Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

临床和转化神经科学分支通过对7q11.23威廉姆斯综合征（WS）基因组区拷贝数变异个体（该位点连续DNA片段的半合子微缺失）进行一系列正在进行的多模态神经影像学研究，继续致力于发现大脑结构、功能和临床相关行为和认知的新遗传贡献。这些研究在阐述7q11.23表型的视觉空间和社会情感方面的神经基础方面取得了开创性的进展。通过多种神经成像技术，包括基于体素和表面的皮层形态测量、弥散张量成像和功能性MRI，我们已经确定WS的视觉空间构建缺陷与会聚性顶叶内沟改变有关。具体来说，在这一脑区，我们已经表明患有WS的个体神经完整性被破坏，空间判断过程中的激活改变，灰质体积和脑沟深度减少，以及相关的神经纤维束异常。同样，在探究WS患者的超社交性和非社交性焦虑的系统水平相关性时，我们发现恐惧面孔刺激引起的杏仁核激活减少，相反，杏仁核对非社交性恐惧刺激的反应增加，结构方程模型中的异常与前额叶调节改变有关。我们还发现了脑岛前部结构、功能和区域间连通性的收敛性改变，这些改变可以预测WS人格的特征。作为我们的纵向WS神经发育计划的一部分，今年的工作重点是在越来越多的有和没有WS关键区域拷贝数变异的儿童（即在WS关键区域有一个WS、两个典型发育或三个受影响基因的Dup7拷贝的个体）中收集这些相同的视觉空间和社会情感系统完整性的结构和功能测量数据。

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