Do ADHD Drugs Take a Toll on the Brain?

Research hints that hidden risks might accompany long-term use of the medicines that treat attention-deficit hyperactivity disorderBy Edmund S. Higgins

A few years ago a single mother who had recently moved to town came to my office asking me to prescribe the stimulant drug Adderall for her sixth-grade son. The boy had been taking the medication for several years, and his mother had liked its effects: it made homework time easier and improved her son’s grades.

At the time of this visit, the boy was off the medication, and I conducted a series of cognitive and behavioral tests on him. He performed wonderfully. I also noticed that off the medication he was friendly and playful.
On a previous casual encounter, when the boy had been on Adderall, he had seemed reserved and quiet. His mother acknowledged this was a side effect of the Adderall. I told her that I did not think her son had attention-deficit hyperactivity disorder (ADHD) and that he did not need medication. That was the last time I saw her.

Attention-deficit hyperactivity disorder afflicts about 5 percent of U.S. children—twice as many boys as girls—age six to 17, according to a recent survey conducted by the Centers for Disease Control and Prevention. As its name implies, people with the condition have trouble focusing and often are hyperactive or impulsive. An estimated 9 percent of boys and 4 percent of girls in the U.S. are taking stimulant medications as part of their therapy for ADHD, the CDC reported in 2005. The majority of patients take methylphenidate (Ritalin, Concerta), whereas most of the rest are prescribed an amphetamine such as Adderall.

Although it sounds counterintuitive to give stimulants to a person who is hyperactive, these drugs are thought to boost activity in the parts of the brain responsible for attention and self-control. Indeed, the pills can improve attention, concentration and productivity and also suppress impulsive behavior, producing significant improvements in some people’s lives. Severe inattention and impulsivity put individuals at risk for substance abuse, unemployment, crime and car accidents. Thus, appropriate medication might keep a person out of prison, away from addictive drugs or in a job.

Over the past 15 years, however, doctors have been pinning the ADHD label on—and prescribing stimulants for—a rapidly rising number of patients, including those with moderate to mild inattention, some of whom, like the sixth grader I saw, have a normal ability to focus. This trend may be fueled in part by a relaxation of official diagnostic criteria for the disorder, combined with a lower tolerance in society for mild behavioral or cognitive problems.

In addition, patients are no longer just taking the medicines for a few years during grade school but are encouraged to stay on them into adulthood. In 2008 two new stimulants—Vyvanse (amphetamine) and Concerta—received U.S. Food and Drug Administration ­indications for treating adults, and pharmaceutical firms are pushing awareness of the adult forms of the disorder. What is more, many people who have no cognitive deficits are opting to take these drugs to boost their academic performance. A number of my patients—doctors, lawyers and other professionals—have asked me for stimulants in hopes of boosting their productivity. As a result of these developments, prescriptions for methylphenidate and amphetamine rose by almost 12 percent a year between 2000 and 2005, according to a 2007 study.

With the expanded and extended use of stimulants comes mounting concern that the drugs might take a toll on the brain over the long run. Indeed, a smattering of recent studies, most of them involving animals, hint that stimulants could alter the structure and function of the brain in ways that may depress mood, boost anxiety and, contrary to their short-term effects, lead to cognitive deficits. Human studies already indicate the medications can adversely affect areas of the brain that govern growth in children, and some researchers worry that additional harms have yet to be unearthed.

Medicine for the MindTo appreciate why stimulants could have negative effects over time, it helps to first understand what they do in the brain. One hallmark of ADHD is an underactive frontal cortex, a brain region that lies just behind the forehead and controls such “executive” functions as decision making, predicting future events, and suppressing emotions and urges. This area may, in some cases, be smaller than average in ADHD patients, compromising their executive abilities. Frontal cortex function depends greatly on a signaling chemical, or neurotransmitter, called dopamine, which is released in this structure by neurons that originate in deeper brain structures. Less dopamine in the prefrontal cortex is linked, for example, with cognitive difficulty in old age. Another set of dopamine-releasing neurons extends to the nucleus accumbens, a critical mediator of motivation, pleasure and reward whose function may also be impaired in ADHD.

Stimulants enhance communication in these dopamine-controlled brain circuits by binding to so-called dopamine transporters—the proteins on nerve endings that suck up excess dopamine—thereby deactivating them. As a result, dopamine accumulates outside the neurons, and the additional neurotransmitter is thought to improve the operation of neuronal circuits critical for motivation and impulse control.


Not only can methylphenidate and amphetamine ameliorate a mental deficit, they also can enhance cognitive performance. In studies dating back to the 1970s, researchers have shown that normal children who do not have ADHD also become more attentive—and often calmer—after taking stimulants. In fact, the drugs can lead to higher test scores in students of average and above-average intellectual ability

Since the 1950s, when doctors first started prescribing stimulants to treat behavior problems, millions of people have taken them without obvious incident. A number of studies have even exonerated them from causing possible adverse effects. For example, researchers have failed to find differences between stimulant-treated children and those not on meds in the larger-scale growth of the brain. In January 2009 child psychiatrist Philip Shaw of the National Institute of Mental Health and his colleagues used MRI scans to measure the change in the thickness of the cerebral cortex (the outer covering of the brain) of 43 youths between the ages of 12 and 16 who had ADHD.

The researchers found no evidence that stimulants slowed cortical growth. In fact, only the unmedicated adolescents showed more thinning of the cerebrum than was typical for their age, hinting that the drugs might facilitate normal cortical development in kids with ADHD.

Altering MoodDespite such positive reports, traces of a sinister side to stimulants have also surfaced. In February 2007 the FDA issued warnings about side effects such as growth stunting and psychosis, among other mental disorders. Indeed, the vast majority of adults with ADHD experience at least one additional psychiatric illness—often an anxiety disorder or drug addiction—in their lifetime. Having ADHD is itself a risk factor for other mental health problems, but the possibility also exists that stimulant treatment during childhood might contribute to these high rates of accompanying diagnoses.

After all, stimulants activate the brain’s reward pathways, which are part of the neural circuitry that controls mood under normal conditions. And at least three studies using animals hint that exposure to methylphenidate during childhood may alter mood in the long run, perhaps raising the risk of depression and anxiety in adulthood.

In an experiment published in 2003 psychiatrist Eric Nestler of the University of Texas Southwestern Medical Center and his colleagues injected juvenile rats twice a day with a low dose of methylphenidate similar to that prescribed for children with ADHD. When the rats became adults, the scientists observed the rodents’ responses to various emotional stimuli. The rodents that had received methylphenidate were significantly less responsive to natural rewards such as sugar, sex, and fun, novel environments than were untreated rats, suggesting that the drug-exposed animals find such stimuli less pleasurable. In addition, the stimulants apparently made the rats more sensitive to stressful situations such as being forced to swim inside a large tube. Similarly, in the same year psychiatrist William Carlezon of Harvard Medical School and his colleagues reported that methylphenidate-treated preadolescent rats displayed a muted response to a cocaine reward as adults as well as unusual apathy in a forced-swim test, a sign of depression.

In 2008 psychopharmacologist Leandro F. Vendruscolo and his co-workers at Federal University of Santa Catarina in Brazil echoed these results using spontaneously hypertensive rats, which—like children with ADHD—sometimes show attention deficits, hyperactivity and motor impulsiveness. The researchers injected these young rats with methylphenidate for 16 days at doses approximating those used to treat ADHD in young people. Four weeks later, when the rats were young adults, those that had been exposed to methylphenidate were unusually anxious: they avoided traversing the central area of an open, novel space more so than did rats not exposed to methylphenidate. Adverse effects of this stimulant, the authors speculate, could contribute to the high rates of anxiety disorders among ADHD patients.

Copying Cocaine? The long-term use of any drug that affects the brain’s reward circuitry also raises the specter of addiction. Methyl-phenidate has a chemical structure similar to that of cocaine and acts on the brain in a very similar way. Both cocaine and methamphetamine (also called “speed” or “meth”)—another highly addictive stimulant—block dopamine transporters just as ADHD drugs do [see “New Weapons against Cocaine Addiction,” by Peter Sergo; Scientific American Mind, April/May 2008]. In the case of the illicit drugs, the dopamine surge is so sudden that in addition to making a person unusually energetic and alert, it produces a “high.”

Recent experiments in animals have sounded the alarm that methylphenidate may alter the brain in ways similar to that of more powerfully addictive stimulants such as cocaine.

In February 2009 neuroscientists Yong Kim and Paul Greengard, along with their colleagues at the Rockefeller University, reported cocainelike structural and chemical alterations in the brains of mice given methylphenidate. The researchers injected the mice with either methylphenidate or cocaine daily for two weeks. Both treatments increased the density of tiny extensions called spines at the ends of neurons bearing dopamine receptors in the rodent nucleus accumbens. Compared with cocaine, methylphenidate had a somewhat more localized influence; it also had more power over longer spines and less effect on shorter ones. Otherwise, the drugs’ effects were strikingly similar.

Furthermore, the scientists found that methylphenidate boosted the amount of a protein called ΔFosB, which turns genes on and off, even more than cocaine did. That result could be a chemical warning of future problems: excess ΔFosB heightens an animal’s sensitivity to the rewarding effects of cocaine and makes the animal more likely to ingest the drug. Many former cocaine addicts struggle with depression, anxiety and cognitive problems. Researchers have found that cocaine has remodeled the brains of such ex-users. Similar problems—principally, perhaps, difficulty experiencing joy and excitement in life—could occur after many years of Ritalin or Adderall use.

Amphetamine and methylphenidate can also be addictive if abused by, say, crushing or snorting the pills. In a classic study published in 1995 research psychiatrist Nora Volkow, then at Stony Brook University, and her colleagues showed that injections of methylphenidate produced a cocainelike high in volunteers. More than seven million people in the U.S. have abused methylphenidate, and as many as 750,000 teenagers and young adults show signs of addiction, according to a 2006 report.

Typical oral doses of ADHD meds rarely produce such euphoria and are not usually addicting. Furthermore, the evidence to date, including two 2008 studies from the National Institute on Drug Abuse, indicates that children treated with stimulants early in life are not more likely than other children to become addicted to drugs as adults. In fact, the risk for severe cases of ADHD may run in the opposite direction. (A low addiction risk also jibes with Carlezon’s earlier findings, which indicated that methylphenidate use in early life mutes adult rats’ response to cocaine.)

Corrupting CognitionAmphetamines such as Adderall could alter the mind in other ways. A team led by psychologist Stacy A. Castner of the Yale University School of Medicine has documented long-lasting behavioral oddities, such as hallucinations, and cognitive impairment in rhesus monkeys that received escalating injected doses of amphetamine over either six or 12 weeks.

Compared with monkeys given inactive saline, the drug-treated monkeys displayed deficits in working memory—the short-term buffer that allows us to hold several items in mind—which persisted for at least three years after exposure to the drug. The researchers connected these cognitive problems to a significantly lower level of dopamine activity in the frontal cortex of the drug-treated monkeys as compared with that of the monkeys not given amphetamine.
Underlying such cognitive and behavioral effects may be subtle structural changes too small to show up on brain scans. In a 1997 study psychologists Terry E. Robinson and Bryan Kolb of the University of Michigan at Ann Arbor found that high injected doses of amphetamine in rats cause the major output neurons of the nucleus accumbens to sprout longer branches, or dendrites, as well as additional spines on those dendrites. A de­cade later Castner’s team linked lower doses of amphetamine to subtle atrophy of neurons in the prefrontal cortex of monkeys.

A report published in 2005 by neurologist George A. Ricaurte and his team at the Johns Hopkins University School of Medicine is even more damning to ADHD meds because the researchers used realistic doses and drug delivery by mouth instead of by injection. Ricaurte’s group trained baboons and squirrel monkeys to self-administer an oral formulation of amphetamine similar to Adderall: the animals drank an amphetamine-laced orange cocktail twice a day for four weeks, mimicking the dosing schedule in humans. Two to four weeks later the researchers detected evidence of amphetamine-induced brain damage, encountering lower levels of dopamine and fewer dopamine transporters on nerve endings in the striatum—a trio of brain regions that includes the nucleus accumbens—in amphetamine-treated primates than in untreated animals. The authors believe these observations reflect a drug-related loss of dopamine-releasing nerve fibers that reach the striatum from the brain stem.

One possible consequence of a loss of dopamine and its associated molecules is Parkinson’s disease, a movement disorder that can also lead to cognitive deficits. A study in humans published in 2006 hints at a link between Parkinson’s and a prolonged exposure to amphetamine in any form (not just that prescribed for ADHD). Before Parkinson’s symptoms such as tremors and muscle rigidity appear, however, dopamine’s function in the brain must decline by 80 to 90 percent, or by about twice as much as what Ricaurte and his colleagues saw in baboons that were drinking a more moderate dose of the drug. And some studies have found no connection between stimulant use and Parkinson’s.

Stimulants do seem to stunt growth in children. Otherwise, however, studies in humans have largely failed to demonstrate any clear indications of harm from taking ADHD medications as prescribed. Whether the drugs alter the human brain in the same way they alter that of certain animals is unknown, because so far little clinical data exist on their long-term neurological effects. Even when the dosing is similar or the animals have something resembling ADHD, different species’ brains may have varying sensitivities to stimulant medications.

Nevertheless, in light of the emerging evidence, many doctors and researchers are recommending a more cautious approach to the medical use of stimulants. Some are urging the adoption of strict diagnostic criteria for ADHD and a policy restricting prescriptions for individuals who fit those criteria. Others are advocating behavior modification—which can be as effective as stimulants over the long run—as a first-line approach to combating the disorder. Certain types of mental exercises may also ease ADHD symptoms [see “Train Your Brain,” by Ulrich Kraft; Scientific American Mind, February/March 2006]. For patients who require stimulants, some neurologists and psychiatrists have also suggested using the lowest dose needed or monitoring the blood levels of these drugs as a way of keeping concentrations below those shown to be problematic in other mammals. Without these or similar measures, large numbers of people who regularly take stimulants may ultimately struggle with a new set of problems spawned by the treatments themselves.

Growing ProblemsSo far the best-documented problem associated with the stimulants used to treat attention-deficit hyperactivity disorder (ADHD) concerns growth. Human growth is controlled at least in part through the hypothalamus and pituitary at the base of the brain. Studies in mice hint that stimulants may increase levels of the neurotransmitter dopamine in the hypothalamus as well as in the striatum (a three-part brain structure that includes part of its reward circuitry) and that the excess dopamine may reach the pituitary by way of the bloodstream and act to retard growth.

Recent work strongly indicates that the drugs can stunt growth in children. In a 2007 analysis of a National Institute of Mental Health study of ADHD treatments involving 579 children, research psychiatrist Nora Volkow, who directs the National Institute of Drug Abuse, and her colleagues compared growth rates of unmedicated seven- to 10-year-olds over three years with those of kids who took stimulants throughout that period. Relative to the unmedicated youths, the drug-treated youths showed a decrease in growth rate, gaining, on average, two fewer centimeters in height and 2.7 kilograms less in weight. Although this growth-stunting effect came to a halt by the third year, the kids on the meds never caught up to their counterparts.

Brain with ADHD develops differently

• Some brain regions of kids with ADHD are delayed in maturing, says study

• Their brains are delayed an average of three years compared to those without ADHD

• Delay is most evident in brain regions that control thinking, attention and planning

Bottom Line: This may explain why some kids seem to grow out of the disorder

A National Institutes of Health study from November 2007 found that in youth with attention deficit hyperactivity disorder, the brain matures in a normal pattern. However, it is delayed three years in some regions, on average, compared with youth without the disorder.

The researchers used a new image analysis technique that allowed them to pinpoint the thinning and thickening of sites in the cortex of the brains of hundreds of children and teens with and without the disorder. The findings bolster the idea that ADHD results from a delay in the maturation of the cortex.

Questions and answersHow does the brain development of kids to ADHD compare with that of other kids?

Dr. Sanjay Gupta, CNN chief medical correspondent: For years, the big question with ADHD has been: Are these kids' brains developing more slowly or are they developing in a completely different way? This NIH study tells us the kids' brains develop more slowly, especially those areas important for control, action and attention. For example, a child who has a healthy brain might achieve maturity in those regions at age 7, while a child with ADHD might not until age 10.

What is important to note about both the "healthy" brain and the "ADHD" brain is that they mature or develop in pretty much the same way, starting from the back to the front. However, the ADHD brain is maturing much more slowly than the brain that does not have ADHD.

What can parents of children with ADHD learn from this?

Gupta: The good news for parents: Your child's brain is developing the same way as the brain of a healthy child, but it may take a few years longer. They will probably outgrow the behaviors that come with ADHD. Will your kids ever catch up with kids who don't have ADHD? They may, but it might be well after adolescence or into adulthood. These brain studies are ongoing.

Does this mean a brain scan might one day help diagnose ADHD?

Gupta: We are not at the point of using this as a diagnostic tool, but this information is very important for understanding ADHD. Knowing that this slower development is an issue, we may one day see treatments that try to accelerate this process. We could also see a dulling of impulsivity such as those inappropriate actions that we see in kids with ADHD.

Has Wikipedia Created a Rorschach Cheat Sheet?

There are tests that have right answers, which are returned with a number on top in a red circle, and there are tests with open-ended questions, which provide insight into the test taker’s mind

By NOAM COHEN
July 29, 2009

The Rorschach test, a series of 10 inkblot plates created by the Swiss psychiatrist Hermann Rorschach for his book “Psychodiagnostik,” published in 1921, is clearly in the second category.

Yet in the last few months, the online encyclopedia Wikipedia has been engulfed in a furious debate involving psychologists who are angry that the 10 original Rorschach plates are reproduced online, along with common responses for each. For them, the Wikipedia page is the equivalent of posting an answer sheet to next year’s SAT.

They are pitted against the overwhelming majority of Wikipedia’s users, who share the site’s “free culture” ethos, which opposes the suppression of information that it is legal to publish. (Because the Rorschach plates were created nearly 90 years ago, they have lost their copyright protection in the United States.)

“The only winners seem to be those for whom this issue has become personal, and who see this as a game in which victory means having their way,” one Wikipedia poster named Faustian wrote on Monday, adding, “Just don’t pretend you are doing anything other than harming scientific research.”

What had been a simmering dispute over the reproduction of a single plate reached new heights in June when James Heilman, an emergency-room doctor from Moose Jaw, Saskatchewan, posted images of all 10 plates to the bottom of the article about the test, along with what research had found to be the most popular responses for each.

“I just wanted to raise the bar — whether one should keep a single image on Wikipedia seemed absurd to me, so I put all 10 up,” Dr. Heilman said in an interview. “The debate has exploded from there.”

Psychologists have registered with Wikipedia to argue that the site is jeopardizing one of the oldest continuously used psychological assessment tests.

While the plates have appeared on other Web sites, it was not until they showed up on the popular Wikipedia site that psychologists became concerned.

“The more test materials are promulgated widely, the more possibility there is to game it,” said Bruce L. Smith, a psychologist and president of the International Society of the Rorschach and Projective Methods, who has posted under the user name SPAdoc. He quickly added that he did not mean that a coached subject could fool the person giving the test into making the wrong diagnosis, but rather “render the results meaningless.”

To psychologists, to render the Rorschach test meaningless would be a particularly painful development because there has been so much research conducted — tens of thousands of papers, by Dr. Smith’s estimate — to try to link a patient’s responses to certain psychological conditions. Yes, new inkblots could be used, these advocates concede, but those blots would not have had the research — “the normative data,” in the language of researchers — that allows the answers to be put into a larger context.

And, more fundamentally, the psychologists object whenever diagnostic tools fall into the hands of amateurs who haven’t been trained to administer them. “Our ethics code that governs the behavior of psychologists talks about maintaining test security,” Steve J. Breckler, the executive director for science at the American Psychological Association, said in an interview. “We wouldn’t be in favor of putting the plates out where anyone can get hold of them.”

Alvin G. Burstein, a professor emeritus of psychology at the University of Tennessee, Knoxville, wrote in an e-mail message that his preference was to have the images removed but that he did not think they would harm the psychological process.

“The process of making sense of one’s experience,” he wrote, “is gratifying. To take Rorschach’s test is to make sense of ambiguity in the context of someone who is interested in how you do that.”

Trudi Finger, a spokeswoman for Hogrefe & Huber Publishing, the German company that bought an early publisher of Hermann Rorschach’s book, said in an e-mail message last week: “We are assessing legal steps against Wikimedia,” referring to the foundation that runs the Wikipedia sites.

“It is therefore unbelievably reckless and even cynical of Wikipedia,” she said, “to on one hand point out the concerns and dangers voiced by recognized scientists and important professional associations and on the other hand — in the same article — publish the test material along with supposedly ‘expected responses.’ ”

Mike Godwin, the general counsel at Wikimedia, hardly sounded concerned, saying he “had to laugh a bit” at the legal and ethical arguments made in the statement from Hogrefe.

Hogrefe licenses a number of companies in the United States to sell the plates along with interpretative material. One such distributor, Western Psychological Services, sells the plates themselves for $110 and a larger kit for $185. Dr. Heilman, the man who originally posted the material, compared removing the plates to the Chinese government’s attempt to control information about the Tiananmen massacre. That is, it is mainly a dispute about control, he said.

“Restricting information for theoretical concerns is not what we are here to do,” Dr. Heilman said, adding that he was not impressed by the predictions of harm from those who sought to keep the Rorschach plates secret. “Show me the evidence,” he said. “I don’t care what a group of experts says.”

To illustrate his point, Dr. Heilman used the Snellen eye chart, which begins with a big letter E and is readily available on the Wikipedia site.

“If someone had previous knowledge of the eye chart,” he said, “you can go to the car people, and you could recount the chart from memory. You could get into an accident. Should we take it down from Wikipedia?”

And, Dr. Heilman added, “My dad fooled the doctor that way.”

Schizophrenia and Bipolar Disorder Share Genetic Roots

Chromosomal Hotspot of Immunity/Gene Expression Regulation Implicated
A person holding a gene chip, also known as a DNA microarray.

A trio of genome-wide studies – collectively the largest to date – has pinpointed a vast array of genetic variation that cumulatively may account for at least one third of the genetic risk for schizophrenia. One of the studies traced schizophrenia and bipolar disorder, in part, to the same chromosomal neighborhoods.

"These new results recommend a fresh look at our diagnostic categories," said Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "If some of the same genetic risks underlie schizophrenia and bipolar disorder, perhaps these disorders originate from some common vulnerability in brain development."

Three schizophrenia genetics research consortia, each funded in part by NIMH, report separately on their genome-wide association studies online July 1, 2009, in the journal Nature. However, the SGENE, International Schizophrenia (ISC) and Molecular Genetics of Schizophrenia (MGS) consortia shared their results - making possible meta-analyses of a combined sample totaling 8,014 cases and 19,090 controls.

All three studies implicate an area of Chromosome 6 (6p22.1), which is known to harbor genes involved in immunity and controlling how and when genes turn on and off. This hotspot of association might help to explain how environmental factors affect risk for schizophrenia. For example, there are hints of autoimmune involvement in schizophrenia, such as evidence that offspring of mothers with influenza while pregnant have a higher risk of developing the illness.

"Our study was unique in employing a new way of detecting the molecular signatures of genetic variations with very small effects on potential schizophrenia risk," explained Pamela Sklar, M.D., Ph.D., of Harvard University and the Stanley Center for Psychiatric Research, who co-led the ISC team with Harvard's Shaun Purcell, Ph.D.

"Individually, these common variants' effects do not all rise to statistical significance, but cumulatively they play a major role, accounting for at least one third – and probably much more – of disease risk," said Purcell.

Among sites showing the strongest associations with schizophrenia was a suspect area on Chromosome 22 and more than 450 variations in the suspect area on Chromosome 6. Statistical simulations confirmed that the findings could not have been accounted for by a handful of common gene variants with large effect or just rare variants. This involvement of many common gene variants suggests that schizophrenia in different people might ultimately be traceable to distinct disease processes, say the researchers.

"There was substantial overlap in the genetic risk for schizophrenia and bipolar disorder that was specific to mental disorders," added Sklar. "We saw no association between the suspect gene variants and half a dozen common non-psychiatric disorders."

Still, most of the genetic contribution to schizophrenia, which is estimated to be at least 70 percent heritable, remains unknown.

"Until this discovery, we could explain just a few percent of this contribution; now we have more than 30 percent accounted for," said Thomas Lehner, Ph.D., MPH, chief of NIMH's Genomics Research Branch. "The new findings tell us that many of these secrets have been hidden in complex neural networks, providing hints about where to look for the still elusive – and substantial – remaining genetic contribution."

The MGS consortium pinpointed an association between schizophrenia and genes in the Chromosome 6 region that code for cellular components that control when genes turn on and off. For example, one of the strongest associations was seen in the vicinity of genes for proteins called histones that slap a molecular clamp on a gene's turning on in response to the environment. Genetically rooted variation in the functioning of such regulatory mechanisms could help to explain the environmental component repeatedly implicated in schizophrenia risk.

The MGS study also found an association between schizophrenia and a genetic variation on Chromosome 1 (1p22.1) which has been implicated in multiple sclerosis, an autoimmune disorder.

"Our study results spotlight the importance not only of genes, but also the little-known DNA sequences between genes that control their expression," said Pablo Gejman, M.D., of the NorthShore University HealthSystem Research Institute, of Evanston, ILL, who led the MGS consortium team. "Advances in biotechnology, statistics, population genetics, and psychiatry, in combination with the ability to recruit large samples, made the new findings possible."

The SGENE consortium study pinpointed a site of variation in the suspect Chromosome 6 region that could implicate processes related to immunity and infection. It also found significant evidence of association with variation on Chromosomes 11 and 18 that could help account for the thinking and memory deficits of schizophrenia.

The new findings could eventually lead to multi-gene signatures or biomarkers for severe mental disorders. As more is learned about the implicated gene pathways, it may be possible to sort out what's shared by, or unique to, schizophrenia and bipolar disorder, the researchers say.
Schizophrenia/bipolar disorder genetic overlap

Schizophrenia and bipolar disorder share genetic roots that appear to be specific to serious mental disorders, and are not shared by non-psychiatric illnesses. Bars representing different study samples show that the same genetic variations that account for risk in both mental disorders account for virtually none of the risk for coronary artery disease (CAD), Crohn's disease (CD), hypertension (HT), rheumatoid arthritis (RA), or Type 1 (T1D) or Type 2 (T2D) diabetes.

Source: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Harvard University.
References

Jianxin S, et al. Common variants on chromosome 6p22.1 are associated with schizophrenia. July 1, 2009, Nature

Stefansson H, et al. Common variants conferring risk of schizophrenia. July 1, 2009, Nature

Purcell SM, et al. Common polygenic variation contributes to risk of schizophrenia that overlaps with bipolar disorder. July 1, 2009, Nature

Why is it hard to "unlearn" an incorrect fact?

Cognitive psychologist Gordon H. Bower of Stanford University answers

By The Editors

Why is it that once you learn something incorrectly (say, 7 X 9 = 65), it seems you never can correct your recall?
—J. Kruger, Cherry Hill, N.J.

Cognitive psychologist Gordon H. Bower of Stanford University answers:

Identifying, correcting and averting our memory errors are part of a cognitive process called memory monitoring. Incorrect associations can be tough to change, but we can use techniques to retrain our brain.

When strong habits impede our ability to acquire a desired new habit or association, we experience a common phenomenon known as proactive interference. Wrong associations appear in common spelling errors such as “wierd” for “weird” and “neice” for “niece.” Persistent mistaken connections also can cause embarrassing errors, such as calling a man’s second wife by the name of his first. Interference is stronger the more previous wives you’ve had to deal with, and it is more difficult to overcome the stronger the habits are.

Accurate memory monitoring requires a well-functioning prefrontal cortex (PFC). Young children, who have an immature PFC, and stroke patients with extensive PFC damage make more errors as a result of memory-monitoring failures. They are more likely to confuse the source of information they recall, and they are more susceptible to accepting as true an event they only imagined.

You can overcome proactive interference by consistent (even silent) correction, especially when you space rehearsals over time. But it takes some conscious practice. We have to identify (or be told) when we have just made an error so that we can correct it immediately. Our inability to do so is typically the cause of the error’s persistence.

Building on the correct information can help you learn new associations to it: add something to change how you retrieve the item from your memory. You might replace your question “Name of John’s wife?” with “Name of John’s second wife?”; or use an elaboration that contains the accurate information, such as “We are weird” or “My niece is nice”; or convert 7 X 9 into 7 X (10 – 1) = 70 – 7 = 63. As you practice the elaborated association, the simpler direct association (7 X 9 = 63) eventually replaces the earlier one, which weakens without rehearsals. Labeling and rehearsing the wrong association (for example, saying to yourself, “7 X 9 is not 63”), however, are distinctly counterproductive.

VS Ramachandran on your mind

Vilayanur Ramachandran explains what brain damage can reveal about the connection between celebral tissue and the mind, using three startling delusions as examples.

A POW's 'Tears in the Darkness'

Ben Steele recounts surviving the Bataan Death March in World War II
"Men died like flies," says Steele, now 91
Steele's story is recounted in new book "Tears in the Darkness"
Steele forced to confront hatred through chance meeting after war

By John Blake

CNN -- Ben Steele hated the young man as soon as he saw him.

The man's almond-shaped eyes, dark hair and olive skin -- Steele had seen those Asian facial features before.

He saw that face when he watched Japanese soldiers behead sick men begging for water, run over stumbling prisoners with tanks and split his comrades' skulls with rifle butts.

"Men died like flies," Steele says. "I thought for a while I would never make it."

Steele, now 91, is one of the last survivors of the Bataan Death March.

During World War II, the Japanese army forced American and Filipino prisoners of war on a march so horrific that the Japanese commander was later executed for war crimes.

Steele returned home to Montana after the war to teach, but he still had something to learn.

When he saw a young Japanese-American student seated in his class one day, he felt both anger and anguish.

What, he wondered, do I do with all of the hate I've brought home with me?

'The worst war story' he ever heard

Steele's answer to that question can be found in the new book "Tears in the Darkness," a searing depiction of the Bataan Death March.

The book details how Steele found help through an unlikely source. But he would first have to survive one of the worst defeats in U.S. military history.

In December 1941, Japanese forces attacked an army of American and Filipino soldiers in the Philippine Islands and forced them to surrender. They captured 76,000 prisoners, double what they had expected.

The Japanese forced the POWs to march 66 miles under a tropical sun to a railway station for transport. They shot, bayoneted and beat to death prisoners who couldn't keep pace.

At least 7,000 soldiers died during the march.

More died later. The brutal conditions of the march contributed to the subsequent deaths of an estimated 25,000 Filipinos and 1500 Americans in Japanese prison camps, says Michael Norman, a Vietnam veteran who wrote "Tears in the Darkness," with his wife, Elizabeth.

"It's the worst war story I've ever heard," Norman says. "What they [the Japanese] did was monstrous."

Prisoners were forced to bury others alive and work as slave laborers; some were executed for sport. One Japanese soldier, who later became a Buddhist priest, told the authors that he is still haunted by what he did on Bataan.

Some Filipinos who live today near the march's route say that they, too, cannot forget what happened, Elizabeth Norman says.

"They would tell us that when they lay awake at night, they thought they could still hear the trampling of the men's feet on the death march," she says.

Why Steele survived

The death march was filled with villains, but the authors also found a hero: Steele. The march is told through his eyes and drawings.

Steele was a cowboy from Montana who could ride a horse, rope cattle and shoot by the time he was 8 years old.

"I thought that if anybody gets out of here, I'm going to be one of them," says Steele, who was a 22-year-old Army Air Corps private when he was captured.

At times, though, Steele wondered whether he was being too optimistic. He was bayoneted, starved and beaten. He was constantly ill, and his weight fell to 112 pounds.

Steele found a way to preserve his mind even as his body wasted away: He drew. He started sketching pictures of what he saw during his captivity.

"I felt an obligation to show people what went on there," he says.

Steele was released after three years of captivity when World War II ended. He returned to Billings, Montana, where he became an art professor at a state college.

"I had a lot of anger when I got home," Steele says. "We were beaten for so long. I hated [the Japanese]."

Steele meets his 'nemesis'

Steele's hatred smoldered for 15 years. It threatened to spill out into the open in 1960, when he walked into his classroom on the first day of the semester and saw a Japanese-American student.

In "Tears in the Darkness," Steele says that his "heart hardened and filled with hate." But he was so anguished by what he was feeling, he returned to his office after class to think.

He told himself that the war was over; he wasn't a prisoner anymore, and he had to treat the Japanese-American student like anybody else, because he was an American, too.

Then he did something else. He invited the student to his office for a talk.

The student's name was Harry Koyama, and he, too, had been marked by the war. His family had been imprisoned at a "relocation camp" in Arizona during the war.

Steele also discovered that he and Koyama had something else in common: a passion for drawing Montana's rural life. By the end of the semester, Koyama was one of Steele's best students.

Steele says that talking to Koyama helped his hatred evaporate.

"We had a discussion and finally came to an understanding that we liked each other," he says.

Today, Steele and Koyama remain in touch.

"We're the best of friends," Koyama tells CNN from his Montana art studio. "We see each other regularly."

Koyama says he can't remember exactly what he and Steele talked about first, only that Steele had always treated him well. Steele did tell him later that their relationship helped him recover from the war, he says.

"I was just there," Koyama says. "I just happened to be there for him to use my presence as a way to overcome his dark time."

Koyama says he is still amazed by Steele's survival story.

"Just to be a part of his life is an honor," Koyama says.

Steele's voice is still strong and his mind sharp. He's been married to his wife, Shirley, for 57 years, and they have three children and six grandchildren.

Steele says Bataan taught him to treasure small pleasures, like a drink of cool water and a warm bed at night.

"I'm thankful that I have a plateful of food," he says. "I can remember when that plate was empty."

He still remembers tiny details from the death march as well. He constantly draws pictures of his friends and tormentors on Bataan. Their faces fill his sketchbooks.

Steele's hate may be gone, but the death march lingers.

"I think about it every day," he says. "It's in my mind, and I'll never get it out."