The Section on Integrative Neuroimaging has made substantial progress toward elucidating specific genetic contributions to brain structure and function through multimodal neuroimaging studies of Williams Syndrome (WS) individuals and carefully matched comparison volunteers. As discussed extensively in Eisenberg et al. (1), we have in recent years identified the neural substrates of the characteristic visuospatial construction deficits in this condition by demonstrating 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. (2) 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 provided 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, Munoz et al. (3) 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. To the extent that the insular cortices have also been implicated in mediating social emotional response tendencies that define personality, our most recent multimodal investigations have sought to identify convergent alterations in anterior insula structure, function, and inter-regional connectivity, as well as determine the extent to which these measures predict the characteristic Williams syndrome (WS) personality. In Jabbi et al (4), we show that in WS there is an overall decrease in dorsal anterior insula (AI) gray-matter volume,but locally increased volume in the right ventral AI, as well as reduced white-matter integrity of the uncinate fasciculus connecting the insula with the amygdala and orbitofrontal cortex, widespread reductions in dorsal AI regional cerebral blood flow (rCBF) with locally increased rCBF in the right ventral AI, and abnormal relationships between rCBF in AI and other limbic regions. Importantly, these differences predicted the strength of the WS personality profile. We believe ongoing work in this vein will provide improved understanding of critical links between genetics and behavioral phenomenology relevant beyond WS itself. However, perhaps the greatest recent advancement made by the Section, however, has been the successful initiation of longitudinal multimodal neuroimaging studies of WS children. Though data accrual will require years of careful and concerted effort, the potential for these studies to shed unprecedented light on genetic contributions to brain development are enormous. 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.
