Development and neural mechanisms of repetitive behavior and sensory responsivity in autism

项目摘要 受限和重复行为(RRB)，在DSM 5下现在包括对感官的异常反应 刺激是自闭症谱系障碍(ASD)的定义特征，阻碍适应机会和 在降低受影响个人及其家庭的生活质量方面发挥重要作用。尽管由来已久 认识到这些影响，RRB亚型潜在的神经发育机制是 认识不足，有效的干预和预防战略严重有限。该项目的长期目标是利用发育、行为和神经成像数据来开发针对受限和重复行为领域的风险标记物和新颖的早期个性化干预和战略性预防策略。本申请的主要目的是在前瞻性确定的患有和不患有ASD的儿童样本中，表征RRB特定亚型和特征背后的神经发育和行为机制。我们将通过与NIH自闭症卓越中心网络婴儿脑成像研究(IBIS)的合作来实现这一目标，IBIS是一项持续的前瞻性、纵向脑成像研究，对从婴儿期到学龄期的自闭症儿童和非自闭症儿童进行研究。我们的中心假设是，不同的、具有生物学信息的RRB亚型将在学龄期被识别出来，这些亚型将通过一个从婴儿期开始的动态发育过程而出现，并被其预示。识别受限和重复行为的行为和神经发育前体将为早期发现和基于机制的预防/干预策略的建立提供新的和必要的立足点。这项应用的目标将通过三个具体目标来实现：1)描述RRB与从婴儿期到学龄期的大脑发育的细粒度维度和概况；2)经验地推导出以后RRB的婴幼儿年龄风险标记；以及3)探索RRB与家庭和学校环境之间的关系。通过IBIS收集的现有纵向脑成像和行为数据将与我们的团队专门设计的新措施相结合，以捕获受限和重复行为的维度(包括感官响应性的直接定量测量)，以及与这些行为发生的环境有关的丰富信息。这项工作是创新的，因为它提供了一个前所未有的机会，全面绘制特定RRB亚型背后的行为和神经发育机制，并识别早期出现的后来结果的标志物。该项目的结果将告诉我们：1)RRB亚型的发病机制，2)它们之间的相互关系和与外部环境的关系，以及3)为早期筛查和有针对性的预防/干预程序的发展奠定基础。

Project Summary Restricted and repetitive behaviors (RRB), which under the DSM 5 now include unusual responses to sensory stimuli, are defining features of autism spectrum disorder (ASD) that impede upon adaptive opportunities and play a significant role in lowering quality of life for affected individuals and their families. Despite long standing acknowledgement of these impacts, the neurodevelopmental mechanisms underlying subtypes of RRB are poorly understood, and effective intervention and prevention strategies are severely limited. The long term goal for this project is to utilize developmental behavioral and neuroimaging data to develop risk markers and novel early individualized intervention and strategic prevention strategies targeted to the domain of restricted and repetitive behaviors. The primary objective of the present application is to characterize the neurodevelopmental and behavioral mechanisms underlying specific subtypes and profiles of RRB in a prospectively ascertained sample of children with and without ASD. We will accomplish this objective through partnership with the NIH Autism Center of Excellence Network Infant Brain Imaging Study (IBIS), an ongoing prospective, longitudinal brain imaging study of children with and without autism from infancy through school age. Our central hypothesis is that distinct, biologically informative RRB subtypes will be identified at school-age, and that these subtypes will have emerged through, and be presaged by, a dynamic developmental process beginning in infancy. Identifying behavioral and neurodevelopmental precursors of restricted and repetitive behaviors will provide new and necessary footholds for the creation of early detection and mechanism-based prevention/intervention strategies. The objectives of this application will be addressed through three specific aims: 1) characterize fine-grained dimensions and profiles of RRB in relation to brain development from infancy through school-age; 2) empirically derive infant/toddler age risk markers for later RRB; and 3) explore the relations between RRB and the home and school environments. Existing longitudinal brain imaging and behavioral data collected through IBIS will be integrated with new measures specifically designed by our team to capture dimensions of restricted and repetitive behavior (including direct quantitative measures of sensory responsivity), as well as rich information pertaining to the environments in which these behaviors occur. This work is innovative in that it offers an unprecedented opportunity to comprehensively chart the behavioral and neurodevelopmental mechanisms underlying specific RRB subtypes and identify early-emerging markers of later outcomes. Results from this project will inform: 1) the pathogenesis of subtypes of RRB, 2) their relations to each other and to the external environment, and 3) set the stage for the development of early screening and targeted prevention/intervention procedures.