Translational Developmental Neuroscience of Autism

描述（由申请人提供）：这个指导以患者为导向的研究职业发展奖旨在提供必要的技能，成为一个独立的研究者在新兴的领域的转化发展神经科学专注于自闭症的神经生物学的专业培训。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。需要新的特定治疗来解决自闭症患者的严重障碍，这需要了解潜在的病理生理学，并促使拟议的培训计划（1）发展功能性脑成像技术的专业知识，以优化儿童和青少年的发育相关问题;（2）了解应用于（a）自闭症谱系障碍的纵向随访研究;（B）非人灵长类动物的典型和非典型社会发展的发展科学方法;以及（c）对典型发展轨迹进行深入的定量分析;以及（3）获得一般统计方法和研究设计方面的专业知识。结合相关的正式课程，个性化的指导和积极参与科学会议，这个培训计划将通过进行拟议的研究计划来补充，该计划基于自闭症代表一种神经发育障碍综合征的总体论文，其特征是减少长距离和增加短距离连接。 皮质-皮质功能连接（FC），定义为远程神经生理事件之间的时间相关性，尚未在自闭症儿童和青少年中进行系统研究。我们的实验室已经开发出一种方法来量化FC从功能磁共振成像数据获得没有一个任务（在休息），是精致敏感的发展差异。作为第一步描绘的成熟轨迹的大脑FC在自闭症，我们建议检查FC的前膝前扣带皮层（pgACC）在儿童和青少年的横截面发展。我们选择pgACC网络，因为它参与社会过程，自闭症的结构和功能异常的初步报告，以及其长期的成熟过程。 这些考虑告知了本提案的假设，即自闭症患者pgACC网络中FC的紊乱反映了大脑成熟的根本失败。此外，我们认为自闭症的社会障碍可能与异常的pgACC连接直接相关。因此，我们建议检查大脑FC在40名男性儿童和青少年与高功能完全自闭症（HFA）相比，同等数量的年龄，性别，利手，智商匹配的健康对照。我们的目的是（1）使用静息状态fMRI检查HFA患者和对照组之间pgACC网络中短程和长程FC的差异，从年龄8.0-17.9岁;（2）测试HFA组中社交障碍（以自闭症诊断观察量表社会互动总分为指标）与pgACC网络中短程和长程FC的测量之间的关系;（3）检查对照组和HFA的pgACC网络中短程FC的年龄相关性降低和长程FC的年龄相关性增加的比率。 拟议的研究计划的性能结合广泛的资源的机构环境和强有力的机构支持候选人的持续专业发展将提供未来的纵向建议，将越来越多地告知我们的自闭症和神经发育相关疾病的病理生理学的基础。 公共卫生相关性：这是一个以患者为导向的指导研究职业发展奖，旨在提供成为发展神经科学新领域独立研究者所需技能的专业培训，重点是识别和理解自闭症异常的神经元回路。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。该项目有可能为我们了解自闭症的神经基础提供信息，这是改善早期识别，完善诊断评估和产生新治疗方法所必需的。

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.