| Rare Deficit Maps Thinking Circuitry
Using brain imaging, neuroscientists at the NIH’s National
Institute of Mental Health (NIMH) have pinpointed the site of a
defect in a brain circuit associated with a specific thinking deficit.
Their study demonstrates how a rare genetic disorder, Williams Syndrome,
can offer clues as to how genetic flaws may translate into cognitive
symptoms in more common and complex major mental disorders. Andreas
Meyer-Lindenberg, M.D., Karen Berman, M.D., and colleagues, traced
the thinking deficit to a circuit at the back of the brain that
processes locations of objects in the visual field. The researchers
report on their Magnetic Resonance Imaging (MRI) study in the September
2, 2004 Neuron.
The study focused on the inability to visualize an object as a
set of parts and then construct a replica, as in assembling a puzzle
a key cognitive deficit experienced by people with Williams
Syndrome. In addition to this visuospatial construction deficit,
people with Williams Syndrome also tend to be overly friendly and
anxious and often have mental retardation and learning disabilities.
Compared to most mental disorders, which are thought to involve
complex interactions between multiple genes and environmental triggers,
the genetic basis of Williams Syndrome is remarkably well understood.
People with the disorder lack about 21 genes in a particular part
of chromosome 7.
“Williams Syndrome yields a unique opportunity to study how
genes influence our ability to construct our social and spatial
worlds,” said NIMH Director Thomas Insel, M.D. “By studying
people with this disorder, we can discover how genetic mutations
change not only molecular and cellular processes, but lead to differences
in the brain circuitry for complex aspects of cognition.”
To identify where in the brain things go awry in the visuospatial
construction deficit, Meyer-Lindenberg and Berman recruited 13 “high
functioning” Williams Syndrome patients with normal intelligence.
Even though they were missing the same genes as their mentally retarded
peers, they were able to perform complex cognitive tasks during
functional MRI (fMRI) experiments, and their brain structure and
activity could be compared with matched healthy controls of similar
The researchers suspected that the visuospatial construction deficit
would be found in a visual processing circuit that courses forward
and upward from the back of the brain. This “where”
circuit processes information about locations of objects and spatial
relationships, whereas a parallel “what” circuit, running
downward from the back of the brain, handles information about content
In the fMRI phase of the study, participants were scanned while
performing spatial tasks matching geometric objects, assembling
puzzle-like pieces into a square, and attending to the location
of faces and houses. In each case, only those with Williams Syndrome
failed to activate the “where” circuit, while the controls
showed increased activation in that circuit. The patients’
brains showed no difference from controls on tasks that activated
the “what” circuit.
Using structural MRI, the researchers found a small region early
in the “where” circuit that lacked gray matter (neuron
bodies) in the Williams Syndrome participants. Its location
conspicuously just before the functionally abnormal areas
raised suspicions; and a path analysis confirmed that the functional
abnormalities could be accounted for by defective input from this
structurally abnormal area. The researchers hypothesize that it
is likely the primary site of the visuospatial construction deficit.
They are now attempting to trace the deficit to individual genes
in this structurally abnormal area.
“The location of the abnormality also suggests a strategy
for improving visual-spatial-construction function,” noted
Meyer-Lindenberg. “It is like a roadblock, but it should mainly
affect stimuli that don’t move. Incorporating motion into
stimuli might provide an alternate route and circumvent the problem
by engaging temporal lobe circuitry.”
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 Dr. Carolyn Mervis, University of
Also participating in the study were Philip Kohn, Dr. Shane Kippenhan,
Rosanna Olsen, NIMH, and Dr. Colleen Morris, University of Nevada.
|3-D MRI scan rendering of the brain’s white matter (nerve
fibers), showing small area (yellow) found to lack grey matter in
people with Williams Syndrome. Impaired input from this area is
thought to have resulted in lack of activation in downstream parts
of the circuit, which processes locations of objects, when participants
performed visual-spatial tasks, such as paying attention to locations
of faces and houses (red), assembling puzzle-like pieces and matching
geometric objects (blue). Overlap regions are shown in purple.|
|Structurally abnormal site is obscured within the cortex’s
folds in this full rendering of the brain, showing the functionally
abnormal circuit. Source: Shane Kippenhan, Ph.D., NIMH Clinical
Brain Disorders Branch
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.