Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

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Employing incisive, multimodal neuroimaging methodologies to study individuals with WS and related genetic variation in the WS critical region, the Section on Integrative Neuroimaging has vigorously pursued its mission of elaborating clinically meaningful, specific genetic contributions to brain structure and function. Recent advancements made toward that end have been manifold but are rooted in several foundational WS characteristics. First, prominent visuospatial construction deficits in this condition motivated a series of experiments in WS adults with normal-range IQ and carefully matched control subjects (Eisenberg et al, 2014). Using multiple neuroimaging techniques, including retinotopic mapping, voxel- and surface-based cortical morphometry, and functional MRI, we identified a neural signature of these deficits that converges in the intraparietal sulcus. Specifically, we demonstrated spared early visual cortex functioning, but disrupted intraparietal sulcal region neural integrity, activation during spatial judgments, gray matter volume, and sulcal depth. In addition to visuospatial impairments, WS individuals harbor dyadic contrapuntal a distinctive pattern of 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. We have also identified convergent alterations in anterior insula structure, function, and inter-regional connectivity, which predict the characteristic Williams syndrome (WS) personality. An integral part of the WS phenotype is vascular abnormalities, most commonly supravalvular aortic stenosis and peripheral pulmonary artery stenosis, which have been attributed to hemideletion of the WS-region gene, elastin. Because elastin may be important in defining the structure of intracerebral vasculature, we sought to identify whether WS individuals with deletions that included elastin were at increased risk for clinically relevant anomalous cerebrovasculature. Using magnetic resonance angiography, we have thusfar found no evidence for abnormal dilation or stenosis of intracranial vessels (Wint et al., 2014). Under the auspices of our new longitudinal WS neurodevelopmental study, we have now been able to initiate collection of these same measurements of visuospatial, socio-emotional, and neurovascular systems integrity in a growing cohort of children with and without WS critical region copy number variation (i.e., individuals with one (WS), two (neurotypical), or three (WS region duplication) copies of the WS critical region). Growing this unique dataset will allow understanding of both the developmental trajectory and gene dose-response characteristics of neural abnormalities underlying visuospatial and socio-emotional alterations in this syndrome. Though data accrual will require years of careful and concerted effort to complete, the potential for these studies to shed unprecedented light on genetic contributions to brain development are enormous.