Neural Dissection of Hyperactivity/Inattention in Autism

自闭症多动/注意力不集中的神经解剖

• 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
• 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

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）：自闭症谱系障碍儿童教育和临床障碍最重要的决定因素（ASD）是多动症和注意力不集中症状的经常出现。作为回应，治疗ASD的临床医生越来越多地采用术语，评级量表和用于管理注意力缺陷/多动症障碍（ADHD）的治疗方法。但是，对兴奋剂的反应不如ADHD中获得的，并且具有更大的不利影响风险。可以通过检查这些症状的神经元基材，通过我们的实验室绘制脑功能连通性来阐明这些症状的神经元底物。 fMRI信号包含大幅度低频自发波动。这种波动通常被忽略，但是“功能连通性”（FC）分析表明，固有同步活性的一致模式非常一致，这些模式描绘了整个功能电路，并且在多种精神病障碍中差异很大。在休息期间分析FC非常适合对ASD或ADHD儿童的研究，因为缺乏任务可以最大程度地减少潜在的地板，天花板或实践效果。我们的初步数据证明了与关键神经回路中FC力量指数相关的个体间差异的可行性。为了解决ASD的异质性在类似ADHD的症状方面，我们建议将大脑FC与社会反应量表（SRS）分数以及父母对多动症/冲动性和不集中注意力的评分有关。基于正在进行的ADHD儿童和通常开发控制（TDC）的持续资助的研究（这些项目中已经支持的TDC和ADHD样本中的一半），我们将以8-11岁（ASD，TDC和ADHD）的三个右手儿童（n = 100/组）对父母的态度和依赖的态度来表征三组右手（N = 100/组）（ASD，TDC和ADHD）。每个群体都将与年龄，性别和社会经济状况相匹配，以解决以下特定目的：（1）确定ASD中的多动症/冲动性和不集中注意力的症状可以归因于ADHD中同一神经回路中异常的存在； （2）确定与ASD中多动症/冲动性和注意力不集中的症状独特相关的神经回路； （3）确定ASD中社会互惠的大脑相关性是否与多动症/冲动性和注意力不集中的症状无关。如果成功的话，我们将能够区分与ASD相关的多动症和注意力不集中的个体，与在ADHD中观察到的病理生理学与病理生理学是ASD特异性的病理生理学无法区分。这种分层是对ASD相关症状学的病理生理学引导的治疗响应研究所必需的，从而导致这种高度异质人群的靶向疗法。此外，该提案将通过支持创建五个新的全职职位来实现ARRA的重要目标。 公共卫生的相关性：尽管许多自闭症谱系障碍的学龄儿童也充满活跃和不专心，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这种ADHD样症状的大脑过程是否与典型的ADHD相同，或者它们是否相同，或者它们是否反映了明显的大脑过程。使用新方法来测量自发的大脑功能，我们建议在三组自闭症谱系障碍，多动症以及通常会发展控制的儿童中解散这些问题。如果成功的话，我们将能够更好地理解自闭症儿童中多动症和注意力不集中的大脑机制的类型，然后能够使用该信息来指导目标治疗研究。