Translational Developmental Neuroscience of Autism

描述(由申请者提供)：这个以患者为导向的指导研究职业发展奖旨在提供必要的技能方面的专门培训，以成为翻译发展神经科学新兴领域的独立研究员，专注于自闭症的神经生物学。候选人是一名儿童和青少年精神病学家和儿科神经科医生，在评估和治疗自闭症儿童方面经验丰富。需要新的特定治疗方法来解决自闭症患者的严重障碍，这需要了解其潜在的病理生理学，并促使拟议的培训计划：(1)发展脑功能成像技术方面的专门知识，以检查儿童和青少年的发育相关问题；(2)了解应用于以下领域的发展科学方法：(A)自闭症谱系障碍的纵向跟踪研究；(B)非人类灵长类动物的典型和非典型社会发展；以及(C)对典型发育轨迹的深入定量分析；以及(3)获得一般统计方法和研究设计方面的专业知识。与相关的正式课程、个性化指导和积极参与科学会议相结合，这一培训计划将通过实施拟议的研究计划来补充，该计划基于总体论题，即自闭症代表一种神经发育障碍综合症，其特征是远程连接减少和短期连接增加。皮质-皮质功能连通性(FC)是指远端神经生理事件之间的时间相关性，在自闭症儿童和青少年中尚未得到系统研究。我们的实验室已经开发出一种方法，可以从没有任务(静态)的fMRI数据中量化Fc，该任务对发育差异非常敏感。作为描述自闭症患者脑Fc成熟轨迹的第一步，我们建议研究儿童和青少年先天前扣带回(PgACC)Fc的横断面发育。我们选择pgACC网络是因为它参与了社会过程，关于自闭症结构和功能异常的初步报告，以及它漫长的成熟过程。这些考虑因素形成了这一假设的假设，即自闭症患者pgACC网络内Fc的错乱反映了大脑成熟的根本失败。此外，我们假设自闭症患者的社会功能障碍可能与pgACC连接异常直接相关。因此，我们建议检测40名患有高功能完全自闭症(HFA)的男性儿童和青少年的脑功能障碍，并与年龄、性别、利手和智商匹配的健康对照组进行比较。我们的目标是(1)使用静息状态的功能磁共振成像来检查8.0-17.9岁的HFA患者和对照组之间pgACC网络中短期和长期FC的差异；(2)测试HFA组中以自闭症诊断观察量表社会互动总分为指标的社会损害与pgACC网络中短期和远程FC的测量之间的关系；以及(3)检查对照组和HFA组中pgACC网络中与年龄相关的短期FC的降低和长期FC的年龄相关增加的比率。拟议的研究计划的表现，加上制度环境的广泛资源和对候选人持续专业发展的强有力的制度支持，将为未来的纵向建议提供基础，这些建议将越来越多地告知我们对自闭症和相关神经发育障碍的病理生理学的理解。 公共卫生相关性：这是一个以患者为导向的研究职业发展奖，旨在提供所需技能的专门培训，以成为发展神经科学新领域的独立研究员，重点是识别和理解自闭症中异常的神经元回路。这项拟议的研究项目引入了新的技术，用于研究自闭症儿童和青少年与正常发育儿童相比，参与社会功能的大脑回路。这个项目有可能让我们了解自闭症的神经基础，这对于改进早期识别、完善诊断评估和产生新的治疗方法是必要的。

DESCRIPTION (provided by applicant): This Mentored Patient-Oriented Research Career Development Award is designed to provide specialized training in the skills necessary to become an independent investigator in the emerging field of translational developmental neuroscience focusing on the neurobiology of autism. The candidate is a child and adolescent psychiatrist and pediatric neurologist experienced in the assessment and treatment of children with autism. The need for novel specific treatments to address the profound impairments of individuals with autism requires an understanding of the underlying pathophysiology and motivates the proposed training plan to (1) develop expertise in functional brain imaging techniques optimized to examine developmentally relevant questions in children and adolescents; (2) become knowledgeable regarding developmental science methods applied in (a) longitudinal follow-up studies of autism spectrum disorder; (b) typical and atypical social development in non- human primates; and (c) in-depth quantitative analyses of typical developmental trajectories; and (3) gain expertise in general statistical methods and research design. In conjunction with pertinent formal coursework, individualized mentoring, and active participation in scientific conferences, this training program will be complemented by conducting the proposed research plan which is grounded in the overarching thesis that autism represents a neurodevelopmental dysconnection syndrome characterized by reduced long-range and increased short-range connectivity. Cortico-cortical functional connectivity (FC), defined as the temporal correlations between remote neurophysiological events, has not been systematically studied in children and adolescents with autism. Our lab has developed a method for quantifying FC from fMRI data obtained without a task (at rest) that is exquisitely sensitive to developmental differences. As a first step towards delineating the maturational trajectories of brain FC in autism, we propose to examine the cross-sectional development of FC of the pregenual anterior cingulate cortex (pgACC) in children and adolescents. We selected the pgACC network because of its involvement in social processes, preliminary reports of structural and functional abnormalities in autism, and its prolonged maturational course. These considerations inform the hypothesis of this proposal that the derangements in FC within the pgACC network in autism reflect a fundamental failure of brain maturation. Further, we posit that social impairment in autism can be directly related to abnormal pgACC connectivity. Thus, we propose to examine brain FC in 40 male children and adolescents with high-functioning full autism (HFA) compared to equal numbers of age-, sex-, handedness-, and IQ-matched healthy controls. Our aims are to (1) use resting state fMRI to examine differences in short- and long-range FC in the pgACC network between individuals with HFA and controls, from ages 8.0-17.9 years; (2) test the relationship between social impairment, as indexed by Autism Diagnostic Observation Scale Social Interaction Total Score and measures of short- and long-range FC in the pgACC network in the HFA group; and (3) examine the rates of age-related decreases in short-range FC and age- related increases in long-range FC in the pgACC network in controls and HFA. The performance of the proposed research plan combined with the extensive resources of the institutional environment and the strong institutional support for the candidate's continued professional development will provide the basis for future longitudinal proposals that will increasingly inform our understanding of the pathophysiology of autism and related disorders of neurodevelopment. PUBLIC HEALTH RELEVANCE: This is a Mentored Patient-Oriented Research Career Development Award designed to provide specialized training in the skills needed to become an independent investigator in the new field of developmental neuroscience with a focus on identifying and understanding the neuronal circuits that are abnormal in autism. The proposed research project introduces novel techniques for studying brain circuits involved in social functioning in children and adolescents with autism in comparison to typically developing children. This project has the potential to inform our understanding of the neural bases of autism, which is needed to improve early identification, refine diagnostic assessments, and yield novel treatments.