The Clinical Translational Neuroscience Branch continues to work toward discovery of novel genetic contributions to brain structure, function and clinically relevant behavior and cognition, through execution of an ongoing series of multimodal neuroimaging studies of individuals with copy number variation in the 7q11.23 Williams Syndrome (WS) genomic region (hemizygous microdeletion of a contiguous segment of DNA at this locus). These studies have been responsible for seminal advances in elaborating the neural underpinnings of both visuospatial and socio-emotional aspects of the 7q11.23 phenotype. We have established that the visuospatial construction deficits in WS are linked to convergent intraparietal sulcus alterations, via multiple neuroimaging techniques, including voxel- and surface-based cortical morphometry, diffusion tensor imaging, and functional MRI. Specifically, in this brain region, we have shown that WS individuals harbor disrupted neural integrity, altered activation during spatial judgments, gray matter volume and sulcal depth reductions, and associated neural fiber tracts. Likewise, in pursuit of systems-level correlates of the hypersociability and non-social anxiety observed in WS, we have found decreased amygdala activation evoked by fearful face stimuli and conversely, increased amygdala response to non-social frightening stimuli, abnormalities that were linked to altered prefrontal regulation in structural equation models. We have also identified convergent alterations in anterior insula structure, function, and inter-regional connectivity, which predict the characteristic WS personality. Efforts this year have focused on data collection of these same measurements of visuospatial and socio-emotional 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) as part of our longitudinal WS neurodevelopmental initiative. Preliminary data from our WS developmental cohort, for instance, has already demonstrated parietal hypofunction during visuospatial challenge and altered social network activation during processing of socially salient stimuli, consistent with the hypothesis that both visuospatial and social neurobiological differences in WS are rooted in early life. However, this project seeks not only to expand knowledge of the WS-related brain systems in childhood, but also to identify developmental trajectory (throughout childhood) and gene dose-response characteristics of neural abnormalities underlying visuospatial and socio-emotional alterations in this syndrome using a longitudinal, repeated measures design. 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 is enormous. In parallel, we have undertaken studies of WS-associated DNA sequence variation in individuals without WS. This work has yielded remarkable interactions between genotype in the WS-associated GTF2I gene and a measure of trait neuroticism, harm avoidance, in predicting prefrontal response during an emotional face viewing task. In so far as GTF2I sequence variation affects the neural correlates of anxiety-related behavior, this gene may be of particular relevance to the dichotomous anxiety phenotypes present in WS. To the extent that this finding was identified in individuals without WS, such work exemplifies the translational possibilities of WS-directed research benefiting broader scientific understanding of key neural processes in the human brain. This work includes the following studies: NCT01132885, NCT00004571, NCT00001258
