Sexual dimorphism of neural development underlying childhood stuttering

描述（由申请人提供）：在理解儿童发展性口吃的神经基础方面存在根本性的空白，特别是关于为什么某些儿童自然康复，而另一些儿童终生口吃，以及为什么女孩比男孩康复的可能性更大。本研究的长期目标是确定口吃的神经标记物，并开发导致言语行为和神经生理正常化的干预措施。本应用程序的总体目标是识别与症状发作接近的口吃结构和功能神经标记，并确定性别特异性的大脑发育轨迹标记，以区分那些能够从口吃中恢复或不能从口吃中恢复的儿童。中心假设是，患有持续性口吃的男孩和女孩的大脑区域在结构和功能上的连通性较弱，这些区域由左上纵束连接，包括腹侧运动前区和中央前运动区。随着年龄的增长，从口吃中恢复的儿童预计会表现出与对照组越来越相似的大脑发育轨迹。另一方面，继续口吃的孩子预计会表现出更少的正常化，但右半球的代偿性连接。这项研究的基本原理是，提高对口吃复杂神经表型的理解，可能最终导致确定发展治疗干预的神经靶点。因此，拟议的研究与NIH的使命有关，即发展基础知识以减少疾病和残疾的负担。在强有力的初步数据的指导下，中心假设将通过追求两个具体目标来验证：1)确定早期儿童口吃的大脑结构和功能相关性；2)确定性别特异性的表征口吃持续性的神经标记。为了实现这两个目标，我们将使用已经建立的扩散张量成像和功能连接分析方法来获取客观的大脑数据，这些数据将从男孩和女孩开始纵向获取，尽可能接近口吃的开始。这项提议的工作具有潜在的创新性，因为它将是第一个专门为确定儿童早期发育性口吃风险和持续性的性别二态性和神经基础而设计的系列研究。这一结果意义重大，因为它将为大脑发育和性别与口吃持续与恢复之间的关系提供新的信息。这些结果将产生重要的积极影响，因为它们将为早期诊断提供标记，并指导未来的研究，以确定治疗男孩和女孩口吃的特定神经靶点。

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding the neural bases for childhood developmental stuttering, particularly with respect to why certain children recover naturally whereas others continue to stutter throughout life and why there is a greater probability of recovery among girls than boys. The long-term goal in this research is to identify neural markers for stuttering and to develop interventions that lead to behavioral and neurophysiological normalization in speech. The overall objective in this application is to identify structural and functional neural markers of stuttering close to symptom onset and determine gender-specific brain developmental trajectory markers that serve to differentiate those children who do or do not recover from stuttering. The central hypothesis is that both boys and girls with persistent stuttering have weaker structural and functional connectivity in brain regions interconnected by the left superior longitudinal fasciculus encompassing ventral premotor and precentral motor areas. Children who recover from stuttering are expected to exhibit developmental brain trajectories that become increasingly similar to controls with increasing age. On the other hand, children who continue to stutter are expected to exhibit less normalization, but a compensatory connectivity in the right hemisphere. The rationale that underlies the proposed research is that an improved understanding of the complex neural phenotypes in stuttering may ultimately lead to identification of neural targets for developing therapeutic interventions. Thus, the proposed research is relevant to that part of NIH's mission that pertains to developing fundamental knowledge to reduce the burdens of illness and disability. Guided by strong preliminary data, the central hypotheses will be tested by pursuing two specific aims: 1) Determine brain structural and functional correlates of early childhood stuttering; and 2) Determine gender-specific neural markers that characterize stuttering persistence. For both aims, already established methods in diffusion tensor imaging and functional connectivity analyses will be used to acquire objective brain data, which will be taken longitudinally from boys and girls beginning as close as possible to stuttering onset. The proposed work is potentially innovative, as it will be the first series of studies designed specifically to identify the sexual dimorphism and the neural bases of risk and persistence of developmental stuttering during early childhood. The results will be significant, because they will provide novel information on the correlation of brain development and gender with stuttering persistence versus recovery. Such results will have an important positive impact, as they will provide markers for early diagnosis and guide future research in identifying specific neural targets for therapy that may differ for boys versus girls who stutter.