Researchers at the National Institute of Mental Health (NIMH), part of the National Institutes of Health, have discovered a genetically controlled brain mechanism responsible for social behavior in humans--one of the most important but least understood aspects of human nature. The findings are reported in Nature Neuroscience, published online on July 10, 2005.

The study compared the brains of healthy volunteers to those with a genetic abnormality, Williams Syndrome, a rare disorder that causes unique changes in social behavior. This comparison enabled the researchers to both define a brain circuit for social function in the healthy human brain, and identify the specific way in which it was affected by genetic changes in Williams Syndrome.

People with Williams Syndrome who are missing about 21 genes on chromosome seven are highly social and empathetic, even in situations that would elicit fear and anxiety in healthy people. They will eagerly, and often impulsively, engage in social interactions, even with strangers. However, they experience increased anxiety that is non-social, such as fear of spiders or heights (phobias) and worry excessively.

For several years, scientists have suspected that abnormal processing in the amygdala, an almond-shaped structure deep in the brain, may be involved in this striking pattern of behavior. The amygdala's response and regulation are thought to be critical to people's social behavior through the monitoring of daily life events such as danger signals. Scientists know from animal studies that damage to the amygdala impairs social functioning.

"Social interactions are central to human experience and well-being, and are adversely affected in psychiatric illness. This may be the first study to identify functional disturbances in a brain pathway associated with abnormal social behavior caused by a genetic disorder," said NIMH Director Thomas R. Insel, M.D.

In this study, investigators used functional brain imaging (fMRI) to study the amygdala and structures linked to it in 13 participants with Williams Syndrome who were selected to have normal intelligence (Williams Syndrome is usually associated with some degree of mental retardation or learning impairment) and compared to healthy controls. Andreas Meyer-Lindenberg, M.D., Ph.D., and Karen Berman, M.D., from the NIMH Genes, Cognition, and Psychosis Program, and colleagues, then showed participants pictures of angry or fearful faces. Such faces are known to be highly socially relevant danger signals that strongly activate the amygdala. The fMRI showed considerably less activation of the amygdala in participants with Williams Syndrome than in the healthy volunteers (see graphic below). These findings suggest that reduced danger signaling by the amygdala in response to social stimuli might be responsible for their fearlessness in social interactions.

Next, researchers showed the study participants pictures of threatening scenes (a burning building or a plane crash), which did not have any people or faces in them and thus had no immediate social component. In remarkable contrast to the response to faces, the amygdala response to threatening scenes was abnormally increased in participants with Williams Syndrome (see graphic below), mirroring their severe non-social anxiety.

"The amygdala response perfectly reflected the unique profile of social and non-social anxiety in Williams Syndrome," said Meyer-Lindenberg. "Because our data showed that the amygdala did still function, although abnormally, in Williams Syndrome, we wondered whether it might be its regulation by other brain regions that was the cause of the amygdala abnormalities."

To investigate this, the scientists looked at the whole brain to identify other regions where reactivity was different between Williams's participants and healthy volunteers. They identified three areas of the prefrontal cortex, located in the front part of the brain, that have been implicated in decision-making, representation of social knowledge, and judgment. Those regions are the dorsolateral, the medial, and the orbitofrontal cortex. Specifically, the dorsolateral area is thought to establish and maintain social goals governing an interaction; the medial area has been associated with empathy and regulation of negative emotion; and orbitofrontal region is involved in assigning emotional values to a situation.

The researchers found a delicate network by which these three regions modulate amygdala activity. In Williams Syndrome, this fragile system was significantly abnormal, particularly the orbitofrontal cortex. This area did not activate for either task and was not functionally linked to the amygdala, as it was in healthy controls. Instead, the scientists observed increased activity and linkage in the medial region, which is consistent with the high level of empathy exhibited by people with Williams Syndrome.

"We had previously seen that the orbitofrontal cortex is structurally abnormal in Williams Syndrome, but we didn't know what role it played functionally in the disorder; it is now clear that this area can play a major role in producing social behavioral abnormalities," said Berman. "The over-activity of the medial-prefrontal cortex may be compensatory, but the result is still an abnormal fear response. The medial-prefrontal cortex still works and in fact it is working over-time because it may be the only thing that still regulates the amygdala in Williams Syndrome."

Other releases on this topic:
nimh.nih/press/prwilliams.cfm

For more information visit the NINDS web site on Williams at
ninds.nih/disorders/williams/williams.htm

In addition to the NIMH Intramural Research Program, the research was also funded by a grant from the National Institute on Neurological Disorders and Stroke (NINDS) to co-author Dr. Carolyn Mervis, University of Louisville.

Also participating in the research were Dr. Ahmad Hariri, Karen Munoz, Dr. Venkata Mattay, NIMH, and Dr. Colleen Morris, University of Nevada.

NIMH and NINDS are part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.

Contact: Jennifer Loukissas
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301-443-4536
NIH/National Institute of Mental Health
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