Neurobiological Markers of Rhythm: Risk and Resilience for Language Acquisition

项目总结。特殊语言障碍(SLI)是一种常见的、终生的交流障碍 以获得影响儿童生活质量的语法和词汇为特征的成功 学校，还有生计。迫切需要加强对系统性红斑狼疮儿童的识别和治疗。 虽然已知SLI是可遗传的，但这种疾病的潜在神经生物学尚不清楚。近期工作 PI已经显示了儿童的节奏和语法特征之间的强烈关联，指出了节奏 韧性作为口语语法技能中的一个变量。该领域的新证据表明，这是一种共同疾病 SLI中的节奏缺陷和语法缺陷，指出节奏敏感性的缺陷是SLI的风险 因素。此外，节奏和语法特征都是可遗传的，都涉及动态定向 注意等级结构随着时间的推移，但之前没有研究直接比较遗传基础 节奏和语法。在这里，我们采取了一种未得到充分研究但很有希望的方法来研究潜在的共享 基因结构到节律缺陷和SLI。因为声音模式(跨物种)用于交流 都是有节奏地组织起来的，现在的言语和语言能力很可能是建立在前 现有的用于交流的遗传架构，其中可能包括交流的节奏方面。 因此，患有系统性红斑狼疮的儿童可能会有可遗传的节律缺陷，从而削弱他们(通过常见的神经生物学)的能力 在语法习得过程中处理语言的结构。本提案综合了新的 以节奏认知实验为基础的基因组分析方法 节律缺陷对SLI的潜在贡献。目标1利用大样本生物信息库 和现有的数据，利用基因组范围关联研究(GWAS)方法来表征基因 发展性语言障碍的架构。这种方法使我们能够构建最大的样本 建立系统性红斑狼疮的遗传预测模型和研究基因的临床意义 参与SLI。AIM 2在一个新的数据集中使用了GWAS方法，以提供关于 节奏的遗传基础。拥有关于SLI和节律的神经生物学标记物的新知识 缺陷，然后我们将调查节奏对语法相关特征的潜在影响(目标3a)和 语法状态(目标3b)，使用创新的基因组分析选择和一系列有针对性的 系统性红斑狼疮患儿的实验室实验。通过测试这个节奏风险和弹性的框架，这些 研究为今后改进诊断和治疗的多种途径奠定了必要的基础 患有SLI的儿童。该项目直接响应NIDCD的号召，识别遗传因素和共生现象 导致语言障碍的条件和SLI的生物标记物。此外，新知识 节律的遗传基础也可能与其他患有共病的沟通障碍有关 节奏障碍(例如，口吃、阅读困难)。

PROJECT SUMMARY. Specific Language impairment (SLI) is a common, life-long communication disorder characterized by difficulties acquiring grammar and vocabulary that affect children's quality of life, success in school, and livelihood. There is an urgent need to increase identification and treatment of children with SLI. Although SLI is known to be heritable, the underlying neurobiology of the disorder is not yet clear. Recent work by the PI has shown robust associations between rhythm and grammar traits in children, pointing to rhythm resilience as a variable involved in spoken grammar skills. Emerging evidence in the field points to co-morbid rhythm deficits and grammatical deficits in SLI, pointing to weaknesses in rhythm sensitivity as an SLI risk factor. Furthermore, rhythm and grammatical traits are both heritable, and both involve dynamically orienting attention to hierarchical structure over time, but no prior study has directly compared the genetic basis of rhythm and grammar. Here we take an understudied but promising approach to investigating potentially shared genetic architecture to rhythm deficits and SLI. Since sound patterns (across species) used to communicate are organized rhythmically, it is highly likely that present-day speech and language capacities are built on pre- existing genetic architecture for communication, which may include the rhythmic aspect of communication. Children with SLI may thus have heritable rhythm deficits that impair their ability (via common neurobiology) to process the structure of language during grammatical acquisition. The present proposal integrates new methods of genome analysis with rhythm cognition experiments aimed at understanding the mechanisms underlying the potential contribution of rhythm deficits to SLI. Aim 1 harnesses large-sample bio-repositories and extant data with Genome-Wide Association Studies (GWAS) methodology to characterize the genetic architecture of developmental language disorder. This approach allows us to construct the largest sample sizes yet for developing a genetic prediction model for SLI and to investigate the clinical significance of genes involved in SLI. Aim 2 utilizes a GWAS approach in a novel dataset to provide important new knowledge on the genetic basis of rhythm. Armed with novel knowledge about the neurobiological markers of SLI and rhythm deficits, we will then investigate a potential influence of rhythm on grammar-related traits (Aim 3a) and grammar states (Aim 3b), using an innovative selection of genomic analyses and a series of targeted laboratory experiments in children with SLI. By testing this framework of rhythm risk and resilience, these studies lay essential groundwork for multiple future avenues of improving identification and treatment of children with SLI. This project directly responds to NIDCD's call to identify genetic factors and co-occurring conditions that contribute to language impairment and to develop biomarkers of SLI. Moreover, new knowledge of the genetic basis of rhythm may also have relevance for other communication disorders that have co-morbid rhythm deficits (e.g., stuttering, dyslexia).