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What is going on in teenagers’ brains as their drive for peer approval begins to eclipse their family affiliations? Brain scans of teens sizing each other up reveal an emotion circuit activating more in girls as they grow older, but not in boys. The study by Daniel Pine, M.D., of the National Institute of Mental Health (NIMH), part of National Institutes of Health, and colleagues, shows how emotion circuitry diverges in the male and female brain during a developmental stage in which girls are at increased risk for developing mood and anxiety disorders.

“During this time of heightened sensitivity to interpersonal stress and peers’ perceptions, girls are becoming increasingly preoccupied with how individual peers view them, while boys tend to become more focused on their status within group pecking orders,” explained Pine. “However, in the study, the prospect of interacting with peers activated brain circuitry involved in approaching others, rather than circuitry responsible for withdrawal and fear, which is associated with anxiety and depression.”

Pine, Amanda Guyer, Ph.D., Eric Nelson, Ph.D., and colleagues at NIMH and Georgia State University, report on one of the first studies to reveal the workings of the teen brain in a simulated real-world social interaction, in the July, 2009 issue of the Journal Child Development.

Thirty-four psychiatrically healthy males and females, aged 9 to 17, were ostensibly participating in a study of teenagers’ communications via Internet chat rooms. They were told that after an fMRI (functional magnetic resonance imaging) scan, which visualizes brain activity, they would chat online with another teen from a collaborating study site. Each participant was asked to rate his or her interest in communicating with each of 40 teens presented on a computer screen, so they could be matched with a high interest participant (see picture below).

Two weeks later, the teens viewed the same faces while in an fMRI scanner. But this time they were asked to instead rate how interested they surmised each of the other prospective chatters would be in interacting with them.

Only after they exited the scanner did they learn that, in fact, the faces were of actors, not study participants, and that there would be no Internet chat. The scenario was intended to keep the teens engaged –– maintain a high level of anticipation/motivation –– during the tasks. This helped to ensure that the scanner would detect contrasts in brain circuit responses to high interest versus low interest peers.

Although the faces were selected by the researchers for their happy expressions, their attractiveness was random, so that they appeared to be a mix of typical peers encountered by teens.

As expected, the teen participants deemed the same faces they initially chose as high interest to be the peers most interested in interacting with them. Older participants tended to choose more faces of the opposite sex than younger ones. When they appraised anticipated interest from peers of high interest compared with low interest, older females showed more brain activity than younger females in circuitry that processes social emotion.

“This developmental shift suggested a change in socio-emotional calculus from avoidance to approach,” noted Pine. The circuit is made up of the nucleus accumbens (reward and motivation), hypothalamus (hormonal activation), hippocampus (social memory) and insula (visceral/subjective feelings).

By contrast, males showed little change in the activity of most of these circuit areas with age, except for a decrease in activation of the insula. This may reflect a waning of interpersonal emotional ties over time in teenage males, as they shift their interest to groups, suggest Pine and colleagues.

“In females, absence of activation in areas associated with mood and anxiety disorders, such as the amygdala, suggests that emotional responses to peers may be driven more by a brain network related to approach than to one related to fear and withdrawal,” said Pine. “This reflects resilience to psychosocial stress among healthy female adolescents during this vulnerable period.”

Nodes of a brain circuit for social emotion and approach behavior activated more in teenage girls than in boys with age. Functional MRI data (red) superimposed on anatomical MRI images.

Source: NIMH Emotion and Development Branch

Teenage participants were first asked to rate their interest in peers with whom they might communicate in an internet chat room (left). Two weeks later, while in a brain scanner, they were asked to rate how interested the same peers were in interacting with them (right).

Source: NIMH Emotion and Development Branch

Reference

Probing the neural correlates of anticipated peer evaluation in adolescence. Guyer AE, McClure-Tone EB, Shiffrin ND, Pine DS, Nelson EE. July 2009, Child Development.

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CHAMPAIGN, Ill.—We swim in a sea of information, but filter out most of what we see or hear. New analysis of data from dozens of studies sheds new light on how we choose what we do and do not hear. The study found that while people tend to avoid information that contradicts what they already think or believe, certain factors can cause them to seek out, or at least consider, other points of view.

The analysis, reported this month in Psychological Bulletin published by the American Psychological Association and led by researchers at the University of Illinois and the University of Florida, included data from 91 studies involving nearly 8,000 participants. It puts to rest a longstanding debate over whether people actively avoid information that contradicts what they believe, or whether they are simply exposed more often to ideas that conform to their own because they tend to be surrounded by like-minded people.

“We wanted to see exactly across the board to what extent people are willing to seek out the truth versus just stay comfortable with what they know,” said University of Illinois psychology professor Dolores Albarracín, PhD, who led the study with University of Florida researcher William Hart, PhD. The team also included researchers from Northwestern University and Ohio University.

The studies they reviewed generally asked participants about their views on a given topic and then allowed them to choose whether they wanted to view or read information supporting their own or an opposing point of view.

The researchers found that people are about twice as likely to select information that supports their own point of view (67 percent) as to consider an opposing idea (33 percent). Certain individuals, those with close-minded personalities, are even more reluctant to expose themselves to differing perspectives, Albarracín said. They will opt for the information that corresponds to their views nearly 75 percent of the time.

The researchers also found, not surprisingly, that people are more resistant to new points of view when their own ideas are associated with political, religious or ethical values.

“If you are really committed to your own attitude – for example, if you are a very committed Democrat – you are more likely to seek congenial information, that is, information that corresponds with your views,” Albarracín said. “If the issues concern moral values or politics, about 70 percent of the time you will choose congenial information, versus about 60 percent of the time if the issues are not related to values.”

Perhaps more surprisingly, people who have little confidence in their own beliefs are less likely to expose themselves to contrary views than people who are very confident in their own ideas, Albarracín said.

Certain factors can also induce people to seek out opposing points of view, she said. Those who may have to publicly defend their ideas, such as politicians, for example, are more motivated to learn about the views of those who oppose them. In the process, she said, they sometimes find that their own ideas evolve.

People are also more likely to expose themselves to opposing ideas when it is useful to them in some way, Albarracín said. “If you’re going to buy a house and you really like the house, you’re still going to have it inspected,” she said. Similarly, no matter how much you like your surgeon, you may seek out a second opinion before scheduling a major operation, she said.

For the most part, it seems that people tend to stay with their own beliefs and attitudes because changing those might prevent them from living the lives they’re living,” Albarracín said. “But it’s good news that one out of three times, or close to that, they are willing to seek out the other side.”

Article: “Feeling Validated Versus Being Correct: A Meta-Analysis of Selective Exposure to Information,” Dolores Albarracín, PhD, University of Illinois at Urbana-Champaign; William Hurt, PhD, Inge Brechan, PhD, and Lisa Merrill, PhD, University of Florida; Alice H. Eagly, PhD, Northwestern University, Matthew J. Lindberg, PhD, Ohio University; Psychological Bulletin, Vol. 135, No. 4.

(Full text of the article is available from the APA Public Affairs Office and at http://www.apa.org/journals/releases/bul1354555.pdf.)

Contact Dolores Albarracín by e-mail and by phone at 217-244-7019

Chromosomal Hotspot of Immunity/Gene Expression Regulation Implicated

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 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

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New Look at Data Confirms Strong Association between Depression and Stressful Life Events

Stressful life events are strongly associated with a person’s risk for major depression, but a certain gene variation long thought to increase risk in conjunction with stressful life events actually may have no effect, according to researchers funded by the National Institute of Mental Health (NIMH), part of the National Institutes of Health. The study, published in the June 17, 2009, issue of the Journal of the American Medical Association, challenges a widely accepted approach to studying risk factors for depression.

“Rigorous re-evaluations of published studies provide the checks and balances necessary for scientific progress,” said Thomas R. Insel, M.D., director of NIMH. “We are still in the early days of understanding how genes and environment interact to increase the risk for depression.”

Most mental disorders are thought to be caused by a combination of many genetic risk factors interacting with environmental triggers. However, finding the exact combinations continues to present significant challenges to research.

Advances in scientific understanding and technologies during the past decade have led to powerful tools for studying how genetic and environmental factors can affect a person’s risk for disease. Such advances allowed mental health researchers in 2003 to show that a gene involved in serotonin activity increased the risk of major depression in people who had a number of stressful life events over a five-year period (see “More About the Science” below for more information about this gene and serotonin). Coming at a time of heightened research interest in these gene-environment interactions and the relative lack of progress in the field for mental disorders, this study received wide acclaim and had a far-reaching influence. Not only have considerable resources been invested in subsequent studies that built on this finding, but also some researchers have proposed marketing the gene test to the public, claiming to be able to predict a person’s risk for depression.

However, efforts to replicate the 2003 study’s findings—a key step in scientific progress that helps show whether a particular finding was a chance event—have had inconsistent results.

To examine whether the 2003 study’s finding had been confirmed, a group of scientists from NIMH and six universities with expertise in epidemiology, biostatistics, genetics, and psychiatry reviewed the status of relevant replication studies. Led by Kathleen Merikangas, Ph.D., of the NIMH Intramural Research Program, the workgroup did a meta-analysis, re-analyzing data on 14,250 participants in 14 studies published from 2003 through March 2009. Of these, the researchers also re-analyzed original data, including unpublished information, on 10,943 participants from 10 studies published before 2008. The workgroup analyzed these original data to see whether there were gender differences in the associations between the serotonin genotype, stressful life events, and depression.

By applying the same definitions of study variables and data analysis methods used in the 2003 study, the workgroup found a strong association between the number of stressful life events and risk of depression across the studies. However, the presumed high-risk version of the serotonin transporter gene did not show a relationship to increased risk for major depression, alone or in interaction with stressful life events, in the analysis of the 14 studies. Their findings were the same in men and women alone in the analysis of original data from 10 studies.

The workgroup noted that their analysis had some limitations. Individual level data were available for only 10 of the 14 studies published before 2008. However, these limitations would have had little effect on the overall findings because the number of participants in the studies not included was only a small proportion of the total sample.

These findings may account for the difficulty many researchers have faced in attempting to replicate the 2003 study. This analysis confirms some earlier reviews that had also questioned the validity of the gene’s effect on depression risk. However, the workgroup emphasized that the intent of its analysis was not to deter research on gene-environment interactions for mental disorders.

“Identifying gene-environment interactions is most successful when studies can focus on a single gene with a major effect, or when the environmental exposure has a strong effect,” said lead author Neil Risch, Ph.D., University of California, San Francisco and Kaiser Permanente Northern California. “In the case of modest gene effects or environmental impacts, the statistical power to detect an interaction will be low, and thus weak positive results should be interpreted carefully.”

The authors concluded that incorporating environmental exposures in candidate gene studies (those that study a particular gene) may be as likely to yield false positive findings as the candidate gene studies themselves. Therefore, the results of other studies using the same approach as the 2003 study also deserve thorough review and meta-analysis.

“Even though our re-analysis did not confirm an association between the serotonin gene and depression, the finding that the environmental factor was strongly associated with depression in several studies reminds us that environmental factors are also involved in the complex pathways leading to mental disorders,” noted Merikangas. “Future progress will require thoughtful integration of the tools of genetics, epidemiology, and clinical and behavioral sciences.”

The authors on the paper include Neil Risch, Ph.D., University of California at San Francisco and Kaiser Permanente Northern California; Richard Herrell, Ph.D., NIMH; Thomas Lehner, Ph.D., NIMH; Kung-Yee Liang, Ph.D., Johns Hopkins University; Lindon Eaves, Ph.D., Virginia Commonwealth University; Josephine Hoh, Ph.D., Yale University; Andrea Griem, NIMH; Maria Kovacs, Ph.D., University of Pittsburgh; Jurg Ott, Ph.D., Rockefeller University; Kathleen Ries Merikangas, Ph.D., NIMH.

Reference

Risch N, Herrell R, Lehner T, Liang KY, Eaves L, Hoh J, Griem A, Kovacs M, Ott J, Merikangas KR. Interaction between the Serotonin Transporter Gene, Stressful Life Events and Risk of Depression: A Meta-Analysis. JAMA. 2009 Jun 17;301(23):2462-71.

Rarity Makes Definitive Assessment Elusive

A study examining stimulant use among children and adolescents found an association between stimulants and sudden unexplained death in youth with no evidence of pre-existing heart disease. The finding draws attention to the potential risks of stimulant medication, according to the study’s authors; an accompanying editorial notes that the rarity of sudden unexplained death and the lack of long-term data on the effectiveness of these medications for reducing other health risks make a full benefit/risk assessment difficult.

Background

Stimulant medications are widely used to treat children with attention deficit hyperactivity disorder (ADHD). The medications help reduce hyperactivity and impulsivity and improve the ability of affected children to focus and learn. Research has shown that stimulants can also have effects on the cardiovascular system, for example, raising blood pressure and heart rate. There have also been reports of sudden deaths in children receiving the medications, prompting the U.S. Food and Drug Administration (FDA) to direct drug manufacturers to inform consumers of possible risks of stimulant medications in children and adolescents with known pre-existing heart problems. In order to assess the association between stimulants and risk of death in young people, the National Institute of Mental Health and the FDA jointly funded a study looking at records of children and adolescents who died suddenly and unexpectedly.

This Study

Madelyn Gould, Ph.D., and colleagues at Columbia University College of Physicians & Surgeons and the New York State Psychiatric Institute identified 564 children and adolescents who had died suddenly for unexplained reasons. These youth had no known structural heart defects or other co-existing physical disorders known or suspected to be associated with sudden death. Each of these young people was then matched with a comparison young person who had also died suddenly, but in a motor vehicle accident. Information from family, medical, and autopsy records were systematically reviewed. The results revealed that stimulants were used by 10 of the young people whose deaths were unexplained and by 2 who died in crashes. (The stimulant found in each case was methylphenidate [Ritalin]. This study examined deaths that occurred between 1985 and 1996, before mixed amphetamine preparations [Adderall] became commonly used).

Because sudden death is extremely rare in childhood, randomized controlled studies—the ideal approach to studying health effects in populations—cannot be conducted to investigate such events. The authors employed a case-control design in which child or adolescent with the condition of interest—in this case sudden unexplained death—was matched with someone who died suddenly as a passenger in a motor vehicle accident. Using this approach, the authors were able to control for many relevant factors other than those being studied, such as asthma and other conditions associated with sudden death, although it was not possible to control for all potentially confounding factors.

Significance

According to the authors, the results of this study draw attention to concerns that stimulant medications increase the risk of sudden unexplained death in children and adolescents. The accompanying editorial, by coauthors Benedetto Vitiello, M.D. and Kenneth Towbin, M.D., both at NIMH, points out that the study, though rigorous in its approach, could not provide information on whether ADHD itself could increase the risk of sudden death, given its association with high-risk behaviors such as substance abuse.

The editorial went on to note that while randomized prospective studies are not practical—given the large numbers of subjects needed to detect such rare events—additional case/control studies would still be informative. In addition, research to improve screening methods for heart conditions that raise the risk of sudden death is essential.

Finally, the editorial notes that “1) sudden unexplained death is a rare event, 2) this is only the first such study, 3) it relies on small numbers, and 4) it is not possible to quantify the risk beyond estimating that it is very small.”

Reference

Gould, M.S., Walsh, T., Munfakh, J.L., Kleinman, M., Duan, N., Olfson, M., Greenhill, L, and Cooper, T. Sudden death and use of stimulant medications in youth. American Journal of Psychiatry AIA:1-10, 2009.

Vitiello, B. and Towbin, K. Stimulant treatment of ADHD and risk of sudden death in children. American Journal of Psychiatry AIA:1-10, 2009.