Multimodal Neuroimaging of Gene-Brain Relationships in Williams Syndrome

威廉姆斯综合征基因-大脑关系的多模式神经影像

基本信息

批准号：
9589756
负责人：
Karen FAITH Berman
金额：
$ 177.31万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
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/9589756
关键词：
7q11.23 Adult Affect Age Amygdaloid structure Anterior Area Autistic Disorder Behavior Behavioral Behavioral Mechanisms Brain Brain region Cerebellum Characteristics Child Childhood Chromosomes, Human, Pair 7 Clinical Cognition Cognitive Complement Complex Copy Number Polymorphism DNA DNA Sequence Data Data Collection Development Diffusion Diffusion Magnetic Resonance Imaging Dorsal Dose Emotional Employee Strikes Equation Face Fiber Functional Magnetic Resonance Imaging GTF2I gene Gene Dosage General Population Genes Genetic Genetic Determinism Genomic Segment Genotype Handedness Hippocampus (Brain)Human Impairment Incidence Individual Insula of Reil Judgment Knowledge Life Light Link Literature Live Birth Magnetic Resonance Imaging Measurement Measures Mental Retardation Methodology Methods Mind Modeling Molecular Abnormality Multimodal Imaging Mutation Nature Neurobiology Neurodevelopmental Disorder Neurotic Disorders Neurotics Parietal Pathology Personality Persons Phenotype Plant Roots Population Positron-Emission Tomography Process Rare Diseases Regression Analysis Regulation Research Rest Seminal Series Single Nucleotide Polymorphism Social Behavior Social Network Stimulus Stream Structure Surface Syndrome System Techniques Variant Visual Visuospatial Williams Syndrome Work anxiety-related behavior base boys brain size clinically relevant cognitive function cohort connectome design experience experimental study gray matter indexing insight intraparietal sulcus microdeletion morphometry multimodality neural correlate neurodevelopment neurogenetics neuroimaging neuromechanism neuropsychiatric disorder novel relating to nervous system response sex social social cognition success trait translational neuroscience

项目摘要

The Clinical and Translational Neuroscience Branch continues to work toward discovery of novel genetic contributions to brain structure, function, and clinically relevant behavior and cognition, through a series of ongoing multimodal neuroimaging studies of individuals with copy number variation in the 7q11.23 Williams Syndrome (WS) genomic region (hemizygous microdeletion of a contiguous segment of DNA at this locus). These studies have been responsible for seminal advances in elaborating the neural underpinnings of both visuospatial and socio-emotional aspects of the 7q11.23 phenotype. Via multiple neuroimaging techniques, including voxel- and surface-based cortical morphometry, diffusion tensor imaging, and functional MRI, we have established that the visuospatial construction deficits in WS are linked to convergent intraparietal sulcus alterations. Specifically, in this brain region, we have shown that individuals with WS harbor disrupted neural integrity, altered activation during spatial judgments, gray matter volume and sulcal depth reductions, and associated neural fiber tract anomalies. Likewise, in pursuit of systems-level correlates of the hypersociability and non-social anxiety observed in WS, we have found decreased amygdala activation evoked by fearful face stimuli and conversely, increased amygdala response to non-social frightening stimuli, abnormalities that were linked to altered prefrontal regulation in structural equation models. We have also identified convergent alterations in anterior insula structure, function, and inter-regional connectivity, which predict the characteristic WS personality. Efforts this year have focused on data collection of these same structural and functional measurements of visuospatial and socio-emotional systems integrity in a growing cohort of children with and without WS critical region copy number variation (i.e., individuals with one WS, two typically developing, or three Dup7 copies of affected genes in the WS critical region) as part of our longitudinal WS neurodevelopmental initiative. In proof-of-concept work aimed at establishing neurostructural gene-dosage effects, we have studied microanatomical measures and found increasing overall brain size with increasing copy number (Dup7>TD>WS), but decreasing relative cerebellar size (WS>TD>Dup7) with copy number of affected genes. Interestingly, both of these Dup7 phenotypes (larger brain size and relatively smaller cerebellum) have been described in the autism literature, particularly in boys, although these findings are not without controversy. Following this work, we are undertaking similar gene-dosage analyses of more localized morphometry throughout the brain, as well as local gyrification index and resting-state whole-brain connectivity, the latter using a recently-developed connectome-wide association study approach as well as independent component and dual-regression analyses. In parallel, we continue to undertake studies of WS-associated DNA sequence variation in individuals without WS. This work has yielded remarkable interactions between genotype in the WS-associated GTF2I gene and a measure of trait neuroticism, harm avoidance, in predicting prefrontal response during an emotional face viewing task. Insofar as GTF2I sequence variation affects the neural correlates of anxiety-related behavior, this gene may be of particular relevance to the dichotomous social versus non-social anxiety phenotypes present in WS. To the extent that this finding was identified in individuals without WS, such work exemplifies the translational possibilities of WS-directed research in benefiting a broader scientific understanding of key neural processes in the human brain. Preliminary data from our WS developmental cohort has already demonstrated parietal hypofunction during visuospatial challenge and altered social network activation during processing of socially salient stimuli, consistent with the hypothesis that both visuospatial and social neurobiological differences in WS are rooted in early life. This project seeks not only to expand knowledge of the WS-related brain systems in childhood, but also to identify developmental trajectory (throughout childhood) and gene dose-response characteristics of neural abnormalities underlying visuospatial and socio-emotional alterations in this syndrome using a longitudinal, repeated measures design. 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 is enormous. This work includes the following studies: NCT01132885, NCT00004571, NCT00001258

临床和转化神经科学分支通过对 7q11.23 威廉姆斯综合征中拷贝数变异的个体进行一系列正在进行的多模式神经影像学研究，继续致力于发现对大脑结构、功能以及临床相关行为和认知的新遗传贡献。 WS) 基因组区域（该位点连续 DNA 片段的半合子微缺失）。这些研究在阐述 7q11.23 表型的视觉空间和社会情感方面的神经基础方面取得了开创性的进展。通过多种神经影像技术，包括基于体素和表面的皮质形态测量、扩散张量成像和功能性 MRI，我们已经确定 WS 的视觉空间结构缺陷与会聚的顶内沟改变有关。具体来说，在这个大脑区域，我们发现患有 WS 的个体存在神经完整性破坏、空间判断过程中的激活改变、灰质体积和脑沟深度减少以及相关的神经纤维束异常。同样，在追求 WS 中观察到的超社交性和非社交焦虑的系统级相关性时，我们发现由恐惧的面部刺激引起的杏仁核激活减少，相反，杏仁核对非社交恐惧刺激的反应增加，这些异常与改变结构方程模型中的前额调节。我们还发现了前岛叶结构、功能和区域间连接的趋同性改变，这些改变可以预测 WS 的特征特征。今年的工作重点是在越来越多具有或不具有 WS 关键区域拷贝数变异的儿童群体中（即具有 1 个 WS、2 个典型发育中、或 WS 关键区域中受影响基因的三个 Dup7 拷贝）作为我们纵向 WS 神经发育计划的一部分。在旨在建立神经结构基因剂量效应的概念验证工作中，我们研究了显微解剖学测量，发现随着拷贝数的增加，整体大脑尺寸也随之增加（Dup7>TD>WS），但相对小脑尺寸却减小（WS>TD>Dup7））以及受影响基因的拷贝数。有趣的是，这两种 Dup7 表型（较大的大脑尺寸和相对较小的小脑）在自闭症文献中都有描述，特别是在男孩中，尽管这些发现并非没有争议。在这项工作之后，我们正在对整个大脑的更局部形态测量以及局部回旋指数和静息态全脑连接进行类似的基因剂量分析，后者也使用最近开发的全连接组关联研究方法作为独立成分和双回归分析。与此同时，我们继续对没有 WS 的个体中与 WS 相关的 DNA 序列变异进行研究。这项工作在 WS 相关 GTF2I 基因的基因型与特征神经质、伤害避免的测量之间产生了显着的相互作用，在预测情绪面部观看任务期间的前额叶反应方面。就 GTF2I 序列变异影响焦虑相关行为的神经相关性而言，该基因可能与 WS 中存在的二分社交与非社交焦虑表型特别相关。就这一发现是在没有 WS 的个体中发现的而言，此类工作例证了 WS 导向的研究的转化可能性，有利于对人脑关键神经过程进行更广泛的科学理解。我们的 WS 发育队列的初步数据已经证明，在视觉空间挑战期间，顶叶功能减退，并在处理社会显着刺激期间改变了社交网络激活，这与 WS 的视觉空间和社会神经生物学差异植根于早期生活的假设一致。该项目不仅旨在扩展对儿童期 WS 相关大脑系统的了解，而且还利用纵向研究来确定该综合征视觉空间和社会情感改变背后的神经异常的发育轨迹（整个童年期）和基因剂量反应特征。、重复措施设计。尽管数据积累需要多年的仔细和共同努力才能完成，但这些研究在揭示遗传对大脑发育的贡献方面具有前所未有的潜力是巨大的。这项工作包括以下研究：NCT01132885、NCT00004571、NCT00001258