Multimodal Neuroimaging of Gene-Brain Relationships in W

W 基因-大脑关系的多模态神经影像

• 批准号: 7312933
• 负责人: Karen FAITH Berman
• 金额: --
• 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/7312933
• 关键词: Multimodal; Neuroimaging; Gene; Brain; Relationships

The Section on Integrative Neuroimaging of the Clinical Brain Disorders Branch employs multimodal neuroimaging methodologies, functional magnetic resonance imaging (fMRI), structural magnetic resonance imaging (MRI), and positron emission tomography (PET) to help characterize the specific neurocognitive deficits that are seen in people with Williams syndrome (WS). Studying this rare genetically based neurodevelopmental disorder having a well characterized hemideletion containing some 20 contiguous genes on chromosome 7, and having well characterized cognitive and social phenotypes allows us to closely examine: 1) genetic determinants of the function, structure, and organization of neural systems relevant to cognition and behavior, in general; 2) the neural basis of genetically-determined of visuospatial constructive abilities; and 3) the neural mechanism by which genetic factors influence social cognition and behavior. Each of our studies compares high functioning groups of people with WS with healthy normal controls. These comparison groups are matched for age, sex, handedness, and IQ scores. By controlling these variables, we eliminate the possibility that factors such as mental retardation or developmental level would influence interpretation of results. Our multimodal neuroimaging approach incorporates various methodologies to address specific concerns of analyzing brain images from special populations. Over the past year, we have made significant progress in characterizing intermediate brain phenotypes that are unique to WS patients when compared to normal healthy controls. In a study aimed at exploring the neural basis for a genetically determined visuospatial construction deficit, our findings have demonstrated effects of a localized abnormality on visual information processing in WS. By having our participants perform a series of fMRI experiments designed to access visual system function at several levels of processing hierarchy followed by examining the morphology of the brain, we were able to link abnormalities in a localized structural and functional parietal region of the dorsal stream, giving rise to a neural systems-level phenotype for WS which may be used as a model for determination of the molecular mechanism of the visuospatial construction deficit. In another study, we examined the role of the amygdala (the brain region that processes emotions) and its connections in abnormal social behavior that is commonly observed in those with WS. The amygdala?s response and regulation are thought to be central to socially protective neural processing through monitoring environmental events such as danger. It has been reported that lesions of the amygdala and associated regions, such as the orbitofrontal cortex (OFC), impair social function and therefore can cause disinhibition. Our fMRI analyses demonstrate reduced amygdala activation in persons with WS for threatening faces, but showed increased activation for threatening scenes. It is also noted that activation and interactions of prefrontal brain regions linked to amygdala were abnormal and that these regions (dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and OFC) may exert indirect influence suggesting a genetically controlled neural circuitry for regulating human social behavior. To further characterize WS intermediate phenotypes, we examined the functional, structural, and metabolic abnormalities of hippocampal formation (HF) in our special population. Deficits in spatial navigation, long-term memory, and major cognitive domains depend on hippocampal function suggesting involvement of the HF in the pathophysiology of WS. Recent studies of mice lacking the LIM Kinase 1 (LIMK1) and cytoplasmic linker protein 2 (CYLN2) genes demonstrated significant functional and metabolic abnormalities in the hippocampus while structural integrity of the HF was grossly maintained while only showing subtly altered shape. Our PET and MRI studies showed profound reduction in resting cerebral blood flow (rCBF) which is indicative of disorders having an impact on hippocampal integrity and neural function. Measures of N-acetyl aspirate, the biological marker for synaptic activity were reduced indicating reduced excitation of the glutamatergic transporters and receptors. In contrast to these marked functional deficits, structural abnormalities of the HF in Williams syndrome were subtle and consisted of a change in the anterior-posterior distribution of HF volume. These data implicate LIMK1 and CYLN2 in human hippocampal function as was demonstrated in the mouse model and suggests that hippocampal abnormalities may contribute to neurocognitive abnormalities described in WS. We also explored the genetic contributions to human cerebral gyrification by examining sulcal morphology in our subjects with WS. To date, very little is known about the genetics or abnormal gyrification or the resulting functional consequences. Using our two matched study groups, participants with WS and normal healthy controls we compared group differences with those obtained from a voxel-based morphometry analysis (VBM). Our findings revealed significant reductions in depth in the intraparietal/occipitoparietal sulcus (PS), orbitofrontal region and the left collateral sulcus. We have also demonstrated locally high variance in structure of the left PS region in WS participants as compared with controls. These morphological changes may be attributed to pathological processes consistent with the visuoconstructive deficit that is the unique neuropsychological feature of WS. Most recently, we reviewed the current advances for examining the functional and structural neural mechanisms specifically altered in WS. We have identified specific neural mechanisms that are more than likely associated to the unique behavioral phenotype of this condition. Data have consistently shown that WS is the result of complex interplay between these altered neural systems most likely during brain development. Our continued research will delve into a more detailed mechanistic inquiry of specific mechanisms for executive and social cognition by examining individual genes and gene-gene interactions using animal models and special populations. In addition, we hope to pursue developmental studies which investigate the time course for the emergence of WS and modifications of altered neural circuitry. Because this rare condition offers an unprecedented view into the genetic mechanisms underlying complex behavior, the potential research and clinical impact will extend beyond those with WS.

临床脑部疾病分支的综合神经影像科采用多模态神经影像方法、功能磁共振成像 (fMRI)、结构磁共振成像 (MRI) 和正电子发射断层扫描 (PET) 来帮助表征威廉姆斯综合征 (WS) 患者的特定神经认知缺陷。研究这种罕见的基于遗传的神经发育障碍具有明确特征的半缺失，其中包含 7 号染色体上约 20 个连续基因，并且具有明确特征的认知和社会表型，使我们能够仔细检查：1）一般而言，与认知和行为相关的神经系统的功能、结构和组织的遗传决定因素； 2）视觉空间建构能力基因决定的神经基础； 3）遗传因素影响社会认知和行为的神经机制。我们的每项研究都将患有 WS 的高功能人群与健康正常对照组进行比较。这些比较组在年龄、性别、惯用手和智商分数方面进行了匹配。通过控制这些变量，我们消除了智力迟钝或发育水平等因素影响结果解释的可能性。 我们的多模态神经影像方法结合了各种方法来解决分析特殊人群大脑图像的具体问题。在过去的一年里，我们在表征 WS 患者与正常健康对照组相比所特有的中间脑表型方面取得了重大进展。在一项旨在探索遗传决定的视觉空间构建缺陷的神经基础的研究中，我们的研究结果证明了局部异常对 WS 视觉信息处理的影响。通过让我们的参与者进行一系列旨在访问多个处理层次级别的视觉系统功能的功能磁共振成像实验，然后检查大脑的形态，我们能够将背侧流的局部结构和功能顶叶区域的异常联系起来，从而产生 WS 的神经系统级表型，该表型可用作确定视觉空间结构缺陷的分子机制的模型。 在另一项研究中，我们研究了杏仁核（处理情绪的大脑区域）的作用及其与 WS 患者常见的异常社会行为的联系。杏仁核的反应和调节被认为是通过监测危险等环境事件进行社会保护性神经处理的核心。据报道，杏仁核和相关区域（例如眶额皮质（OFC））的病变会损害社会功能，因此可能导致抑制解除。我们的功能磁共振成像分析表明，WS 患者的杏仁核对威胁性面孔的激活减少，但对威胁性场景的激活增加。还值得注意的是，与杏仁核相关的前额叶大脑区域的激活和相互作用是异常的，并且这些区域（背外侧前额叶皮层（DLPFC）、内侧前额叶皮层（MPFC）和 OFC）可能产生间接影响，表明基因控制的神经回路用于调节人类社会行为。 为了进一步表征 WS 中间表型，我们检查了特殊人群中海马结构 (HF) 的功能、结构和代谢异常。空间导航、长期记忆和主要认知领域的缺陷取决于海马功能，表明 HF 参与 WS 的病理生理学。最近对缺乏 LIM 激酶 1 (LIMK1) 和细胞质连接蛋白 2 (CYLN2) 基因的小鼠的研究表明，海马体存在显着的功能和代谢异常，而 HF 的结构完整性大体上保持不变，但形状仅略有改变。我们的 PET 和 MRI 研究显示静息脑血流量 (rCBF) 大幅减少，这表明存在影响海马完整性和神经功能的疾病。 N-乙酰抽吸物（突触活性的生物标志物）的测量值减少，表明谷氨酸转运蛋白和受体的兴奋减少。与这些明显的功能缺陷相反，威廉姆斯综合征中心力的结构异常是微妙的，包括心力体积前后分布的变化。这些数据表明 LIMK1 和 CYLN2 与人类海马功能有关，正如在小鼠模型中所证明的那样，并表明海马异常可能导致 WS 中描述的神经认知异常。 我们还通过检查 WS 受试者的脑沟形态来探讨遗传对人类大脑回旋的贡献。迄今为止，人们对遗传学或异常回旋或由此产生的功能后果知之甚少。使用我们的两个匹配的研究组，即患有 WS 的参与者和正常健康对照，我们将组间差异与通过基于体素的形态测量分析 (VBM) 获得的差异进行比较。我们的研究结果显示顶内/枕顶沟（PS）、眶额区和左侧副沟的深度显着减少。我们还证明，与对照组相比，WS 参与者的左侧 PS 区域结构存在局部高差异。这些形态学变化可能归因于与视觉建构缺陷一致的病理过程，视觉建构缺陷是 WS 独特的神经心理学特征。 最近，我们回顾了检查 WS 中特别改变的功能和结构神经机制的最新进展。我们已经确定了特定的神经机制，这些机制很可能与这种情况的独特行为表型相关。数据一致表明，WS 很可能是在大脑发育过程中这些改变的神经系统之间复杂相互作用的结果。我们的后续研究将通过使用动物模型和特殊人群检查个体基因和基因-基因相互作用，深入研究执行和社会认知的具体机制的更详细的机械探究。此外，我们希望开展发育研究，调查 WS 出现的时间过程和神经回路改变的改变。由于这种罕见疾病为复杂行为背后的遗传机制提供了前所未有的视角，因此潜在的研究和临床影响将超出 WS 范围。