Public release date: 10-Jul-2005
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Contact: Jennifer Loukissas
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NIH/National Institute of Mental Health

Scientists uncover new clues about brain function in human behavior
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."


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

For more information visit the NINDS web site on Williams at
http://www.ninds.nih.gov/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.





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