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.

我们之前使用多模态神经影像学来定义 WS 中与临床特征相关的大脑表型的三个基本方面：1）在该综合征的认知特征、视觉空间结构障碍的基础上，是神经结构异常（灰质体积减少）和邻近功能减退。背侧视觉处理流的顶沟区域。 2) 海马区域脑血流、神经功能激活和 N-乙酰天冬氨酸浓度（通过 MR 光谱在体内测量）的异常，以及微妙的结构变化也导致了这些视觉空间构建问题。 3) 这些综合征的社会认知特征的标志是眶额皮质的结构和功能异常，眶额皮质是参与额杏仁调节网络的重要社会和情感调节区域，在 WS 中被发现功能失调。 因为这些特征是在极其罕见的 WS 和正常智商的人中定义的，使我们能够将 WS 个体与智商匹配的健康对照进行比较，从而避免重要的潜在混淆，这些大脑表型可能最接近该综合征的遗传核心。 在一项新的研究中，我们问道，人类大脑的接线是否受到遗传影响？在这项工作中，我们的团队使用扩散张量成像 (DTI) 来研究极其罕见的威廉姆斯综合征 (WS) 患者，这是一种最近开发的强大 MRI 技术，可以识别传统成像不可见的白质结构。这种非常罕见的遗传性疾病为研究白质发育的遗传调控提供了独特的机会，例如：神经元细胞骨架动力学的调控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远程白质连接的完整性，从而影响大型神经元群的协调，从而赋予该综合征独特的认知和社会表型。这些数据揭示了在明确的临床现象背景下大脑连接的变化。鉴于这些基因在受孕时就缺失了，这项研究提供了对神经发育遗传学的见解，这是一个很大程度上尚未探索的领域。 因为这些相同的参与者已经用其他成像方式进行了研究，所以我们能够根据先前在这些个体中发现的灰质结构和功能异常的特定区域来调整我们的分析，从而允许进行特别深入的调查并提供更大的能力来识别基因决定的对白质的影响。 我们首次表明，在 WS 个体中，紧邻灰质区域下方的白质中发现的纤维定向不同，产生异常的后束，并显示出改变的偏侧化模式。所发现的 WS 个体大脑中水扩散的总体减少还揭示了组织结构的微观变化。 此外，该样本的特征还在于胼胝体上方存在多余的纵束，并且在某些 WS 病例中不存在前连合。根据这些数据，我们提出了这样的假设：WS 中的一个或多个受影响的基因在发育的最后阶段控制纤维的发育，并且这些纤维通常以从右到左的方向生长，但纵向偏离。 该报告首次描述了 WS 中的白质结构异常，并提供了第一份数据，表明发现异常的轴突束可能与 WS 受试者特别受影响的认知和社会功能密切相关。我们的观察还首次将 7 号染色体微缺失区域的基因与大脑中远程连接的发展联系起来。基于这些数据，提出了关于这些基因作用机制和时间的假设，可以指导未来对 WS 死后组织和动物模型的研究，特别是对白质发育的研究。 在 WS 的另一项研究中，我们基于之前对海马结构（HF）、前额叶区域和背侧视觉流功能和结构异常的发现，扩展了我们对非常明确的超社会人格和显着视觉空间结构障碍的认识。视觉流分为两个处理流：处理空间信息的背侧流和促进物体处理的腹侧流。 WS 的标志性认知障碍在于视觉空间构造，即将对象（或图片）可视化为一组部件并从这些部件构造复制品的能力。这种损伤的神经生理学特征是在块设计或模式构建测试中表现不佳。 这导致了背侧流功能受到损害而不是腹侧流功能受到损害的假设。尽管尚未发现异常的腹侧流激活，但在腹侧流中处理的与物体相关的视觉信息是输入到这些异常区域的关键来源。本研究使用被动面部和房屋观察功能磁共振成像范式检查了 WS 腹侧流区域的神经相互作用。 在观看房屋期间，WS 参与者和匹配的对照组之间在大脑区域顶内沟（空间环境的处理方面）观察到显着的激活差异。 在海马旁回（位置处理区）和顶叶皮层之间，以及梭状回（面部处理区）和包括杏仁核（恐惧处理区）和部分前额叶皮层在内的大脑区域网络之间发现了异常的功能连接。 这些结果表明，异常的上游视觉对象处理可能导致 WS 中复杂的认知/行为表型，并提供遗传介导的神经相互作用异常的系统级表征。