Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

威廉姆斯综合征基因-大脑关系的多模态神经影像

• 批准号: 8342155
• 负责人: Karen FAITH Berman
• 金额: $ 83.11万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8342155
• 关键词: Adult; Affect; Age; Amygdaloid structure; Anterior; Anxiety; Behavior; Behavioral; Behavioral Genetics; Brain; Brain Diseases; Categories; Characteristics; Child; Chromosomes, Human, Pair 7; Clinical; Cognition; Cognitive; Complement; Complex; Coupled; Data; Development; Diffusion Magnetic Resonance Imaging; Discrimination; Disease; Dorsal; Emotional; Employee Strikes; Equation; Face; Force of Gravity; Functional Magnetic Resonance Imaging; Functional disorder; General Population; Genes; Genetic; Genetic Determinism; Handedness; Hippocampus (Brain); Housing; Human; Impairment; Incidence; Individual; Insula of Reil; Investigation; Judgment; Knowledge; Language Development; Light; Limbic System; Link; Live Birth; Magnetic Resonance Imaging; Maps; Measures; Mediating; Memory; Mental Retardation; Methodology; Methods; Mind; Modeling; Multimodal Imaging; Mutation; Nature; Neuroanatomy; Neurobiology; Neurodevelopmental Disorder; Participant; Pathology; Personality; Phenotype; Population; Positron-Emission Tomography; Prevalence; Process; Rare Diseases; Regulation; Relative (related person); Research; Single Nucleotide Polymorphism; Social Behavior; Social Environment; Staging; Stimulus; Stream; Structure; Sum; System; Taxes; Techniques; Veins; Visual; Visual Fields; Visuospatial; Williams Syndrome; Work; area striata; base; candidate identification; cognitive function; comparison group; developmental genetics; emotional stimulus; experience; follow-up; improved; microdeletion; neurochemistry; neurodevelopment; neurogenetics; neuroimaging; neuromechanism; neuropsychiatry; neuropsychological; relating to nervous system; research study; response; sex; social; social cognition; spectroscopic imaging; success; visual process; visual processing; visual stimulus; volunteer

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. (NeuroImage, 2010), 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. (Brain, 2009) 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 provides 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, our current study by Munoz et al. (NeuroImage, 2010) 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 personality. We believe burgeoning results 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.

通过对威廉姆斯综合征（WS）个体和精心匹配的对照志愿者进行多模态神经影像学研究，综合神经影像学在阐明大脑结构和功能的特定遗传贡献方面取得了实质性进展。正如Eisenberg等人（NeuroImage, 2010）广泛讨论的那样，近年来，我们通过多模态神经成像实验证明，在这种情况下，特征性的视觉空间构建缺陷的神经基础是背流中断，特别是在空间判断、神经完整性和结构时，顶叶内沟区激活。这些具有里程碑意义的发现引发了一个至关重要的问题，即初级视觉皮层是否也存在上游异常，这些异常也可能在发育过程中导致大脑或行为WS表型。在Olsen等人（Brain, 2009）中，我们使用基于磁共振成像的视野映射来建立WS患者早期视觉加工的神经功能状态，相对于年龄和智商相匹配的对照组。虽然初级视觉皮层（V1）边界在WS参与者中有所不同，但该区域在两组之间的大小没有差异，重叠图显示两组的平均重心在很大程度上是重合的。这项工作首次使用视网膜截形术来定义WS中V1的功能神经解剖学，也是该技术首次用于影响视觉空间处理的人类病理状况之一。这些结果与视觉空间构建背后的神经异常出现在背侧视觉处理流的后期阶段的观点一致，可能在或直接接近我们在顶叶内沟区观察到的。