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. 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,
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: http://www.nimh.nih.gov/press/prwilliams.cfm.

For more information visit the NINDS web site on Williams
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.

For a press release photo that depicts abnormal regulation of the amygdala
in participants with Williams Syndrome compared to controls please visit
http://www.nih.gov/news/pr/jul2005/nimh-10.htm#brain.

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.

The National Institutes of Health (NIH) -- "The Nation's Medical Research
Agency" -- is comprised of 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational
medical research, and investigates the causes, treatments, and cures for
both common and rare diseases. For more information about NIH and its
programs, visit www.nih.gov.