Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

综合神经成像部分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。正如Eisenberg等人广泛讨论的那样。(1)，近年来，我们通过多模式神经成像实验证明，在这种情况下，特征性视觉空间结构缺陷的神经基础是特异性地扰乱了背侧流、空间判断过程中顶内沟区的激活、神经完整性和结构。这些里程碑式的发现引出了一个至关重要的问题，即初级视觉皮质是否也存在上游异常，这些异常可能在发育过程中对大脑或行为WS表型也有贡献。在Olsen等人中。(2)我们使用基于磁共振成像的视野图来确定WS早期视觉加工相对于年龄和智商匹配的对照组的神经功能状态。虽然WS参与者的初级视觉皮质(V1)边界不同，但该区域的大小在不同组之间没有差异，重叠图显示两组的平均重心在很大程度上是共同定位的。这项工作提供了第一次使用视网膜光学来确定WS中V1的功能神经解剖学，也是该技术在影响视觉空间加工的人类病理条件下的最早使用之一。这些结果与以下观点一致，即潜在的视觉空间结构的神经异常出现在背侧视觉处理流的后期阶段，可能发生在我们在顶沟内观察到的区域或紧邻我们的观察区域。 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。为了跟进这一重要的结果，穆尼奥斯等人。(3)在言语辨别任务中使用了社会性和非社会性情绪刺激，这项任务除了对情绪和边缘系统征税外，还会对认知、前额叶过程产生可靠的影响。这项研究的证据证实了我们之前的发现，即在WS中，杏仁核对非社会性惊恐视觉刺激的反应被夸大，并且进一步表明，任务困难调节了参与者的前额叶反应，但不是杏仁核反应。这些数据支持WS患者杏仁核-前额叶回路中断的证据，但重要的是表明社会背景相关情绪反应的核心偏差不受认知挑战的影响。 在某种程度上，岛叶皮质也被牵连到调节定义人格的社会情绪反应倾向，我们最近的多模式调查试图确定前岛结构、功能和区域间连通性的趋同变化，以及确定这些测量预测威廉姆斯综合征(WS)特征人格的程度。在Jabbi等人(4)中，我们发现WS患者脑岛背侧灰质体积整体减少，但右脑腹侧灰质体积局部增加，连接脑岛与杏仁核和眶前皮质的钩状束白质完整性降低，右脑腹侧脑灰质局部血流量增加，脑血流量广泛减少，脑脊液与其他边缘区域的脑血流量关系异常。重要的是，这些差异预测了WS个性特征的强度。我们相信，这方面正在进行的工作将提供对遗传学和行为现象学之间关键联系的更好理解，这些联系超越了WS本身。 然而，该科最近取得的最大进展可能是成功地启动了对WS儿童的纵向多模式神经成像研究。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，并且在更好地确定这些障碍的确切遗传、发育和神经化学贡献方面的持续进展正在进行中。

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. As discussed extensively in Eisenberg et al. (1), 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 disrupted dorsal stream specifically, intraparietal sulcal region activation during spatial judgments, neural integrity, and structure. These landmark findings invited the vital question of whether there were also upstream abnormalities in primary visual cortex that might also contribute during development to either the brain or behavioral WS phenotypes. In Olsen et al. (2) we used magnetic resonance imaging-based visual field mapping in order to establish the neurofunctional status of early visual processing in WS relative to that in controls matched for age and IQ. Although primary visual cortex (V1) boundaries varied in WS participants, this region did not differ in size between groups, and overlap maps showed that the average centers of gravity for the two groups were largely colocalized. This work provided the first use of retinotopy to define the functional neuroanatomy of V1 in WS and one of the first uses of this technique in a human pathological condition that affects visuospatial processing. These results are consistent with the notion that neural abnormalities underlying visuospatial construction arise at later stages in the dorsal visual processing stream, likely at or immediately proximal to our observations in the intraparietal sulcal region. 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. To follow up on this important set of results, Munoz et al. (3) used social and non-social emotional stimuli during a verbal discrimination task that would reliably tax cognitive, prefrontal processes in addition to emotional, limbic systems. Evidence from this study confirmed our previous findings of exaggerated amygdala response to non-social frightening visual stimuli in WS and, further, indicated that task difficulty modulates prefrontal, but not amygdala, response in participants. These data support evidence of disruption in amygdala-prefrontal circuitry in WS but importantly indicate that core biases in social context-dependent emotional responsivity are unaffected by cognitive challenge. To the extent that the insular cortices have also been implicated in mediating social emotional response tendencies that define personality, our most recent multimodal investigations have sought to identify convergent alterations in anterior insula structure, function, and inter-regional connectivity, as well as determine the extent to which these measures predict the characteristic Williams syndrome (WS) personality. In Jabbi et al (4), we show that in WS there is an overall decrease in dorsal anterior insula (AI) gray-matter volume,but locally increased volume in the right ventral AI, as well as reduced white-matter integrity of the uncinate fasciculus connecting the insula with the amygdala and orbitofrontal cortex, widespread reductions in dorsal AI regional cerebral blood flow (rCBF) with locally increased rCBF in the right ventral AI, and abnormal relationships between rCBF in AI and other limbic regions. Importantly, these differences predicted the strength of the WS personality profile. We believe ongoing work in this vein will provide improved understanding of critical links between genetics and behavioral phenomenology relevant beyond WS itself. However, perhaps the greatest recent advancement made by the Section, however, has been the successful initiation of 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, and continued progress toward better defining precise genetic, developmental and neurochemical contributions toward these disturbances is ongoing.