Imaging genetics study of twins who stutter

口吃双胞胎的影像遗传学研究

• 批准号: 9243151
• 负责人: Soo-Eun Chang
• 金额: $ 24.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243151
• 关键词: Address; Adult; Affect; Area; Attention; Auditory; Basal Ganglia; Base of the Brain; Behavioral; Biological; Biological Neural Networks; Brain; Brain region; Candidate Disease Gene; Child; Childhood; Childhood Stuttering; Complex; Data; Development; Developmental Stuttering; Dizygotic Twins; Early Diagnosis; Emotions; Environment; Environmental Exposure; Environmental Risk Factor; Etiology; Exhibits; Future; Genes; Genetic; Genetic Drift; Genetic Risk; Heritability; Human; Intervention; Investigation; Knowledge; Lead; Left; Link; Mediating; Methods; Molecular Genetics; Monozygotic twins; Motor; Neural Pathways; Neurobiology; Neurologic; Neurosciences; Outcomes Research; Phenotype; Preventive Intervention; Production; Reporting; Research; Research Design; Risk; Risk Factors; Severities; Speech; Speech Disorders; Structure; Stuttering; Symptoms; System; Testing; Therapeutic Intervention; Time; Translating; Twin Multiple Birth; Twin Studies; Work; base; clinical practice; design; early childhood; endophenotype; gene discovery; genetic variant; genomic variation; imaging genetics; improved; indexing; innovation; insight; multimodality; neural circuit; neuroimaging; novel strategies; relating to nervous system; segregation; support network; targeted treatment

Despite decades of research, the precise etiology and pathophysiological mechanisms underlying persistent developmental stuttering remain unclear. While genetics and neuroimaging research have respectively contributed new knowledge pertaining to possible molecular genetic and neurobiological bases of stuttering, what is presently not clear is how these genetic variants link to stuttering-relevant anomalous neural networks, which may mediate emergence and persistence of stuttering. In this application, we will employ multimodal connectomics analyses of functional and structural neuroimaging data acquired from twins discordant for stuttering (both identical and fraternal twins with only one of the pair who stutters). By combining comprehensive whole brain topological analyses and a powerful discordant twin design, the expected results will be significant, because it will help elucidate, for the first time, the extent of genetic versus environmental influences on brain changes associated with developmental stuttering. The overall objective of this application is to identify the relative influence of genetics and environment on brain structure and function as they pertain to persistent stuttering. The central hypothesis is that, decreased connectivity involving the left auditory-motor and basal ganglia-supplementary motor networks previously reported to be associated with stuttering are likely genetically mediated risk factors, whereas aberrant connections with major intrinsic neural networks that interconnect with these networks may be clarified as environmental risk factors relevant to persistent stuttering. The rationale for the proposed research is that, results from this investigation would lead to a better understanding of the basis for stuttering that not only considers potential mechanisms linking genes to stuttering, but also effects of environmental factors that may modulate stuttering risk. We plan to test our central hypothesis and, thereby, accomplish our overall objective for this project, by pursuing the following specific aims: 1. Identify functional and structural connectivity markers that are associated with environmental risk of persistent stuttering, and 2. Identify functional and structural connectivity markers that are associated with genetic risk of persistent stuttering. The proposed work is innovative, as it should provide comprehensive and more accurate heritable neural markers for persistent stuttering during early childhood. Further, the results generated using this new approach are expected to help differentiate genetic versus environmental risk factors underlying brain-based anomalies that lead to stuttering symptoms during childhood. Understanding these mechanisms of risk for persistent stuttering is essential to our efforts to find markers for early diagnosis and guide future research in identifying neural targets for therapy.

尽管经过数十年的研究，持续性发育性口吃的确切病因和病理生理机制仍不清楚。虽然遗传学和神经影像学研究分别为口吃的可能分子遗传学和神经生物学基础提供了新的知识，但目前尚不清楚这些遗传变异如何与口吃相关的异常神经网络联系起来，这些异常神经网络可能介导口吃的出现和持续。在本应用中，我们将对从口吃不一致的双胞胎（同卵双胞胎和异卵双胞胎，其中只有一对口吃）中获得的功能和结构神经成像数据进行多模式连接组学分析。通过结合全面的全脑拓扑分析和一个强大的不协调双胞胎设计，预期的结果将是显着的，因为它将有助于阐明，第一次，遗传与环境对大脑变化的影响程度与发展口吃。本申请的总体目标是确定遗传和环境对大脑结构和功能的相对影响，因为它们与持续性口吃有关。中心假设是，以前报道的与口吃相关的涉及左侧中枢运动和基底神经节辅助运动网络的连接减少可能是遗传介导的风险因素，而与这些网络互连的主要内在神经网络的异常连接可能被澄清为与持续性口吃相关的环境风险因素。这项研究的基本原理是，这项调查的结果将有助于更好地了解口吃的基础，不仅考虑了基因与口吃之间的潜在机制，还考虑了可能调节口吃风险的环境因素的影响。我们计划测试我们的中心假设，从而实现我们的总体目标，为这个项目，追求以下具体目标：1。识别与持续性口吃的环境风险相关的功能和结构连接标记，以及2。识别与持续性口吃遗传风险相关的功能和结构连接标记。这项工作是创新的，因为它应该为儿童早期持续性口吃提供全面和更准确的遗传神经标记。此外，使用这种新方法产生的结果预计将有助于区分导致儿童期口吃症状的大脑异常的遗传与环境风险因素。了解这些持续性口吃的风险机制对于我们寻找早期诊断标记物和指导未来确定治疗神经靶点的研究至关重要。