Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

点击翻译按钮获取中文摘要

The Clinical and Translational Neuroscience Branch continues to work toward discovery of novel genetic contributions to brain structure, function, and clinically relevant behavior and cognition, through a series of ongoing 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. Via multiple neuroimaging techniques, including voxel- and surface-based cortical morphometry, diffusion tensor imaging, and functional MRI, we have established that the visuospatial construction deficits in WS are linked to convergent intraparietal sulcus alterations. Specifically, in this brain region, we have shown that individuals with WS harbor disrupted neural integrity, altered activation during spatial judgments, gray matter volume and sulcal depth reductions, and associated neural fiber tract anomalies. 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 structural and functional 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 typically developing, or three Dup7 copies of affected genes in the WS critical region) as part of our longitudinal WS neurodevelopmental initiative. In proof-of-concept work aimed at establishing neurostructural gene-dosage effects, we have studied microanatomical measures and found increasing overall brain size with increasing copy number (Dup7>TD>WS), but decreasing relative cerebellar size (WS>TD>Dup7) with copy number of affected genes. Interestingly, both of these Dup7 phenotypes (larger brain size and relatively smaller cerebellum) have been described in the autism literature, particularly in boys, although these findings are not without controversy. Following this work, we are undertaking similar gene-dosage analyses of more localized morphometry throughout the brain, as well as local gyrification index and resting-state whole-brain connectivity, the latter using a recently-developed connectome-wide association study approach as well as independent component and dual-regression analyses. In parallel, we continue to undertake 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. Insofar as GTF2I sequence variation affects the neural correlates of anxiety-related behavior, this gene may be of particular relevance to the dichotomous social versus non-social 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 in benefiting a broader scientific understanding of key neural processes in the human brain. Preliminary data from our WS developmental cohort 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. 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. This work includes the following studies: NCT01132885, NCT00004571, NCT00001258