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: 7594590
• 负责人: Karen FAITH Berman
• 金额: $ 79.93万
• 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/7594590
• 关键词: Adult; Affect; Age; Amygdaloid structure; Animal Model; Architecture; Area; Behavior; Behavioral; Brain; Brain region; Categories; Cerebrovascular Circulation; Child; Chromosomes, Human, Pair 7; Clinical; Cognition; Cognitive; Complement; Complex; Conceptions; Control Groups; Corpus Callosum; Data; Development; Diffusion Magnetic Resonance Imaging; Disease; Dorsal; Employee Strikes; Environment; Face; Face Processing; Facility Construction Funding Category; Fiber; Fright; Functional Magnetic Resonance Imaging; Fusiform gyrus; Future; General Population; Genes; Genetic; Genetic Determinism; Handedness; Hereditary Disease; Hippocampus (Brain); Housing; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Incidence; Individual; Investigation; Knowledge; Left; Link; Live Birth; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mediating; Mental Retardation; Methodology; Microscopic; Mind; Modeling; Multimodal Imaging; Mutation; N-acetylaspartate; Nature; Neurobiology; Neurodevelopmental Disorder; Neurons; Nucleic Acid Regulatory Sequences; Other Imaging Modalities; Parahippocampal Gyrus; Parietal; Parietal Lobe; Participant; Pathology; Pattern; Performance; Personality; Persons; Phenotype; Population; Positron-Emission Tomography; Prefrontal Cortex; Prevalence; Process; Range; Rare Diseases; Regulation; Reporting; Sampling; Score; Single Nucleotide Polymorphism; Social Behavior; Social Functioning; Source; Staging; Steam; Stream; Structure; Syndrome; System; Testing; Time; Tissues; Visual; Visuospatial; Williams Syndrome; Work; anterior commissure; base; cognitive function; comparison group; design; experience; follow-up; gray matter; in vivo; insight; intraparietal sulcus; microdeletion; migration; neurodevelopment; neurogenetics; neuroimaging; neuromechanism; neuropsychiatry; relating to nervous system; research study; sex; social; social cognition; success; visual information; visual object processing; visual process; visual processing; water diffusion; white matter

We previously used multimodal neuroimaging to define three fundamental aspects of the brain phenotype in WS that are related to clinical features: 1) Underlying the syndromes cognitive hallmark, visuospatial construction impairment, is a neurostructural anomaly (decreased gray matter volume) and adjacent hypofunction in the parietal sulcus region of the dorsal visual processing stream. 2) Hippocampal abnormalities in regional cerebral blood flow, neurofunctional activation, and N-acetyl aspartate concentration (measured in vivo with MR spectroscopy), as well as subtle structural changes also contribute to these visuospatial construction problems. 3) Underlying the syndromes hallmark social cognition features are structural and functional abnormalities in the orbitofrontal cortex, an important social and affect regulatory region that participates in a frontoamygdalar regulatory network found to be dysfunctional in WS. Because these features were defined in extremely rare persons with WS and normal IQs, allowing us to compare WS individuals to IQ-matched healthy controls and thus obviating an important potential confound, these brain phenotypes are likely proximal to the genetic core of the syndrome. In a new study, we asked, is the wiring of the human brain genetically influenced? In this work, our group used diffusion tensor imaging (DTI), a powerful, recently developed MRI technique that allows identification of white matter architecture invisible to conventional imaging, to study extremely rare individuals with Williams syndrome (WS). This highly uncommon genetic disorder affords a unique opportunity to study genetic regulation of white matter development such as: the regulation of cytoskeletal dynamics in neurons, and neuronal migration and targeting. We found that the missing genes confers the unique cognitive and social phenotype of the syndrome by affecting the integrity of long-range, white matter connections between cortical areas, thus affecting the coordination of large ensembles of neurons. These data uncovered alterations in brain connectivity in the context of clear clinical phenomena. Given that these genes are missing from the time of conception, this study offers insights into the genetics of neural development, a largely unexplored territory. Because these same participants had been studied with other imaging modalities, we were able to tailor our analysis to specific areas of grey matter structural and functional abnormality previously identified in these very individuals, thus permitting a particularly incisive investigation and affording increased power to identify genetically determined effects on white matter. We showed for the first time that fibers found in white matter immediately underlying gray matter regions previously shown to be abnormal, are oriented differently, give origin to aberrant posterior tracts, and show altered lateralization patterns in individuals with WS. The identified overall reduction of water diffusion in the brain of WS individuals additionally reveals microscopic alterations of tissue structure. Moreover, this sample was also characterized by the presence of excess longitudinal bundles above the corpus callosum and the absence of an anterior commissure in some WS cases. From these data, we advance the hypothesis that one or more of the affected genes in WS control development of fibers in the final stages of development and that these fibers, normally growing in a right to left orientation, are deviated longitudinally. This report is the first delineation of white matter structural abnormalities in WS and provides the first data indicating that the axonal tracts where abnormalities were found may be critically involved in the cognitive and social functions specifically affected in WS subjects. Our observations also link the genes in the microdeleted region of chromosome 7 for the first time to the development of long-range connectivity in the brain. Based on these data, a hypothesis on the mechanism and timing of action of these genes is put forth that could guide future investigations in post-mortem tissue and animal models of WS, in particular, and of white matter development, in general. In another study of WS we extended our knowledge regarding the very well characterized hypersocial personality and prominent visuospatial construction impairments, building on our previous findings of functional and structural abnormalities in the hippocampus formation (HF), prefrontal regions, and the dorsal visual stream. The visual stream is divided into two processing steams: a dorsal stream which processes spatial information and a ventral stream which subserves object processing. The hallmark cognitive impairment in WS is in visuospatial construction, the ability to visualize an object (or picture) as a set of parts and construct a replica from those parts. This impairment is characterized neurophysiologically by poor performance on tests of block design or pattern construction. This has led to the hypothesis that dorsal, but not the ventral stream function is compromised. Although aberrant ventral stream activation has not been found, object-related visual information that is processed in the ventral stream is a critical source of input into these abnormal regions. This study examined the neural interactions of ventral stream areas in WS using a passive face- and house-viewing fMRI paradigm. During house-viewing, significant activation differences were observed between participants with WS and a matched control group in the brain region, intraparietal sulcus (processes aspects of the spatial environment). Abnormal functional connectivity was found between parahippocampal gyrus (place-processing area) and parietal cortex, and between fusiform gyrus (face-processing area) and a network of brain regions including amygdala (fear processing area) and portions of prefrontal cortex. These results indicate that abnormal upstream visual object processing may contribute to the complex cognitive/behavioral phenotype in WS, and provide a systems-level characterization of genetically-mediated abnormalities of neural interactions.

我们之前使用多模式神经成像来定义与临床特征相关的WS脑表型的三个基本方面：1)在综合征的认知标志，视觉空间构建障碍的基础上，是神经结构异常（灰质体积减少）和背侧视觉加工流顶沟区域邻近的功能低下。2)海马在区域脑血流、神经功能激活、n -乙酰天冬氨酸浓度（用磁共振光谱在体内测量）以及细微的结构变化方面的异常也导致了这些视觉空间构建问题。3)这些综合征标志性社会认知特征的基础是眼窝额叶皮质的结构和功能异常，眼窝额叶皮质是一个重要的社会和情感调节区域，参与了在WS中发现的功能失调的额杏仁核调节网络。因为这些特征是在极其罕见的WS和正常智商的人群中定义的，允许我们将WS个体与智商匹配的健康对照进行比较，从而避免了一个重要的潜在混淆，这些大脑表型可能接近于该综合征的遗传核心。