Discovering Neural Biomarkers of Language and Social Development in ASD Toddlers

项目摘要/摘要 尽管在美国，ASD每年的成本为2680亿美元，每年在研究上花费数千万美元， 对于ASD婴儿和蹒跚学步的孩子来说，“精确”医学不存在任何有意义的方式。异质性 ASD早期神经和行为发育轨迹的研究阻碍了对解释的寻找， 以及识别临床上有用的预后生物标记物以及发现 可以用来开发最有效的治疗方法。在我们建议的研究中，175名自闭症患者，典型，语言 迟缓(LD)和全球发育迟缓(GDD)幼儿将参与一系列语言- 相关的(童谣与音乐)和社会情绪功能磁共振范式(亲生母亲的声音与陌生人的声音) 以及静止状态连接范例，以开始解决该领域的这一重大差距。蹒跚学步的孩子 使用我们新颖的基于一般人群的筛选方法进行招聘，该方法提供了独特的 与婴儿兄弟姐妹研究的数据相辅相成。为了生成每个人丰富的临床资料 将采取多种语言和社交措施，包括CELF-R、Mullen和Vinland。在……里面 为了检查变化并利用强大的纵向建模方法，幼儿将在临床上 在1-2岁和3-4岁时进行评估和成像。现场状态成员和ME-ICA去噪方法 将用于产生高可靠的高信噪比功能成像，其性能优于以前的功能磁共振成像 接近并增强效果大小估计和统计能力；这极大地提高了我们的 分析、可靠性、分割样本可行性和探索性预后生物标记物建模。多重分析 方法(如偏最小二乘法、种子偏最小二乘法、独立分量分析、频谱DCM、PPI)将被应用于脑-语言和脑-语言的识别。 社会情感关系；模拟1-2年至3-4年的神经和临床轨迹；揭示语言- 以及1-2年内与社会情绪相关的功能磁共振激活和连接模式，可预测 语言和社会结果；发现潜在的神经临床亚型；模型连续变化 还有预测连续语言和社交测量的其他神经测量；识别fMRI-MRI 关系；定义语言和社会情感神经缺陷如何利用共享的神经网络 早期发育中的资源；并检查大脑-行为关系的异同 这将允许对大脑行为模式是否常见进行敏感测试 跨越诊断界限(例如，RDoC方式中语言能力较差的LD、GDD和ASD幼儿)或 特定于一小部分个体的。我们的研究将确定具有临床意义的早期神经生物标记物 预测哪些ASD儿童会有好的语言成绩，哪些语言成绩差，以及其他 来预测社会结果。令人信服的ASD语言和社会生物目标将被发现，可以测试 在未来的实验性治疗范例中对特定的、有针对性的干预措施做出反应。

Project Summary/Abstract Despite the annual $268 billion cost of ASD in the U.S. and the tens of millions spent annually on research, “precision” medicine does not exist in any meaningful way for ASD infants and toddlers. The heterogeneity of early neural and behavioral developmental trajectories in ASD has stymied the search for explanations, and the identification of clinically useful biomarkers of prognosis as well as the discovery of biotargets that could be used to develop maximally effective treatments. In our proposed studies, 175 ASD, typical, language delayed (LD) and global developmental delayed (GDD) toddlers will participate in a series of language- relevant (nursery rhymes vs music) and social emotion fMRI paradigms (own mother’s voice vs stranger’s) as well as resting state connectivity paradigms to begin to address this major gap in the field. Toddlers will be recruited using our novel general population based screening approach that provides unique and complementary data to those from baby sibling studies. In order to generate a rich clinical profile of each toddler, multiple language and social measures will be taken, including CELF-R, Mullen and Vineland. In order to examine change and leverage powerful longitudinal modeling approaches, toddlers will be clinically assessed and imaged at both 1-2 and 3-4 years. State-of-the-field MEMB and ME-ICA denoising approaches will be utilized that yield highly reliable high signal-to-noise functional imaging that outperforms previous fMRI approaches and enhances effect size estimates and statistical power; this greatly benefits robustness in our analyses, reliability, split sample feasibility, and exploratory prognostic biomarker modeling. Multiple analytic methods (e.g., PLS, seed-PLS, ICA, spectral DCM, PPI) will be applied to identify brain-language and brain- social emotion relationships; model neural and clinical trajectories from 1-2 to 3-4 years; reveal language- and social emotion-relevant fMRI activation and connectivity patterns at 1-2 years that are predictive of language and social outcomes; discover underlying neural-clinical subtypes; model continuous variation in still other neural measures that predict continuous language and social measures; identify fMRI-MRI relationships; define how language and social emotion neural deficits tap into shared neural network resources in early development; and examine similarities and differences in brain-behavioral relationships across multiple groups which then allows for sensitive tests of whether brain-behavioral patterns are common across diagnostic boundaries (e.g., LD, GDD and ASD poor language toddlers in an RDoC fashion) or specific to a subgroup of individuals. Our studies will identify clinically meaningful early-age neural biomarkers that predict which ASD children will go on to have good language outcomes and which poor ones, and others that predict social outcome. Compelling ASD language and social biotargets will be found that can be tested for response to specific, targeted interventions in future experimental therapeutic paradigms.