Discovering Neural Biomarkers of Language and Social Development in ASD Toddlers

项目总结/摘要 尽管美国ASD每年花费2680亿美元，每年花费数千万美元用于研究， “精确”医学对ASD婴儿和幼儿没有任何意义。异质性 自闭症早期神经和行为发展轨迹的研究阻碍了对自闭症的解释， 以及鉴定临床上有用的预后生物标志物以及发现 可以用来开发最有效的治疗方法。在我们提出的研究中，175名ASD，典型的，语言 延迟（LD）和全球发育迟缓（GDD）幼儿将参加一系列的语言- 相关（童谣与音乐）和社会情感功能磁共振成像范例（自己母亲的声音与陌生人的声音） 以及静息状态连接范例，以开始解决该领域的这一主要差距。蹒跚学步的孩子会 使用我们新的基于一般人群的筛选方法招募，该方法提供独特的 与婴儿兄弟姐妹研究的数据互补。为了生成每种药物的丰富临床特征， 幼儿，多语言和社会措施将采取，包括CELF-R，马伦和葡萄园。在 为了检查变化和利用强大的纵向建模方法，幼儿将在临床上 在1-2年和3-4年进行评估和成像。MEMB和ME-ICA去噪方法 将被利用，产生高度可靠的高信噪比功能成像，优于以前的功能磁共振成像 方法和增强效应大小估计和统计功效;这极大地有利于我们的鲁棒性。 分析、可靠性、分离样本可行性和探索性预后生物标志物建模。多个分析 方法（例如，偏最小二乘、种子偏最小二乘、伊卡分量分析、谱DCM、PPI）将被应用于识别脑语言和脑 社会情感关系;从1-2到3-4年的神经和临床轨迹模型;揭示语言- 和社会情绪相关的功能磁共振成像激活和连接模式在1-2年，是预测 语言和社会结果;发现潜在的神经临床亚型;模型连续变化， 还有其他神经测量，预测连续的语言和社会措施;确定功能磁共振成像-磁共振成像 关系;定义语言和社会情感神经缺陷如何进入共享神经网络 早期发展的资源;并检查大脑行为关系的相似性和差异 跨多个群体，然后可以对大脑行为模式是否常见进行敏感测试 跨越诊断边界（例如，以RDoC方式的LD、GDD和ASD语言差幼儿）或 对一群个体来说是特定的我们的研究将确定具有临床意义的早期神经生物标志物， 预测哪些自闭症儿童会有好的语言成绩，哪些会有差的语言成绩， 来预测社会结果。令人信服的ASD语言和社会生物靶点将被发现，可以进行测试 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作出反应。

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.