As discussed extensively in Eisenberg et al. (NeuroImage, 2010), investigation of the neurobiology of Williams Syndrome (WS), a condition with a well-defined causitive microdeletion and characteristic neuropsychiatric manifestations, poses a unique opportunity to understand the genetic foundations of complex social and cognitive neural systems in a bottom-up fashion. Accordingly, the Section on Integrative Neuroimaging has capitalized on this opportunity to make substantial progress toward defining the nature and boundaries of these gene-brain relationships in WS and carefully matched comparison volunteers. A key recent example is the precise delineation of the neural abnormalities underlying classic visuospatial deficits in WS. Though visuospatial constructive problems have long been appreciated in this syndrome, we have in recent years demonstrated via multi-modal neuroimaging experiments disrupted dorsal stream specifically, intraparietal sulcal region activation during spatial judgments, neural integrity, and structure. These landmark findings invited the vital question of whether there were also upstream abnormalities in primary visual cortex that might also contribute during development to either the brain or behavioral WS phenotypes. In Olsen et al. (Brain, 2009) we used magnetic resonance imaging-based visual field mapping in order to establish the neurofunctional status of early visual processing in WS relative to that in controls matched for age and IQ. Although primary visual cortex (V1) boundaries varied in WS participants, this region did not differ in size between groups, and overlap maps showed that the average centers of gravity for the two groups were largely colocalized. This work provides the first use of retinotopy to define the functional neuroanatomy of V1 in WS and one of the first uses of this technique in a human pathological condition that affects visuospatial processing. These results are consistent with the notion that neural abnormalities underlying visuospatial construction arise at later stages in the dorsal visual processing stream, likely at or immediately proximal to our observations in the intraparietal sulcal region. In addition to visuospatial impairments, WS individuals harbor dyadic contrapuntal socio-emotional functioning, such that hypersociability is coupled with heightened non-social anxiety. This dramatic aspect of WS, with obvious implications for understanding neurogenetic bases for social cognition and anxiety generally, serves as a second focus of our research, and we have had considerable success in identifying plausible systems-level correlates of these phenotypes. In particular, we have found decreased fearful face stimuli evoked amygdala activation in WS for compared to IQ matched healthy controls and conversely, an increased in amygdala response in WS to non-social frightening stimuli as compared with matched healthy control participants. Importantly, using structural equation modeling, we found these differences to be linked to altered prefrontal regulation. To follow up on this important set of results, our current study by Munoz et al. (NeuroImage, 2010) used social and non-social emotional stimuli during a verbal discrimination task that would reliably tax cognitive, prefrontal processes in addition to emotional, limbic systems. Evidence from this study confirmed our previous findings of exaggerated amygdala response to non-social frightening visual stimuli in WS and, further, indicated that task difficulty modulates prefrontal, but not amygdala, response in participants. These data support evidence of disruption in amygdala-prefrontal circuitry in WS but importantly indicate that core biases in social context-dependent emotional responsivity are unaffected by cognitive challenge. In sum, our efforts have resulted in the identification of candidate neurofunctional substrates for hallmark neuropsychological abnormalities in WS, and continued progress toward better defining precise genetic, developmental and neurochemical contributions toward these disturbances is ongoing.
