Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

综合神经影像学部分通过对威廉姆斯综合征（WS）个体和仔细匹配的对照志愿者进行多模式神经影像学研究，在阐明特定遗传对脑结构和功能的贡献方面取得了实质性进展（研究10-M-0112，NCT 01132885; 00-M-0085，NCT 00004571）。近年来，我们通过多模态神经影像学实验证明，在这种情况下，特征性视觉空间结构缺陷的神经基质保留了早期视觉皮层功能，但破坏了顶内沟区神经的完整性，在空间判断过程中的激活和结构。 除了视觉空间障碍外，WS个体还具有二元对立的社会情感功能，例如过度社交与高度的非社交焦虑相结合。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基础具有明显的意义，是我们研究的第二个重点，我们在确定这些表型的合理系统水平相关性方面取得了相当大的成功。特别是，我们已经发现，减少恐惧的脸刺激诱发杏仁核激活WS相比，智商匹配的健康对照组，相反，增加杏仁核反应WS非社会可怕的刺激相比，匹配的健康对照组参与者。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。（Jabbi等人，2012年） WS表型的一个组成部分是血管异常，最常见的是瓣上主动脉狭窄和外周肺动脉狭窄，这归因于WS区域基因弹性蛋白的半缺失。 由于弹性蛋白在定义脑内血管结构方面可能很重要，因此我们试图确定包括弹性蛋白在内的缺失的WS个体是否具有临床意义的异常脑血管的风险增加。 使用磁共振血管造影术，我们没有发现颅内血管异常扩张或狭窄的证据（Wint等人，2013年）。 然而，该科最近取得的最大进展可能是成功地开展了WS儿童纵向多模式神经影像学研究并积极获取数据。虽然数据积累需要多年的仔细和协调一致的努力，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。 总之，我们的努力已经导致在识别的候选神经功能基板的标志性神经心理学异常的WS，可靠的证据保留脑内血管，并继续朝着更好地定义精确的遗传，发育和神经化学的贡献对WS的神经表型正在进行中。 总之，我们的努力已经导致在识别的候选神经功能基板的标志性神经心理学异常的WS，可靠的证据保留脑内血管，并继续朝着更好地定义精确的遗传，发育和神经化学的贡献对WS的神经表型正在进行中。

The Section on Integrative Neuroimaging has made substantial progress toward elucidating specific genetic contributions to brain structure and function through multimodal neuroimaging studies of Williams Syndrome (WS) individuals and carefully matched comparison volunteers (Study 10-M-0112, NCT01132885; 00-M-0085, NCT00004571). We have in recent years identified the neural substrates of the characteristic visuospatial construction deficits in this condition by demonstrating via multi-modal neuroimaging experiments spared early visual cortical functioning, but disrupted intraparietal sulcal region neural integrity, activation during spatial judgments, and structure. In addition to visuospatial impairments, WS individuals harbor dyadic contrapuntal 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. (Jabbi et al., 2012) 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 meaningful anomalous cerebrovasculature. Using magnetic resonance angiography, we found no evidence for abnormal dilation or stenosis of intracranial vessels (Wint et al., 2013). Perhaps the greatest recent advancement made by the Section, however, has been the successful launch and active data acquisition for longitudinal multimodal neuroimaging studies of WS children. Though data accrual will require years of careful and concerted effort, the potential for these studies to shed unprecedented light on genetic contributions to brain development are enormous. In sum, our efforts have resulted in the identification of candidate neurofunctional substrates for hallmark neuropsychological abnormalities in WS, reassuring evidence for sparing of intracerebral vasculature, and continued progress toward better defining the precise genetic, developmental and neurochemical contributions toward the WS neurophenotype is ongoing. In sum, our efforts have resulted in the identification of candidate neurofunctional substrates for hallmark neuropsychological abnormalities in WS, reassuring evidence for sparing of intracerebral vasculature, and continued progress toward better defining the precise genetic, developmental and neurochemical contributions toward the WS neurophenotype is ongoing.