of the games claim, there isn’t a reasonably foolproof way to measure a program’s specific effects on mental performance. In other words, buyer beware.

Let’s begin with a look at “Brain Fitness Program.” Its Web site explains that as we grow older, the processing speed of our brains slows down. Thus the program is “designed to speed up auditory processing, improve working memory, and encourage the brain to produce more of the chemicals that help it remember.” Taken together, “these changes help people feel better equipped to communicate in every setting, making them more confident and more willing to engage in new experiences.”

The training consists of six exercises. One involves listening to sounds and determining whether the pitch rises or falls. Originators of the program believe the ability to process these sounds, similar in frequency to human speech, will lead to “quicker thinking, faster responses and fuller understanding.” A second exercise promises to “strengthen your brain’s ability to perceive and remember subtle differences between similar sounds that are common in English.”

Immediately these claims bring us face-to-face with a seldom-discussed problem in contemporary cognitive science — how to detect changes in mental performance. If you want to study whether a drug lowers the rate of progression of coronary artery disease, you have objective endpoints. You can compare the incidence of laboratory-documented heart attacks or heart-related deaths in a treated group and a non-treated or control group. Ditto for cancer treatment. You can assess cancer-related mortality with and without treatment. Even with the inevitable differences of design and interpretation, studies with clear-cut endpoints are the bedrock of evidence-based medicine.

But measurements of reading skills, ability to navigate mazes, memorize nonsense words, or the speed with which we learn new material — the kinds of improvements heralded by brain games — aren’t subject to the same kind of independent confirmation. Functional brain imaging can show whether areas of the brain are more or less active than a control group, but cannot accurately predict how these changes will be reflected in ordinary activities of daily life.

At present, the only way a brain fitness program can demonstrate its value is through traditional “neuropsychological testing.” But these tests are subjective. They are not an objective counterpart to EKGs, cardiac muscle enzymes, coronary angiogram and death certificate registries. Their validity is solely dependent upon the establishment of “statistical norms” against which a subject’s performance is compared.

For example, if 1,000 randomly chosen people read a paragraph in an average of 50 seconds, and you take 55 seconds, that doesn’t mean that you have a 10 percent impairment in your reading skills. The test can’t tell you the meaning of the five-second difference. Because brain-fitness games rely on the quantification of mental performances to substantiate their claims, we need to understand some of the inherent limits imposed by neuropsychological testing in general.

Neuropsychological testing is good at detecting changes in mental abilities but isn’t very good at telling us why these changes are occurring. One major limitation is their relative inability to sort out cognitive changes due to psychological factors. After an in-depth review of neuropsychological tests, the American Academy of Neurology concluded, “Anxiety, depression, psychosis, apathy, and irritability all have an impact on the patient’s ability to cooperate with testing and may directly affect cognition.” If we’re depressed or anxious, or even if we are uninterested, it will be reflected in our test scores.

The converse is also true. If we feel good about taking a test, and yes, even about the men or women administering the test, we will tend to do better. The caveats common to all mental test performances, from IQ tests to SAT scores, are intrinsic to neuropsychological tests, but with a mega-difference. IQ and SAT tests don’t suggest why we perform well or poorly. But in order to know whether a “brain therapy” is worthwhile, we need to know whether a test score improvement is a direct and real effect of the therapy.

To put this into everyday perspective, imagine asking Al Gee, a perfectly healthy 65-year-old retiree, to learn a new foreign language. Al randomly picks a computer program in beginning Greek — “It’s Greek to Me” — and studies the program for a month. His performance, including speed of recognition of individual Greek letters and comprehension of simple phrases, is measured before beginning the program, at the end of the program and periodically over the next five years.

On formal testing, Al’s speed of processing new visual symbols (Greek letters) would dramatically improve, as would his Greek-reading ability; a good percentage of this skill would persist months, even years later. None of this is surprising. Even old-timers can learn to play golf or the piano, albeit not as proficiently as when younger, and, once learned, these skills deteriorate relatively slowly over time. Their fMRI scans will show increased activity in regions related to whatever skill they acquired. This measurable improvement is to be expected; by itself, it tells us nothing about the overall “mind enhancement” of acquiring a new skill.

In addition, there may be nonspecific benefits that fall into the general category of placebo effect. If Al is thrilled at having mastered the basics of a notoriously difficult-to-learn language, he is likely to believe and report that his overall cognition has improved. He may overlook or downplay his ongoing occasional memory lapses and misplacing his car keys. Rejuvenated by his “newfound powers,” his increased self-confidence might even translate into better test performance.

In this scenario, it isn’t necessary for the program to provide any general cognitive enhancement as long as the patient believes that it does. Al’s neuropsychology report will show increased processing speed, task-specific improvement in memory and comprehension, and may well show a generalized improved performance effect.

But such improvements don’t necessarily translate into better performance in daily activities. According to Michael Marsiske, associate director for research at the Institute on Aging at the University of Florida, “All the available data on cognitive training show that when a person practices something — for example, short-term memory retrieval — the person can get better at doing that test, but that the improvement does not necessarily generalize into the real world. People may believe that they are doing some mental cross-training and that they will generally improve their cognitive efficiency. That may be true, but there is no evidence for that just yet.” Similarly, the American Academy of Neurology warns against blanket acceptance of claims of task-specific improvement correlating with better performance of daily activities.

The Greek example also points to one of the central difficulties in interpreting neuropsychological testing. To establish that improved performance isn’t just a placebo effect, we need a comparison with a suitable control group. But what would constitute a reasonable comparison? Would it be adequate to compare Al to someone studying another Greek language program? Would Russian suffice? Or Arabic? Or would you choose a completely different task, such as learning to play the accordion? Meditate? Do crossword puzzles and read a newspaper?

Even seemingly similar tasks may represent quite different brain functions. If we want to see the effect of reading the Washington Post, is it sufficient to have the control group read the New York Times? It is nearly impossible to control the articles being read. If the Post has a book review of a Jackson Pollock biography without a photo of a Pollock painting, while the Times includes one, different brain regions will be activated. A podcast of the same article will activate yet other regions. Just being familiar or unfamiliar with Pollock’s work will have different effects.

Equally challenging is the problem of minimizing the nocebo effect. “Nocebo” refers to the creation of a negative expectation that results in reducing or negating the value of a treatment. In a classic study from the University of California at San Francisco pain clinic, a group of post-surgical dental patients were warned that the pain injection they were to receive was a new drug that might have no pain-relieving effect. So when given IV morphine, the patients reported no difference from IV saline. In the same vein, telling subjects that, “Yes, I know the test is hard and not much fun, and we don’t expect major improvements,” can produce significantly different results than offering subjects full-scale encouragement and support.

The standard approach to controlling for placebo and nocebo effects is to run double-blind clinical studies. This is straightforward if the treatment can be made to look identical to the placebo control. You ask the pharmacy to make up a placebo pill of the same size, color and taste as the active pill. Only the pharmacist knows; neither the patient nor the nurse or doctor administering the pill has any idea which pill the patient is receiving.

But it isn’t easy to create a double-blind study for a computerized brain exercise program. The difference between a brain game that teaches new phonemes will be strikingly different from one that offers crossword puzzles. An inadvertent (or not so inadvertent) word or gesture of encouragement or discouragement by a research assistant or computer tech setting up the program can readily influence the test results in ways that cannot be detected.

Armed with this perspective on the limitations of neuropsychology testing, let’s return to the “Brain Fitness Program.” Posit Science states that the “Brain Fitness Program has been subjected to several large, rigorous clinical trials that demonstrate it speeds up auditory processing by 131 percent, improves memory by an average of 10 years, and more.” It touts a study called “IMPACT” (“Improvement in Memory With Plasticity-based Adaptive Cognitive Training”). The study states “that people can make statistically significant gains in memory and processing speed if they do the right kind of scientifically designed cognitive exercises … and that people who used the Posit Science program reported positive changes in their everyday lives.”

But we already knew that learning new sounds would lead to improved processing speed in the same way that Al learned to read Greek faster. And we could have predicted the high likelihood that Al would report improved overall performance. None of these already expected results tell us anything about a specific benefit of the “Brain Fitness Program,” as opposed to, say, reading “Ulysses.”

Although the IMPACT study is cited on Posit Science’s site as “proof” of the value of the program, it has not appeared in a peer-reviewed publication. So, to be fair, I examined the last published article that Posit Science cites to uphold its claims — the 2006 Memory Enhancement study published in the Proceedings of the National Academy of Sciences.

A couple of major problems are immediately apparent. The first is that the study is sponsored by and conducted by the company. This is largely unavoidable; there isn’t enough independent or government grant money to study every proposed program. A second and even more serious concern is the authors’ representation that the study was both properly controlled and double-blinded. Despite the claim of Posit Science, it’s a real stretch to believe that reading the New York Times or watching an educational DVD is a comparable brain activity to concentrating on recognizing sudden changes in pitches of a sound.

Worse, according to the study protocol, research assistants visited participants in their homes in order to properly set up the computers and explain how to use the training activity, and then made weekly visits to ensure that the participants were properly using the programs. Given the dramatic differences in assigned tasks, it requires a giant leap of faith to state that participants “received identical interaction with and coaching from research assistants.” It is difficult to accept that the assistants did not, in any fashion, communicate their observations either to the participants or to those administering the neuropsychology tests. In fact, the study doesn’t clearly specify the qualifications of the researchers who did administer these tests.

There’s no need to cite chapter and verse of how similar logistical problems plague each of the brain-fitness programs that I checked out. Studies designed, conducted and paid for by those with a vested interest can’t be construed as independent scientific evidence.

Admittedly, these problems don’t negate the possibility that brain programs could help cognition. So if you have the time, money and the desire, there’s no harm in firing one up. As the British Medical Journal stated earlier this year, “Most researchers believe that the risk of harm is low, even if the clinical benefit of brain training products is unproved.” If, however, you want to limit yourself to evidence-based treatments, don’t hold your breath. The question of whether brain games can effectively enhance your life isn’t likely to be resolved before you’re too old to care.

But modern biology is pointing in a different direction. It is telling us that despite how certainty feels, it is neither a conscious choice nor even a thought process. Certainty and similar states of “knowing what we know” arise out of primary brain mechanisms that, like love or anger, function independently of rationality or reason. Feeling correct or certain isn’t a deliberate conclusion or conscious choice. It is a mental sensation that happens to us.

The importance of being aware that certainty has involuntary neurological roots cannot be overstated. If science can shame us into questioning the nature of conviction, we might develop some degree of tolerance and an increased willingness to consider alternative ideas — from opposing religious or scientific views to contrary opinions at the dinner table.

I call the mental sensation of certainty the “feeling of knowing.” Everyone is familiar with the most commonly recognized feeling of knowing. When asked a question, you feel strongly that you know an answer that you cannot immediately recall. Psychologists refer to this easily recognizable feeling as a tip-of-the-tongue sensation. The frequent accompanying comment as you scan your mental Rolodex for the forgotten name or phone number is: “I know it but I just can’t think of it.” You are aware of knowing something, without knowing exactly what this sensation refers to. The most profound feeling of knowing is the “aha,” a spontaneous notification from a subterranean portion of our mind, an involuntary all-clear signal that we have grasped the heart of a problem. It isn’t just that we can solve the problem; we “know” that we understand it.

To understand what I mean about the feeling of knowing, read the following paragraph at normal speed. Don’t skim, give up halfway through or skip to the explanation. Because this experience can’t be duplicated once you know the explanation, take a moment to ask yourself how you feel about the paragraph. After reading the clarifying word, reread the paragraph. As you do, pay close attention to the shifts in your mental state and your feeling about the paragraph:

A newspaper is better than a magazine. A seashore is a better place than the street. At first it is better to run than to walk. You may have to try several times. It takes some skill but it is easy to learn. Even young children can enjoy it. Once successful, complications are minimal. Birds seldom get too close. Rain, however, soaks in very fast. Too many people doing the same thing can also cause problems. One needs lots of room. If there are no complications it can be very peaceful. A rock will serve as an anchor. If things break loose from it, however, you will not get a second chance.

Is this paragraph comprehensible or meaningless? Feel your mind sort through potential explanations. Now watch what happens with the presentation of a single word: kite.

In an instant, you are flooded with the “aha” feeling that the paragraph makes sense. There’s no time for deep consideration and evaluation. Before you can reread the paragraph, your unconscious mind has already sorted through various possibilities, determined that the sentences collectively fit the description of a kite and sent you notification.

Determining how this involuntary feeling of knowing happens takes us into the enormously complicated details of neurobiology. To simplify them for this discussion, let me borrow a term, “hidden layer,” from the artificial intelligence community.

By mimicking the way the brain processes information, A.I. scientists have been able to build artificial neural networks (ANNs) that can play chess and poker, read faces, recognize speech and recommend books at Amazon.com. While standard computer programs work line by line, yes or no, all eventualities programmed in advance, the ANN takes an entirely different approach. The ANN is based upon mathematical programs that are initially devoid of any specific values. The programmers only provide the equations; incoming information determines how connections are formed and how strong each connection will be in relationship to all other connections. There is no predictable solution to a problem — rather, as one connection changes, so do all the others. These shifting interrelationships are the basis for “learning.”

With an ANN, the hidden layer is conceptually located within the interrelationships between all the incoming information and the mathematical code used to process it. In the human brain, the hidden layer doesn’t exist as a discrete interface or specific anatomic structure; rather, it resides within the connections between all neurons involved in any neural network. A network can be relatively localized or widely distributed throughout the brain. Proust’s taste of a madeleine triggered a memory that involved visual, auditory, olfactory and gustatory cortices — the multisensory cortical representations of a complex memory. With a sufficiently sensitive fMRI scan, we would see all these areas lighting up when Proust contemplated the madeleine.

The hidden layer thus offers a powerful metaphor for the way the brain processes information. It is in the hidden layer that all elements of biology (from genetic predispositions to neurotransmitter variations and fluctuations) and all past experience, whether remembered or long forgotten, affect the processing of incoming information. It is the interface between incoming sensory data and a final perception, the anatomic crossroad where nature and nurture intersect. It is why your red is not my red, your idea of beauty isn’t mine, why eyewitnesses offer differing accounts of an accident or why we don’t all put our money on the same roulette number.

The powerful feeling of knowing arises out of the hidden layer’s unconscious calculation of correctness, be it recognizing a face or believing an idea is right. The greater the likelihood of correctness, as determined by your unconscious, the stronger the sense of certainty.

In his bestselling “Blink,” New Yorker staff writer Malcolm Gladwell describes gut feelings as “perfectly rational,” as “thinking that moves a little faster and operates a little more mysteriously” than conscious thought. But he’s flying in the face of present-day understanding of brain behavior. Gut feelings and intuitions, the Eureka moment and our sense of conviction, represent the conscious experiences of unconsciously derived feelings.

Look at the feeling of knowing in the light of evolution. It explains how we learn. Compare it with the body’s various sensory systems. It is through sight and sound that we are in contact with the world around us. Similarly, we have extensive sensory functions for assessing our interior milieu. When our body needs food, we feel hunger. When we are dehydrated and require water, we feel thirsty. If we have sensory systems to connect us with the outside world, and sensory systems to notify us of our internal bodily needs, it seems reasonable that we would also have a sensory system to tell us what our minds are doing.

To be aware of thinking, we need a sensation that tells us that we are thinking. To reward learning, we need feelings of being on the right track, or of being correct. And there must be similar feelings to reward and encourage the as-yet unproven thoughts — the idle speculations and musings that will become useful new ideas.

To be an effective, powerful reward, the feeling of conviction must feel like a conscious and deliberate conclusion. As a result, the brain has developed a constellation of mental sensations that feel like thoughts but aren’t. These involuntary and uncontrollable feelings are the mind’s sensations; as sensations they are subject to a wide variety of perceptual illusions common to all sensory systems. Understanding this couldn’t be more important to our sense of ourselves and the world around us.

It’s not easy, of course, but somehow we must incorporate what neuroscience is telling us about the limits of knowing into our everyday lives. We must accept that how we think isn’t entirely within our control. Perhaps the easiest solution would be to substitute the word “believe” for “know.” A physician faced with an unsubstantiated gut feeling might say, “I believe there’s an effect despite the lack of evidence,” not, “I’m sure there’s an effect.” And yes, scientists would be better served by saying, “I believe that evolution is correct because of the overwhelming evidence.”

I realize that this last sentence runs against the grain of those who have fought the hardest to establish science as the method for determining the facts of the external world. It is particularly loathsome when you feel that you are playing into the hands of religious fanatics, medical quacks and word-twisting politicians. But in pointing out the biological limits of reason, including scientific thought, I’m not making the case that all ideas are equal or that scientific method is mere illusion. My purpose is not to destroy the foundations of science, but only to point out the inherent limitations of the questions that science asks and the answers it provides.

Substituting believe for know doesn’t negate scientific knowledge; it only shifts a hard-earned fact from being unequivocal to being highly likely. Saying that evolution is extremely likely rather than absolutely certain doesn’t reduce the strength of the argument, and at the same time it serves a more fundamental purpose. Hearing myself saying “I believe” where formerly I would have said “I know” serves as a constant reminder of the limits of knowledge and objectivity. At the same time as I am forced to consider the possibility that contrary opinions might have a grain of truth, I am provided with the perfect rebuttal for those who claim that they “know that they are right.” It is in the leap from 99.99999 percent likely to 100 percent guaranteed that we give up tolerance for conflicting opinions, and provide the basis for the fundamentalist’s claim to pure and certain knowledge.

A related consideration is to distinguish between felt knowledge — such as hunches and gut feelings — and knowledge that arises out of empiric testing. Any idea that either hasn’t been or isn’t capable of being independently tested should be considered a personal vision. Shakespeare does not demand that we accept Hamlet as representing a universal truth. We agree and judge him according to the standards of art, literature and personal experience. Hamlet is neither right nor wrong. If in the future, Hamlet is found to have a gene for bipolar disorder, we are entitled to reassess our initial interpretations of Hamlet’s relationship to his mother. Hamlet is a vision. No matter how seemingly reasonable and persuasive, each begins with a very idiosyncratic perception that seeks its own reflection in the external world. Each writer’s personal sense of purpose drives the arguments, picks out the evidence and draws conclusions. Such ideas should be judged accordingly — as visions, not as obligatory lines of reasoning that must be universally shared.

To retreat from claims of absolute “knowing” and certainty, popular psychology needs to explore how mental sensations play a fundamental role in generating and shaping our thoughts. We can’t afford to continue with the outdated claims of a perfectly rational unconscious or knowing when we can trust gut feelings. We need to rethink the very nature of a thought, including the recognition of how various perceptual limitations are inevitable.

At the same time, if the goal of science is to gradually overcome deeply embedded superstition, it must be seen as a more attractive and comforting alternative, not as inflammatory exhortation and confrontation with a none-too-subtle whiff of condescension. Try to peddle the vision of a cold, pointless world at a Pentecostal revival meeting and you have an inkling of the challenge. In a recent survey, nearly 90 percent of Americans expressed the belief that their souls will survive the death of their bodies and ascend to heaven. Such beliefs, no matter how counter to the evidence, provide the majority of Americans with a personal sense of meaning. If forced to choose between reason and a sense of purpose, most of us would side with purpose. This apparent choice isn’t even an entirely conscious decision. If science hasn’t yet made a dent in such beliefs, it seems unlikely that further efforts will miraculously turn the tide.

Such discussions pose the same ethical problems inherent in placebo treatments. Simply put, a placebo effect is a false belief that has real value. To insist that there is no soul or afterlife is the moral equivalent of taking away the placebo effect arising out of an unscientific belief. Studies have shown that sham arthroscopic surgery can allow some patients to walk comfortably again. No one should recommend sham knee surgery, yet many physicians are comfortable recommending less drastic but unproven treatments for pain.

The answer lies in a personal risk-reward calculation — how to provide comfort without undue side effects or cost. But the intentional use of a placebo comes at a cost. Even without side effects or excessive cost, the precedent of falsely representing benefits of a treatment has its own long-term undesirable effects. The most serious would be the erosion of trust between the physician and patient. On the other hand, eliminating all placebo treatments because they are intellectually dishonest raises its own set of problems, including the cynical zeitgeist of valuing science over compassion. There isn’t an easy solution or right answer; each of us will calculate the risk versus reward according to our own biology and experience.

In medicine, we are increasingly developing ethical standards for complex medical decisions that allow for hope and the placebo effect, yet don’t fly in the face of evidence-based medical knowledge. The guiding principle of the Hippocratic oath is primum no nocerum — above all, do no harm. This same principle should be a cornerstone of how science competes in the world of ideas. Science needs to maintain its integrity while it retains compassionate respect for aspects of human nature that aren’t “reasonable.”

This balance of opposites extends to all aspects of modern thought. For example, it doesn’t make sense to ask someone if he’d like to take a placebo; the very question strips the placebo of much of its intended benefit. Similarly, it isn’t clear how to have a reasonable discussion on the nature of the self that both maintains the integrity of science — the self is an emergent phenomenon and not some separately existing entity — and allows each of us to feel that we are individuals and not mere machinery. I cannot imagine a world in which we fully accepted and felt that we were nothing more than fictional narratives arising out of “mindless” neurons. And I cannot imagine how much empathy we would have with others if we saw disappointment, love and grief solely as chemical reactions. Faced with this chilling interpretation of our lives, it isn’t surprising that most people opt for the belief in material “souls” and/or anticipate that real live virgins are patiently awaiting their arrival in heaven.

F. Scott Fitzgerald described an easy-to-accept but difficult-to-accomplish solution: “The test of a first rate intelligence is the ability to hold two opposed ideas in the mind at the same time and still retain the ability to function.” This juggling act requires us to keep in mind what science is telling us about ourselves while acknowledging the positive benefits of nonscientific or unreasonable beliefs. Each opposing position has its own risks and rewards; both need to be considered and balanced within the overarching mandate — above all, do no harm.

Just as we learn to cope with the anxieties of sickness and death, we must learn to tolerate contradictory aspects of our biology. Our minds have their own agendas. We can intervene through greater understanding of what we can and cannot control, by knowing where potential deceptions lurk, and by a willingness to accept that our knowledge of the world around us is limited by fundamental conflicts in how our minds work.

Which leads us back to the beginning. Certainty is not biologically possible. We must learn (and teach our children) to tolerate the unpleasantness of uncertainty. Science has given us the language and tools of probabilities. That is enough. We do not need and cannot afford the catastrophes born out of a belief in certainty.

From “On Being Certain” by Robert A. Burton, M.D. © 2008 by the author and reprinted by permission of St. Martin’s Press.