Imaging genetics study of twins who stutter

尽管经过数十年的研究，但持续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可能的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，而这些异常神经网络可能介导口吃的发生和持续。在这个应用中，我们将采用多模态连接组学分析从患有口吃的双胞胎（包括同卵双胞胎和异卵双胞胎，其中只有一个患有口吃）中获得的功能和结构神经成像数据。通过结合全面的全脑拓扑分析和强大的不协调双胞胎设计，预期的结果将是重要的，因为它将首次有助于阐明遗传与环境对与发育性口吃相关的大脑变化的影响程度。本应用程序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，先前报道的与口吃相关的左听-运动网络和基底神经节-辅助运动网络的连通性下降可能是遗传介导的危险因素，而与这些网络相互连接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。提出这项研究的基本原理是，这项调查的结果将有助于更好地理解口吃的基础，不仅考虑基因与口吃的潜在机制，而且考虑可能调节口吃风险的环境因素的影响。我们计划通过追求以下具体目标来检验我们的中心假设，从而实现这个项目的总体目标：1 .识别与持续性口吃环境风险相关的功能和结构连接标记；识别与持续性口吃遗传风险相关的功能和结构连接标记。提出的工作是创新的，因为它应该为儿童早期持续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有望有助于区分导致儿童口吃症状的基于大脑的异常的遗传和环境风险因素。了解这些持续口吃的风险机制对于我们寻找早期诊断的标记物和指导未来研究确定治疗的神经靶点至关重要。

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.