Neural Dissection of Hyperactivity/Inattention in Autism

描述（由申请人提供）：自闭症谱系障碍（ASD）学龄儿童教育和临床障碍的最重要决定因素是多动和注意力不集中症状的频繁共同发生。作为回应，治疗ASD的临床医生越来越多地采用为管理注意力缺陷/多动障碍（ADHD）而建立的术语，评级量表和药物治疗。然而，对兴奋剂的反应不如ADHD中获得的那么大，并且具有更大的不良反应风险。这个难题可以澄清，通过检查这些症状的神经元基板与新的静息态功能磁共振成像方法所采用的我们的实验室映射大脑功能连接。FMRI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）分析揭示了惊人的一致模式的内在同步活动，描绘了整个功能电路，并在多种精神疾病显着不同。在休息时分析FC非常适合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地板，天花板或练习效果。我们的初步数据表明，个体间的差异，多动症，注意力不集中，社会互惠指数的FC强度在关键的神经回路的可行性。为了解决ASD的异质性方面的ADHD样症状，我们建议将大脑FC社会反应量表（SRS）的分数，并与父母的多动/冲动和注意力不集中的评级。基于正在进行的ADHD儿童和典型发展对照组（TDC）的资助研究[已经支持了本项目中包含的一半TDC和ADHD样本]，我们将描述三组8-11岁右利手儿童（n=100/组）（ASD，TDC和ADHD）的父母SRS评级，以及多动/冲动和注意力不集中的Conners评级。每组将在年龄、性别和社会经济状况上进行分组匹配，以解决以下具体目标：（1）确定ASD中的多动/冲动和注意力不集中的症状在多大程度上可归因于与ADHD中相同的神经回路中存在异常;（2）鉴定与ASD中的多动/冲动和注意力不集中的症状唯一相关的神经回路;以及（3）确定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，我们将能够区分与ASD相关的多动症和注意力不集中的个体，其潜在的病理生理学与ADHD中观察到的病理生理学无法区分。这种分层是ASD相关神经病学的病理生理学指导的治疗反应研究所必需的，从而在这种高度异质性的人群中产生靶向治疗。此外，该提案将通过支持设立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：虽然许多患有自闭症谱系障碍的学龄儿童也是过度活跃和注意力不集中的，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，或者它们是否反映了不同的大脑过程。使用新的方法来测量自发脑功能，我们建议解开这些问题在三组儿童自闭症谱系障碍，多动症，通常发展控制。如果成功，我们将能够更好地了解自闭症儿童多动症和注意力不集中的大脑机制类型，然后能够使用这些信息来指导有针对性的治疗研究。

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.