Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

综合神经成像科通过对威廉姆斯综合征(WS)患者和精心匹配的对照志愿者进行多模式神经成像研究，在阐明特定基因对大脑结构和功能的贡献方面取得了实质性进展(研究10-M-0112，NCT01132885；00-M-0085，NCT00004571)。近年来，我们通过多模式神经成像实验证明，在这种情况下，特有的视觉空间结构缺陷的神经基础没有出现，但保留了早期的视觉皮质功能，但破坏了顶内沟区神经完整性、空间判断时的激活和结构。 除了视觉空间障碍外，WS个体还具有对位社会情绪功能，因此，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。(Jabbi等人，2012) 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，我们试图确定包含弹性蛋白缺失的WS患者是否会增加临床上有意义的异常脑血管系统的风险。使用磁共振血管成像，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启动了WS儿童的纵向多模式神经成像研究并积极获取数据。尽管积累数据需要多年的谨慎和协调努力，但这些研究对揭示基因对大脑发育的贡献的潜力是巨大的。 总而言之，我们的努力已经确定了WS显著神经心理异常的候选神经功能底物，为保留脑内血管提供了可靠的证据，并在更好地确定WS神经表型的确切遗传、发育和神经化学贡献方面继续取得进展。 总而言之，我们的努力已经确定了WS显著神经心理异常的候选神经功能底物，为保留脑内血管提供了可靠的证据，并在更好地确定WS神经表型的确切遗传、发育和神经化学贡献方面继续取得进展。

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.