Translational Developmental Neuroscience of Autism

自闭症转化发展神经科学

• 批准号: 8197070
• 负责人: Adriana Di Martino
• 金额: $ 16.81万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197070
• 关键词: 2 year old; Address; Adolescent; Adult; Age; Anterior; Autistic Disorder; Brain; Brain imaging; Child; Childhood; Complement; Computer Analysis; Data; Development; Diagnostic; Diffuse; Disease; Early identification; Environment; Event; Exhibits; Failure; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Growth; Handedness; Imaging Techniques; Impairment; Individual; Lead; Literature; Magnetic Resonance Imaging; Measures; Medial; Mentored Patient-Oriented Research Career Development Award; Mentors; Methods; Modeling; Neurobiology; Neurologist; Neurons; Neurosciences; Pattern; Performance; Preparation; Process; Psychiatrist; Psychopathology; Relative (related person); Reporting; Research; Research Design; Research Personnel; Research Project Grants; Resources; Rest; Sampling; Science; Seeds; Social Characteristics; Social Development; Social Functioning; Social Interaction; Statistical Methods; Symptoms; Syndrome; Techniques; Testing; Training; Training Programs; age group; age related; autism spectrum disorder; base; cingulate cortex; design; experience; follow-up; gray matter; improved; indexing; joint attention; male; neurodevelopment; neurophysiology; nonhuman primate; novel; public health relevance; relating to nervous system; sex; skills; social; symposium; white matter; young adult

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.

描述（由申请人提供）：这项受过指导的面向患者的研究职业发展奖旨在提供专门的培训，以成为成为自闭症神经生物学的转化发展神经科学新兴领域所必需的独立研究者。候选人是一名儿童和青少年的精神科医生和儿科神经科医生在评估和治疗自闭症儿童方面经历的。需要新颖的特定治疗方法来解决自闭症患者的深远障碍，需要了解潜在的病理生理学，并激励拟议的培训计划，以（1）在功能性脑成像技术方面发展专业知识，以优化以检查儿童和青少年的发展相关问题； （2）在（a）自闭症谱系障碍的纵向后续研究中应用的发展科学方法知识渊博； （b）非人类灵长类动物的典型和非典型社会发展； （c）对典型发育轨迹的深入定量分析； （3）在一般统计方法和研究设计中获得专业知识。结合相关的正式课程，个性化的指导和积极参与科学会议，该培训计划将通过制定拟议的研究计划来补充，该计划基于自闭症代表神经发育障碍性综合综合征的高度综合论点，其长量降低并增加了短距离连接性。 Cortico-Cortical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，在自闭症的儿童和青少年中尚未系统地研究。我们的实验室开发了一种方法，可以从没有任务（在其余）的情况下获得的fMRI数据量化FC，该数据对发育差异非常敏感。作为描述自闭症中脑FC的成熟轨迹的第一步，我们建议检查儿童和青少年中骨前扣带回皮层（PGACC）FC的横截面发育。我们之所以选择PGACC网络，是因为它参与了社会过程，自闭症结构和功能异常的初步报道以及其长期的成熟过程。 这些考虑因素可以说明了这一提议的假设，即自闭症PGACC网络中FC的毁灭反映了大脑成熟的根本失败。此外，我们认为自闭症中的社会障碍可能与异常的PGACC连通性直接相关。因此，我们建议在40名男性和青少年中检查具有高功能的全自闭症（HFA）的大脑FC，而年龄，性别，疗法和IQ匹配的健康对照组相等。我们的目的是（1）使用静止状态fMRI检查HFA和对照人在8.0-17.9岁之间的PGACC网络中短期和长期FC的差异； （2）测试社会障碍之间的关系，如自闭症诊断观察量表社会互动量表和HFA组PGACC网络中短期和长期FC的度量的索引； （3）检查对照和HFA中PGACC网络中远程FC的短期FC和年龄相关的年龄相关降低率。 拟议的研究计划的绩效以及机构环境的广泛资源以及对候选人持续专业发展的强烈机构支持将为未来的纵向提案提供基础，这些建议将越来越多地为我们对自闭症的病理生理学及其相关疾病的理解提供信息。 公共卫生相关性：这是一个受过指导的面向患者的研究职业发展奖，旨在为成为新的发育神经科学领域的独立研究者提供专门的培训，重点是识别和了解自闭症异常的神经元回路。拟议的研究项目介绍了与通常患有自闭症的儿童和青少年相比，与典型的儿童相比，研究了与自闭症儿童和青少年有关的脑回路的新技术。该项目有可能告知我们对自闭症神经基础的理解，这是改善早期识别，完善诊断评估并产生新颖治疗所需的。