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

• 批准号: 8939985
• 负责人: Karen FAITH Berman
• 金额: $ 111.21万
• 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/8939985
• 关键词: Adult; Affect; Age; Amygdaloid structure; Anterior; Anxiety; Area; Behavior; Behavioral; Blood Vessels; Brain; Brain Diseases; Characteristics; Child; Chromosomes, Human, Pair 7; Clinical; Cognition; Cognitive; Collection; Complement; Complex; Copy Number Polymorphism; Coupled; Data; Data Set; Development; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Dose; Elastin; Emotional; Employee Strikes; Equation; Face; Functional Magnetic Resonance Imaging; Functional disorder; General Population; Genes; Genetic; Genetic Determinism; Genetic Variation; Handedness; Hippocampus (Brain); Housing; Human; Impairment; Incidence; Individual; Insula of Reil; Judgment; Knowledge; Language Development; Light; Link; Live Birth; Magnetic Resonance Angiography; Magnetic Resonance Imaging; Maps; Measurement; Memory; Mental Retardation; Methodology; Methods; Mind; Mission; Modeling; Multimodal Imaging; Mutation; Nature; Neurobiology; Neurodevelopmental Disorder; Normal Range; Participant; Pathology; Pattern; Peripheral; Personality; Phenotype; Plant Roots; Population; Positron-Emission Tomography; Prevalence; Pulmonary artery structure; Rare Diseases; Regulation; Research; Risk; Series; Single Nucleotide Polymorphism; Social Behavior; Stenosis; Stimulus; Stream; Structure; Supravalvular aortic stenosis; Surface; Syndrome; System; Techniques; Visual; Visual Cortex; Visuospatial; Williams Syndrome; Work; artery stenosis; base; clinically relevant; cognitive function; cohort; comparison group; experience; follow-up; gray matter; intraparietal sulcus; microdeletion; morphometry; neurodevelopment; neurogenetics; neuroimaging; neuromechanism; neuropsychiatry; relating to nervous system; research study; response; retinotopic; sex; social cognition; spectroscopic imaging; success

Employing incisive, multimodal neuroimaging methodologies to study individuals with WS and related genetic variation in the WS critical region, the Section on Integrative Neuroimaging has vigorously pursued its mission of elaborating clinically meaningful, specific genetic contributions to brain structure and function. Recent advancements made toward that end have been manifold but are rooted in several foundational WS characteristics. First, prominent visuospatial construction deficits in this condition motivated a series of experiments in WS adults with normal-range IQ and carefully matched control subjects (Eisenberg et al, 2014). Using multiple neuroimaging techniques, including retinotopic mapping, voxel- and surface-based cortical morphometry, and functional MRI, we identified a neural signature of these deficits that converges in the intraparietal sulcus. Specifically, we demonstrated spared early visual cortex functioning, but disrupted intraparietal sulcal region neural integrity, activation during spatial judgments, gray matter volume, and sulcal depth. In addition to visuospatial impairments, WS individuals harbor dyadic contrapuntal a distinctive pattern of 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. 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 relevant anomalous cerebrovasculature. Using magnetic resonance angiography, we have thusfar found no evidence for abnormal dilation or stenosis of intracranial vessels (Wint et al., 2014). Under the auspices of our new longitudinal WS neurodevelopmental study, we have now been able to initiate collection of these same measurements of visuospatial, socio-emotional, and neurovascular systems integrity in a growing cohort of children with and without WS critical region copy number variation (i.e., individuals with one (WS), two (neurotypical), or three (WS region duplication) copies of the WS critical region). Growing this unique dataset will allow understanding of both the developmental trajectory and gene dose-response characteristics of neural abnormalities underlying visuospatial and socio-emotional alterations in this syndrome. 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 are enormous.

采用深刻的，多模态神经影像学方法来研究个人与WS和相关的遗传变异的WS关键区域，部分综合神经影像学积极追求其使命，阐述临床意义，具体的遗传贡献的大脑结构和功能。最近朝着这个目标取得的进展是多方面的，但植根于几个基本的WS特征。首先，在这种情况下，突出的视觉空间结构缺陷促使在具有正常范围智商的WS成年人和仔细匹配的对照受试者中进行一系列实验（Eisenberg et al，2014）。 使用多种神经成像技术，包括视网膜定位映射，体素和表面为基础的皮质形态测量，功能性MRI，我们确定了这些赤字，在顶内沟收敛的神经签名。 具体来说，我们证明了保留早期视觉皮层功能，但破坏了顶内沟区神经的完整性，激活空间判断，灰质体积和沟的深度。除了视觉空间障碍外，WS个体还具有一种独特的社会情感功能模式，即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非社会性的可怕的刺激相比，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。 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个体是否具有临床相关异常脑血管的风险增加。使用磁共振血管造影术，我们迄今没有发现颅内血管异常扩张或狭窄的证据（Wint等人，2014年）。 在我们新的纵向WS神经发育研究的主持下，我们现在已经能够在一个不断增长的有和没有WS关键区域拷贝数变异的儿童队列中开始收集这些相同的视觉空间、社会情感和神经血管系统完整性的测量结果（即，具有WS关键区的一个（WS）、两个（神经型）或三个（WS区重复）拷贝的个体）。 增长这一独特的数据集将允许了解这种综合征中视觉空间和社会情感改变的神经异常的发育轨迹和基因剂量反应特征。 虽然数据积累需要多年的仔细和协调一致的努力才能完成，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。