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: 9152112
• 负责人: Karen FAITH Berman
• 金额: $ 198.62万
• 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/9152112
• 关键词: 7q11.23; Adult; Affect; Age; Amygdaloid structure; Anterior; Anxiety; Area; Behavior; Behavioral; Behavioral Mechanisms; Brain; Characteristics; Child; Chromosomes, Human, Pair 7; Clinical; Cognition; Cognitive; Collection; Complement; Complex; Copy Number Polymorphism; DNA; DNA Sequence; Data; Data Set; Development; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Dose; Emotional; Employee Strikes; Equation; Face; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; General Population; Genes; Genetic; Genetic Determinism; Genomic Segment; Genotype; Handedness; Hippocampus (Brain); Housing; Human; Incidence; Individual; Insula of Reil; Judgment; Knowledge; Language Development; Light; Link; Live Birth; Magnetic Resonance Imaging; Measurement; Measures; Mental Retardation; Methodology; Methods; Mind; Modeling; Multimodal Imaging; Mutation; Nature; Neurobiology; Neurodevelopmental Disorder; Neurotic Disorders; Pathology; Personality; Phenotype; Population; Positron-Emission Tomography; Prevalence; Process; Rare Diseases; Regulation; Research; Seminal; Series; Single Nucleotide Polymorphism; Social Behavior; Stimulus; Stream; Structural defect; Structure; Surface; Syndrome; System; Techniques; Variant; Visual; Visuospatial; Williams Syndrome; Work; anxiety-related behavior; base; clinically relevant; cognitive function; cohort; comparison group; experience; follow-up; gray matter; intraparietal sulcus; microdeletion; morphometry; neural correlate; neurodevelopment; neurogenetics; neuroimaging; neuromechanism; neuropsychiatry; relating to nervous system; research study; response; sex; social cognition; spatial memory; spectroscopic imaging; success; trait; translational neuroscience

In order to delineate specific genetic contributions to brain structure, function and clinically relevant behavior and cognition, we have executed an ongoing series of multimodal neuroimaging studies of individuals with copy number variation in the 7q11.23 Williams Syndrome (WS) genomic region. 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. We have established that the visuospatial construction deficits in WS (hemizygous microdeletion of a contiguous segment of DNA at this locus) are linked to convergent intraparietal sulcus alterations, via multiple neuroimaging techniques, including voxel- and surface-based cortical morphometry, diffusion tensor imaging and functional MRI. Specifically, we have shown that WS individuals harbor disrupted intraparietal sulcal region neural integrity, activation during spatial judgments, gray matter volume, sulcal depth, and associated neural fiber tracts. Likewise, in pursuit of plausible 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 Williams syndrome (WS) personality. Under the auspices of our new longitudinal WS neurodevelopmental study, we have now been able to accelerate collection of these same 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 (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. In parallel, we have undertaken studies of 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. In so far as GTF2I sequence variation affects the neural correlates of anxiety-related behavior, this gene may be of particular relevance to the dichotomous 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 benefiting broader scientific understanding of key neural processes in the human brain. This work includes the following studies: NCT01132885, NCT00004571, NCT00001258

为了描述大脑结构、功能和临床相关行为和认知的特定遗传贡献，我们对7q11.23威廉姆斯综合征（WS）基因组区域拷贝数变异的个体进行了一系列多模态神经影像学研究。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。我们已经通过多种神经成像技术，包括体素和基于表面的皮层形态测量、弥散张量成像和功能性MRI，确定了WS的视觉空间构建缺陷（该位点上连续DNA片段的半合子微缺失）与会聚性顶顶内沟改变有关。具体地说，我们已经表明WS个体的顶内沟区神经完整性被破坏，在空间判断、灰质体积、沟深度和相关的神经纤维束中被激活。同样，为了寻找WS中观察到的超社交性和非社交性焦虑之间的合理的系统级相关性，我们发现恐惧面孔刺激引起的杏仁核激活减少，相反，杏仁核对非社交性恐惧刺激的反应增加，结构方程模型中的异常与前额叶调节改变有关。我们还发现了脑岛前部结构、功能和区域间连通性的收敛性改变，这些改变预测了威廉姆斯综合征（WS）的特征性人格。