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.

我们先前使用多模式神经影像来定义与临床特征相关的大脑表型的三个基本方面：1）综合征认知标志的基础，视觉空间构建障碍，是神经结构的构建障碍，是神经结构的异常（灰质量减少）和邻近的功能性在附属硫磺区域中的相邻功能。 2）区域脑血流，神经功能激活和N-乙酰天冬氨酸浓度的海马异常（用MR光谱法在体内测量）以及细微的结构变化也有助于这些视觉性构造问题。 3）综合症的潜在综合症社会认知特征是轨道额皮层中的结构和功能异常，这是一个重要的社会和影响调节区域，参与额纳米菌的调节网络，发现在WS中发现功能障碍。 因为这些特征是在具有WS和正常智商的极稀有人物中定义的，因此我们可以将WS个体与IQ匹配的健康对照进行比较，从而避免了重要的潜在混杂，因此这些大脑表型可能与综合征的遗传核心近端。 我们问，在一项新研究中，人脑的接线是否受到遗传影响？在这项工作中，我们的小组使用了扩散张量成像（DTI），这是一种强大的，最近开发的MRI技术，允许鉴定常规成像可见的白质体系结构，以研究具有威廉姆斯综合征（WS）的极为罕见的人。这种高度罕见的遗传疾病为研究白质发育的遗传调节提供了独特的机会，例如：神经元中细胞骨架动力学的调节以及神经元迁移和靶向。我们发现，缺失的基因通过影响皮质区域之间的远距离，白质连接的完整性，从而影响综合征的独特认知和社会表型，从而影响神经元的大型组合的协调。这些数据在清晰的临床现象中发现了大脑连通性的变化。鉴于这些基因从受孕时期就缺失了，这项研究提供了对神经发育的遗传学的见解，神经发育是一个未开发的领域。 由于这些同一参与者已经通过其他成像方式研究了，因此我们能够根据以前在这些个体中鉴定出的灰质结构和功能异常的特定领域来量身定制分析，从而允许特别尖锐的研究，并提供增加的能力以识别遗传确定对白质作用的遗传确定影响。 我们首次表明，在白质中发现的纤维立即在先前显示为异常的灰质区域，其定向不同，起源于异常的后部区域，并显示了WS个体中的侧向模式改变。 WS个体大脑中水扩散的总体减少揭示了组织结构的微观改变。 此外，该样品的特征在于call体上方存在过多的纵向束，并且在某些WS情况下不存在前；从这些数据中，我们推进了这样一个假设，即在发育的最后阶段，WS控制纤维的一个或多个受影响的基因，并且这些纤维通常在左右方向上生长，纵向偏离。 该报告是WS中白质结构异常的首次描述，并提供了第一个数据，表明发现异常的轴突段可能与WS受试者特异性影响的认知和社会功能非常重要。我们的观察结果还将7号染色体微骨骼区域的基因首次联系起来，以发展大脑中的远距离连通性。基于这些数据，提出了有关这些基因作用机制和时机的假设，可以指导WS的验尸后，尤其是WS，尤其是白质开发的动物模型中的未来研究。 在另一项对WS的研究中，我们扩展了有关高度特征的超社会性格和显着的视觉空间构建障碍的知识，这是基于我们先前关于海马形成（HF），前额叶区域的功能和结构异常发现的发现的基础。视觉流分为两种处理蒸汽：一个背面，该蒸汽处理空间信息和一个腹侧流，该腹部沿对象处理。 WS中的标志性认知障碍是在视觉空间结构中，能够可视化对象（或图片）作为一组零件并从这些部分构造复制品的能力。这种障碍的特征是神经生理学的特征，其在块设计或模式结构的测试中的性能差。 这导致了一个假设，即背，但没有腹侧流功能受到损害。尽管尚未发现异常的腹溪流激活，但在腹侧流中处理的与对象相关的视觉信息是对这些异常区域的关键输入来源。这项研究使用了被动面部和房屋观察的fMRI范式研究了WS中腹溪流区域的神经相互作用。 在房屋观看期间，WS参与者和大脑区域匹配的对照组（空间环境的过程）之间观察到显着的激活差异。 在Parahampocampal Gyrus（位置加工区域）和顶叶皮层之间，梭形的回（面部处理区域）与包括杏仁核（恐惧处理区域）和前额叶皮质的部分大脑区域网络之间发现了异常的功能连通性。 这些结果表明，异常上游的视觉对象处理可能有助于WS中的复杂认知/行为表型，并提供了神经相互作用遗传介导的异常的系统级表征。