Neural Dissection of Hyperactivity/Inattention in Autism

描述（由申请人提供）：学龄儿童自闭症谱系障碍（ASD）的教育和临床障碍最重要的决定因素是多动和注意力不集中症状的频繁共存。作为回应，治疗ASD的临床医生越来越多地采用用于管理注意力缺陷/多动障碍（ADHD）的术语、评分量表和药物治疗。然而，与ADHD相比，对兴奋剂的反应不那么明显，而且有更大的不良反应风险。这个难题可以通过研究这些症状的神经元基质来澄清，我们的实验室采用了新的静息状态fMRI方法来绘制脑功能连接图。功能磁共振成像信号包含大幅度的低频自发波动。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模式，描绘了整个功能回路，在多种精神疾病中差异显著。在休息期间分析FC非常适合于对ASD或ADHD儿童的研究，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多动、注意力不集中和社会互惠的个体间差异与关键神经回路中FC强度指标联系起来的可行性。为了解决ASD在adhd样症状方面的异质性，我们提出将大脑FC与社会反应量表（SRS）评分以及父母对多动/冲动和注意力不集中的评分联系起来。基于正在进行的对多动症儿童和典型发展对照（TDC）的资助研究[这些研究已经支持了该项目中一半的典型发展对照和多动症样本]，我们将对8-11岁的三组右撇子（n=100/组）（ASD、TDC和多动症）的父母SRS评分和Conners对多动/冲动和注意力不集中的评分进行表征。每个组将根据年龄、性别和社会经济地位进行分组匹配，以解决以下具体目标：(1)确定ASD中多动/冲动和注意力不集中的症状在多大程度上可以归因于ADHD中相同神经回路中的异常存在；(2)识别与ASD中多动/冲动和注意力不集中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因素是否独立于多动/冲动和注意力不集中的症状。如果成功，我们将能够区分与自闭症相关的多动和注意力不集中的个体，其潜在的病理生理与ADHD患者无法区分，与那些病理生理是自闭症特异性的患者区分开来。这种分层是病理生理学指导的ASD相关症状的治疗反应研究所必需的，从而导致在这一高度异质性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。

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.