Neural Dissection of Hyperactivity/Inattention in Autism

自闭症多动/注意力不集中的神经解剖

基本信息

批准号：
7843200
负责人：
FRANCISCO XAVIER CASTELLANOS
金额：
$ 114.53万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7843200
关键词：
Accounting Address Adopted Adverse effects Age Anatomy Attention deficit hyperactivity disorder Autistic Disorder Behavioral Biological Markers Biological Neural Networks Brain Brain Mapping Characteristics Child Clinical Cognitive Complement DSM-IV Data Diagnostic Dimensions Dissection Floor Frequencies Functional Magnetic Resonance Imaging Functional disorder Funding Goals Hand Heterogeneity Hyperactive behavior Impairment Impulsivity Individual Individual Differences Matched Group Measures Mental disorders Methods Neurons Parents Pattern Performance Pharmaceutical Preparations Population Heterogeneity Positioning Attribute Process Reaction Time Research Research Personnel Rest Risk Sampling Scanning School-Age Population Schools Signal Transduction Social Functioning Socioeconomic Status Stratification Symptoms Terminology Testing Time age group autism spectrum disorder base blood oxygen level dependent improved inattention indexing interest neural circuit novel public health relevance relating to nervous system response sex social social reciprocity therapeutic target trait treatment response

项目摘要

DESCRIPTION (provided by applicant): The most significant determinant of educational and clinical impairment in school-age children with autism spectrum disorders (ASD) is the frequent co-occurrence of hyperactivity and inattention symptoms. In response, clinicians treating ASD are increasingly adopting the terminology, rating scales and medication treatments established for the management of Attention-Deficit/Hyperactivity Disorder (ADHD). However, responses to stimulants are less substantial than obtained in ADHD, and with greater risk of adverse effects. This conundrum can be clarified by examining the neuronal substrates of these symptoms with novel resting state fMRI methods employed by our lab for mapping brain functional connectivity. FMRI signals contain large amplitude low frequency spontaneous fluctuations. Such fluctuations are usually ignored, but 'functional connectivity' (FC) analyses reveal strikingly consistent patterns of intrinsic synchronized activity that delineate entire functional circuits and that differ significantly in multiple psychiatric disorders. Analyzing FC during rest is well suited for studies of children with ASD or ADHD, because the absence of a task minimizes potential floor, ceiling, or practice effects. Our preliminary data demonstrate the feasibility of relating inter-individual differences in hyperactivity, inattention, and social reciprocity to indices of FC strength in key neural circuits. To address ASD heterogeneity with regard to ADHD-like symptoms, we propose relating brain FC to Social Responsiveness Scale (SRS) scores, and to parent ratings of hyperactivity/impulsivity and inattention. Building on ongoing funded studies of children with ADHD and typically developing controls (TDC) [which are already supporting half of the TDC and ADHD samples that would be included in this project], we will characterize three groups of right-handed children (n=100/group) ages 8-11 years (ASD, TDC, and ADHD) with respect to parent SRS ratings, and Conners ratings of hyperactivity/ impulsivity and inattention. Each group will be group- matched on age, sex, and socioeconomic status to address the following specific aims: (1) To determine the extent to which symptoms of hyperactivity/impulsivity and inattention in ASD can be attributed to the presence of abnormalities in the same neural circuits as in ADHD; (2) to identify neural circuits uniquely associated with symptoms of hyperactivity/impulsivity and inattention in ASD; and (3) to determine if brain correlates of social reciprocity in ASD are independent of symptoms of hyperactivity/impulsivity and inattention. If successful, we will be able to differentiate individuals with ASD-related hyperactivity and inattention with underlying pathophysiology indistinguishable from that observed in ADHD from those in whom the pathophysiology is ASD-specific. Such stratification is required for pathophysiology-guided treatment-response studies of ASD- related symptomatology, leading to targeted therapeutics in this highly heterogeneous population. Additionally, this proposal will implement an important goal of the ARRA by supporting the creation of five new full-time positions. PUBLIC HEALTH RELEVANCE: Although many school-age children with autism spectrum disorders are also hyperactive and inattentive, which further limits their school and social functioning, we have not been able to determine whether the brain processes responsible for such ADHD-like symptoms are the same as in typical ADHD or whether they reflect distinct brain processes. Using new methods to measure spontaneous brain function, we propose to disentangle these issues in three groups of children with autism spectrum disorders, ADHD, and typically developing controls. If successful, we will be able to better understand the types of brain mechanisms that are involved in hyperactivity and inattention in children with autism and then be able to use that information to guide targeted treatment studies.

描述（由申请人提供）：患有自闭症谱系障碍（ASD）的学龄儿童的教育和临床障碍的最重要决定因素是多动症和注意力不集中症状的频繁同时出现。为此，治疗 ASD 的临床医生越来越多地采用为治疗注意力缺陷/多动障碍 (ADHD) 而建立的术语、评分量表和药物治疗。然而，对兴奋剂的反应不如多动症患者明显，并且产生不良反应的风险更大。通过使用我们实验室用于绘制大脑功能连接图的新型静息态功能磁共振成像方法来检查这些症状的神经元基质，可以澄清这个难题。 FMRI 信号包含大幅低频自发波动。这种波动通常被忽略，但“功能连接”（FC）分析揭示了内在同步活动的惊人一致的模式，这些模式描绘了整个功能回路，并且在多种精神疾病中存在显着差异。休息时分析 FC 非常适合对自闭症谱系障碍 (ASD) 或多动症 (ADHD) 儿童进行研究，因为没有任务可以最大限度地减少潜在的下限、上限或练习效果。我们的初步数据证明了将个体间多动、注意力不集中和社交互惠性差异与关键神经回路 FC 强度指数联系起来的可行性。为了解决 ASD 与 ADHD 样症状相关的异质性，我们建议将大脑 FC 与社会反应量表 (SRS) 评分以及家长对多动/冲动和注意力不集中的评分联系起来。基于正在进行的针对 ADHD 儿童和典型发育对照 (TDC) 的资助研究 [这些研究已经支持了本项目中将包含的 TDC 和 ADHD 样本的一半]，我们将描述三组右利手儿童的特征（n= 100 名/组）年龄 8-11 岁（ASD、TDC 和 ADHD），涉及家长 SRS 评级以及 Conners 多动/冲动和注意力不集中评级。每个小组将根据年龄、性别和社会经济地位进行分组匹配，以实现以下具体目标：（1）确定自闭症谱系障碍（ASD）中的多动/冲动和注意力不集中的症状在多大程度上可以归因于大脑功能异常的存在。与 ADHD 相同的神经回路； (2) 识别与 ASD 多动/冲动和注意力不集中症状唯一相关的神经回路；（3）确定自闭症谱系障碍（ASD）中社会互惠的大脑相关性是否独立于多动/冲动和注意力不集中的症状。如果成功，我们将能够将患有 ASD 相关多动和注意力不集中的个体与那些病理生理学是 ASD 特异性的个体区分开来，其潜在病理生理学与 ADHD 中观察到的病理生理学无法区分。这种分层对于病理生理学指导的 ASD 相关症状的治疗反应研究是必需的，从而在这个高度异质的人群中进行靶向治疗。此外，该提案将通过支持创建五个新的全职职位来实现 ARRA 的一个重要目标。公共卫生相关性：尽管许多患有自闭症谱系障碍的学龄儿童也过度活跃和注意力不集中，这进一步限制了他们的学校和社会功能，但我们无法确定导致此类多动症样症状的大脑过程是否相同就像典型的多动症一样，或者它们是否反映了不同的大脑过程。我们建议使用新方法来测量自发大脑功能，在三组患有自闭症谱系障碍、多动症和典型发育对照的儿童中解决这些问题。如果成功，我们将能够更好地了解与自闭症儿童多动和注意力不集中有关的大脑机制类型，然后能够利用这些信息来指导有针对性的治疗研究。