Neural mechanisms of sensory over-responsivity in children with and without ASD

项目摘要 感觉过度反应(SOR)，或对无害的感觉刺激的强烈负面反应和回避； 影响大约五分之一的学龄儿童和大约三分之二的患有自闭症谱系障碍的儿童 (ASD)和其他几种常见的神经发育障碍。患有SOR的儿童经历了相当多的经历 短期和长期的痛苦和损害，包括恐惧和焦虑，睡眠和营养不良，孤立的社会 困难，以及精神疾病风险的增加。儿童时期SOR的代价因其对 适合发展的社会和情景体验及其对家庭功能的有害影响。 尽管它的流行和对健康和福祉的影响，但对SOR的原因了解很少，而且 现有的治疗方法取得的成功有限。确定特定的神经机制， 在SOR中被破坏，可以提供对其病因的见解，并提出有希望的开发方法 有效的干预措施。对典型感觉加工的研究揭示了基本的神经机制， 促进适应性感觉反应，突出了一种强大的新的翻译方法来研究 SOR的神经基础。K99/R00独立之路奖的目标是为申请者提供 测试患有SOR的儿童的这些神经机制是否被破坏并支持她所需的训练 作为一名独立调查员继续取得成功。为了实现这一目标，申请者已经组建了一个 由杰出的导师和专家组成的委员会，他们将为她提供临床演示和 对ASD和SOR(康斯坦蒂诺、西尔维斯特、格林和普鲁特博士)进行功能磁共振成像的评估 扫描患有和不患有自闭症和SOR的儿童(格林、西尔维斯特、达普雷托、普鲁特和多森巴赫博士)， 将多层模型应用于复杂的数据集(杰克逊博士)，并培养成功的技能 主要研究机构的独立调查员(所有委员会成员)。拟议的培训将 允许申请者测试关于一种神经机制(抑制)和 使用现有数据对儿童进行排序，并试验功能磁共振任务以评估第二种神经机制 (惊讶)在K99阶段的儿童中。这项工作的结果将通知R00阶段，这将需要 测试三种神经机制(适应、抑制和惊讶)是否在感觉和 伴和不伴ASD的SOR儿童额叶边缘脑区。这种创新的研究方法 将澄清患有SOR的儿童的预测机制是否受到干扰，并将干扰定位于特定的 大脑区域，促进对SOR的科学理解，并强调有希望的干预目标 在R01上进行了测试。总的来说，拟议的培训和研究将为申请者提供数据、工具、 以及在一流研究机构开始成功职业生涯所需的技能。

PROJECT ABSTRACT Sensory over-responsivity (SOR), or strong negative reactions to and avoidance of innocuous sensory stimuli, affects about one in five school-age children and about two-thirds of children with autism spectrum disorder (ASD) and several other common neurodevelopmental disorders. Children with SOR experience considerable short- and long-term distress and impairment including fear and anxiety, poor sleep and nutrition, isolating social difficulties, and increased risk of mental illness. The cost of SOR in childhood is compounded by its disruption of developmentally appropriate social and situational experiences and its deleterious effects on family functioning. Despite its prevalence and impact on health and wellbeing, the causes of SOR are poorly understood and existing treatment approaches have met with limited success. Identifying the specific neural mechanisms that are disrupted in SOR could provide insights into its etiology and suggest promising approaches for developing effective interventions. Studies of typical sensory processing have revealed basic neural mechanisms that promote adaptive sensory responses, highlighting a powerful new translational approach to investigating the neural bases of SOR. The goal of this K99/R00 Pathway to Independence Award is to provide the applicant with the training needed to test if these neural mechanisms are disrupted in children with SOR and to support her continued success as an independent investigator. To achieve this goal, the applicant has assembled a committee of exceptional mentors and experts who will provide her with training in clinical presentations and assessments of ASD and SOR (Drs. Constantino, Sylvester, Green, and Pruett), administering functional MRI scans to children with and without ASD and SOR (Drs. Green, Sylvester, Dapretto, Pruett, and Dosenbach), applying multilevel models to complex datasets (Dr. Jackson), and developing skills for success as an independent investigator at a major research institution (all committee members). The proposed training will allow the applicant to test predictions about the relationship between one neural mechanism (suppression) and SOR in children using existing data and to pilot a functional MRI task to assess a second neural mechanism (surprise) in children during the K99 phase. Results from this work will inform the R00 phase, which will entail testing whether three neural mechanisms (adaptation, suppression, and surprise) are attenuated in sensory and fronto-limbic brain areas of children with SOR, both with and without ASD. This innovative research approach will clarify whether predictive mechanisms are disrupted in children with SOR and localize disruptions to specific brain areas, advancing scientific understanding of SOR and highlighting promising targets for interventions to be tested in a R01. Collectively, the proposed training and research will provide the applicant with the data, tools, and skills needed to launch a successful career at a top-tier research institution.