Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

综合神经成像科采用精辟的多模式神经成像方法研究WS关键区域的WS患者和相关遗传变异，积极履行其使命，阐述对大脑结构和功能具有临床意义的特定遗传贡献。最近在这方面取得的进展是多方面的，但都植根于几个基本的WS特征。首先，在这种情况下，突出的视觉空间结构缺陷激发了一系列实验，研究对象为智商正常范围的WS成年人和精心匹配的对照组受试者(Eisenberg等人，2014)。使用多种神经成像技术，包括视网膜定位图，基于体素和表面的皮质形态测量，以及功能磁共振成像，我们识别出这些缺陷的神经特征会聚在顶骨内沟。具体地说，我们展示了早期视觉皮质功能，但破坏了顶内脑沟区域神经完整性、空间判断时的激活、灰质体积和脑沟深度。除了视觉空间障碍外，WS个体还具有一种独特的社会情绪功能模式，即过度社交伴随着高度的非社交焦虑。WS的这一戏剧性方面，对于理解社会认知和焦虑的神经遗传学基础具有明显的意义，是我们研究的第二个重点，我们在识别这些表型的合理的系统水平相关性方面取得了相当大的成功。特别是，我们发现与智商匹配的健康对照组相比，恐惧面孔刺激导致WS中杏仁核激活减少，相反，与匹配的健康对照组参与者相比，WS中对非社会性恐惧刺激的杏仁核反应增加。重要的是，使用结构方程模型，我们发现这些差异与前额叶调节的改变有关。我们还确定了前岛结构、功能和区域间连通性的汇聚性变化，这些变化预示着典型的威廉姆斯综合征(WS)个性。 WS表型的一个组成部分是血管异常，最常见的是瓣膜上主动脉狭窄和外周肺动脉狭窄，这些都被归因于WS区基因弹性蛋白的半缺失。因为弹性蛋白在定义脑血管结构中可能很重要，我们试图确定WS患者是否存在包括弹性蛋白在内的缺失，从而增加临床相关异常脑血管的风险。使用磁共振血管成像，到目前为止，我们还没有发现颅内血管异常扩张或狭窄的证据(Wint等人，2014年)。 在我们新的纵向WS神经发育研究的支持下，我们现在已经能够在越来越多患有和没有WS关键区域拷贝数变异的儿童(即具有WS关键区域的一个(WS)、两个(神经典型的)或三个(WS区域重复的)副本的儿童)中收集视觉空间、社会情绪和神经血管系统完整性的相同测量。增加这一独特的数据集将使我们能够了解这种综合征中潜在的视觉空间和社会情感变化的神经异常的发展轨迹和基因剂量反应特征。尽管数据积累需要多年的谨慎和协调努力才能完成，但这些研究揭示基因对大脑发育的贡献的潜力是巨大的。

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.