ADVANCING EARLY BEHAVIORAL AND NEURAL PHENOTYPES OF SOCIAL MOTIVATION IN ASD

项目摘要/摘要 自闭症谱系障碍(ASD)是日益普遍的神经发育疾病，其特征是 社会沟通的核心缺陷和日常生活技能的严重障碍，以及支持 据估计，美国每年受自闭症影响的个人超过110亿美元。没有治愈的方法 对于ASD，尽管3岁之前的早期干预可以改善预后，但 美国还有将近4年的时间。ASD发育机制的阐明对1) 2)优化现有治疗靶点。一个未被充分探索的理论 提出了早期社会动机的不足，即人类优先向社会定向的驱动力 刺激，并寻求和维持社交互动，防止儿童参与社交学习 经历，导致一连串的自闭症症状，包括沟通障碍。目前，有 没有对早期生活中的社会动机进行量化的措施，而这样的工具是开始确定 社会动机的主要缺陷如何影响自闭症的进程，无论是在行为层面还是在 大脑。这个导师K08奖的研究计划建议完善一个初始的社会动机指数，推导出 从美国国立卫生研究院资助的两项研究的现有婴幼儿数据转化为可遗传的、基于问卷的指数 A)对自闭症有更好的预测性，b)可以在自闭症发生之前跟踪婴儿期社会动机的发展过程。 目前被诊断为。然后将1)结合新的基于任务的社会评估对该指数进行测试 动机，以确定这些直接措施是否提高了区分患有和不患有自闭症儿童的能力， 2)结合现有的婴儿神经成像数据进行分析，以确定社会动机与 到早期发育中的结构和功能大脑连接。为了实现这些研究目标， 候选人是一名儿童精神病学家和神经学家，他组建了一个多学科的指导团队，他们将 提供为期5年的必要培训，包括行为表型、统计建模、 发展心理学，弥散加权成像数据(DTI)和静息的处理和分析 状态功能连接磁共振成像数据(RS-fcMRI)。这份职业发展的目标是 奖励是为了使候选人能够开发一个R01资助的研究计划，旨在澄清 核心社会功能、沟通和神经系统发育偏差之间的关系 潜在的ASD，所有这些都是指导新的干预目标的重要途径。此外，在她的未来 R01项目，候选人将提议调整通过该K08产生的社会动机评估以 对于年龄较小的婴儿，它可以作为ASD的早期诊断工具。因此，该项目将有助于 早期识别和干预策略的进展对这种往往是破坏性的疾病 儿童发育的可塑性时期，从而促进受影响者生活质量的显著提高 患有自闭症。

PROJECT SUMMARY/ABSTRACT Autism Spectrum Disorders (ASDs) are increasingly prevalent neurodevelopmental conditions characterized by core deficits in social communication and significant impairments in daily living skills, with the cost of support for ASD-affected individuals estimated at over eleven billion dollars per year in the United States. There is no cure for ASD, and although early interventions prior to age 3 can improve outcomes, the median age of diagnosis in the U.S. is still close to 4 years. The elucidation of developmental mechanisms of ASD will be critical for 1) advancing the age of earliest diagnosis and 2) optimizing current therapeutic targets. One under-explored theory of ASD proposes that early deficiencies in social motivation, the human drive to orient preferentially to social stimuli and to seek and maintain social interactions, prevent children from engaging in social learning experiences, resulting in a cascade of autistic symptoms, including impaired communication. Currently, there is no measure to quantify social motivation in early life, and such a tool is a necessary step to begin to determine how primary deficiencies in social motivation influence the course of ASD, both at the level of behavior and the brain. The research plan for this mentored K08 award proposes to refine an initial social motivation index, derived from existing infant and toddler data from two NIH-funded studies into a heritable, questionnaire-based index that a) is more predictive of ASD and b) can track the course of social motivation in infancy, before ASD is currently diagnosed. This index will then be 1) tested in combination with novel task-based assessments of social motivation, to determine if these direct measures improve the ability to distinguish children with and without ASD, and 2) analyzed in relationship to existing infant neuroimaging data to determine how social motivation relates to structural and functional brain connectivity in early development. To achieve these research objectives, the candidate, a child psychiatrist and neuroscientist, has assembled a multidisciplinary mentoring team who will provide necessary training over a period of 5 years in behavioral phenotyping, statistical modeling, developmental psychology, and processing and analysis of diffusion weighted imaging data (DTI) and resting state functional connectivity magnetic resonance imaging data (rs-fcMRI). The goal of this career development award is to enable the candidate to develop an R01-funded research program aimed at clarifying the relationships between developmental deviations in core social functions, communication, and the neural systems underlying ASD, all of which are important avenues to guide novel targets for intervention. Further, in her future R01 project, the candidate will propose to adapt assessments of social motivation generated through this K08 to younger infants, for whom it could serve as an early diagnostic tool for ASD. This project will thus contribute to advances in early identification and intervention strategies for this often devastating disorder during a more plastic period of child development, thereby promoting significant improvement in quality of life for those affected with ASD.