Translational Developmental Neuroscience of Autism

描述（由申请人提供）：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培训，使其成为专注于自闭症神经生物学的转化发展神经科学新兴领域的独立研究者。候选人是一名儿童和青少年精神病学家和儿科神经学家，在评估和治疗自闭症儿童方面经验丰富。需要新的特殊治疗方法来解决自闭症个体的严重损伤，这需要了解潜在的病理生理学，并促使提出的培训计划：(1)发展功能脑成像技术的专业知识，优化以检查儿童和青少年的发育相关问题；(2)了解在(a)自闭症谱系障碍纵向随访研究中应用的发展科学方法；(b)非人类灵长类动物的典型和非典型社会发育；(c)对典型发展轨迹的深入定量分析；(3)获得一般统计方法和研究设计方面的专业知识。结合相关的正式课程，个性化指导和积极参与科学会议，该培训计划将通过实施拟议的研究计划来补充，该研究计划基于一个总体论点，即自闭症代表一种神经发育障碍综合征，其特征是远程连接减少和近距离连接增加。皮质-皮质功能连通性（FC），定义为远程神经生理事件之间的时间相关性，尚未在儿童和青少年自闭症患者中进行系统研究。我们的实验室已经开发了一种方法，可以从没有任务（静止）的fMRI数据中量化FC，这种方法对发育差异非常敏感。作为描绘自闭症大脑FC成熟轨迹的第一步，我们建议研究儿童和青少年前扣带皮层（pgACC） FC的横断面发育。我们选择pgACC网络是因为它参与社会过程，初步报道了自闭症的结构和功能异常，并且它的成熟过程很长。这些考虑为本研究提出的假设提供了依据，即自闭症中pgACC网络中FC的紊乱反映了大脑成熟的根本失败。此外，我们假设自闭症的社交障碍可能与异常的pgACC连接直接相关。因此，我们建议检查40名患有高功能全自闭症（HFA）的男性儿童和青少年的大脑FC，并与同等数量的年龄、性别、利手性和智商匹配的健康对照进行比较。我们的目标是：(1)使用静息状态功能磁共振成像（fMRI）检查年龄在8.0-17.9岁之间的HFA患者和对照组之间的pgACC网络中短期和长期FC的差异；(2)检验孤独症诊断观察量表社会互动总分指标与HFA组pgACC网络短、远程FC指标之间的关系；(3)研究对照组和HFA患者pgACC网络中与年龄相关的近程FC减少率和与年龄相关的远程FC增加率。拟议的研究计划的表现与机构环境的广泛资源以及对候选人持续专业发展的强大机构支持相结合，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。

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.