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：
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
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/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

项目摘要

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

为了描述对大脑结构，功能和临床相关行为和认知的特定遗传贡献，我们对7q11.23 Williams综合征（WS）基因组区域中具有拷贝数变化的个体进行了一系列持续的多模式神经影像学研究。这些研究负责阐述7q11.23表型的视觉空间和社会情感方面的神经基础。我们已经确定，WS的视觉空间构建缺陷（该基因座DNA连续段的半巧合微骨骼）通过多种神经影像技术的收敛性内沟的变化，包括多种神经影像技术，包括基于体素和表面的基于体素和表面的基于基于体voxel和表面的神经成像技术。具体而言，我们已经表明，WS个体藏有干扰的内部肺内区域神经完整性，空间判断过程中的激活，灰质体积，沟深度和相关的神经纤维区。同样，在WS中观察到的超社交性和非社交焦虑的合理系统水平相关性时，我们发现杏仁核的激活降低了，而杏仁核的激活引起了恐惧的脸部刺激，而杏仁核对非社会可怕刺激的反应增加了对非社会可怕刺激的响应，这些刺激对异常的异常模型链接到更改的模型中，以实现更改的模型。我们还确定了前岛结构，功能和区域间连通性的收敛变化，这些连通性预测了特征性威廉姆斯综合征（WS）人格。 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).发展这个独特的数据集将使该综合征视觉空间和社会情感变化的神经异常的发育轨迹和基因剂量反应特征都可以理解。尽管数据应计算需要多年的仔细和一致的努力才能完成，但这些研究的潜力使对脑发育的遗传贡献前所未有。同时，我们研究了没有WS个体的DNA序列变异的研究。这项工作在与WS相关的GTF2I基因中的基因型与特质神经质的衡量标准，造成了避免的量度，在情感上的观察任务中预测前额叶反应时，产生了显着的相互作用。就GTF2I序列变异影响与焦虑相关行为的神经相关性而言，该基因可能与WS中存在的二分法焦虑表型特别相关。在没有WS的个体中发现了这一发现的范围，这种工作体现了WS指导研究的转化可能性，从而使人们对人脑中关键神经过程的更广泛的科学理解受益。这项工作包括以下研究：NCT01132885，NCT00004571，NCT0000001258