Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

为了描述特定的遗传贡献的大脑结构，功能和临床相关的行为和认知，我们已经执行了一个正在进行的一系列多模态神经影像学研究的个人与拷贝数变异的7q11.23威廉姆斯综合征（WS）基因组区域。 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。我们已经建立了视觉空间的建设赤字在WS（半合子微缺失的一个连续的DNA片段在这个位点）与会聚顶内沟的改变，通过多种神经影像学技术，包括体素和表面为基础的皮质形态测量，扩散张量成像和功能性MRI。具体来说，我们已经表明，WS个体港口中断顶内沟区神经的完整性，激活空间判断，灰质体积，沟的深度，和相关的神经纤维束。同样，在追求合理的系统水平的相关性的过度社交和非社交焦虑观察到的WS，我们发现减少杏仁核激活引起的恐惧的脸刺激，相反，增加杏仁核反应非社会可怕的刺激，异常与改变前额叶调节结构方程模型。我们还发现了前额叶结构、功能和区域间连接的会聚性改变，这些改变可以预测典型的威廉姆斯综合征（WS）人格。 在我们新的纵向WS神经发育研究的主持下，我们现在已经能够在越来越多的有和没有WS关键区域拷贝数变异的儿童队列中加速收集这些相同的视觉空间和社会情感系统完整性测量结果（即，具有WS关键区的一个（WS）、两个（神经型）或三个（WS区重复）拷贝的个体）。增长这一独特的数据集将允许了解这种综合征中视觉空间和社会情感改变的神经异常的发育轨迹和基因剂量反应特征。虽然数据积累需要多年的仔细和协调一致的努力才能完成，但这些研究在揭示基因对大脑发育的贡献方面的潜力是巨大的。 与此同时，我们已经进行了研究的DNA序列变异的个人没有WS。这项工作已经取得了显着的基因型之间的相互作用，在WS相关的GTF2I基因和测量的特质神经质，避免伤害，在预测前额叶反应在情绪化的面孔观看任务。 到目前为止，GTF2I序列变异影响神经相关的焦虑相关行为，这个基因可能是特别相关的二分法焦虑表型存在于WS。在某种程度上，这一发现是在没有WS的个人确定，这样的工作证明了翻译的可能性WS导向的研究，有利于更广泛的科学了解人类大脑中的关键神经过程。 本工作包括以下研究：NCT 01132885、NCT 00004571、NCT 00001258

In order to delineate specific genetic contributions to brain structure, function and clinically relevant behavior and cognition, we have executed an ongoing series of multimodal neuroimaging studies of individuals with copy number variation in the 7q11.23 Williams Syndrome (WS) genomic region. 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 (hemizygous microdeletion of a contiguous segment of DNA at this locus) 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, we have shown that WS individuals harbor disrupted intraparietal sulcal region neural integrity, activation during spatial judgments, gray matter volume, sulcal depth, and associated neural fiber tracts. Likewise, in pursuit of plausible 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 Williams syndrome (WS) personality. Under the auspices of our new longitudinal WS neurodevelopmental study, we have now been able to accelerate 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). 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. In parallel, we have undertaken studies of 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