Functional Neuroimaging of Attention in Autism

描述(由申请人提供)：自闭症谱系障碍(ASD)的病因和治疗研究受到儿童和成人在我们诊所的极端异质性的限制。注意力不集中和多动/冲动症状是ASD异质性的一个促成因素，人们越来越认识到这一点。我们的工作表明，这些症状的存在会导致更糟糕的结果(更多的适应不良行为和更差的日常生活技能)。临床医生已经调整了注意力缺陷/多动障碍(ADHD)的诊断和治疗方法，但这种方法显示出哌醋甲酯(即利他林)对ASD儿童的疗效降低。这表明了ADHD症状的另一种病理生理学。这项拟议的研究将使用功能核磁共振和休息状态核磁共振，以及新的、数据驱动的方法来检查患有自闭症和ADHD症状的儿童的大脑网络中断。这种方法有两个明显的优点：1)由反应抑制敲击的基底节-丘脑皮质环路是明确的，并且已知在患有典型ADHD的儿童中被干扰；2)我们的数据驱动方法不对确定的潜在亚群或大脑区域之间的连接做出先验假设。我们将检查患有自闭症的8-10岁儿童(n=30)和典型发育中的对照组(n=15)在日常生活环境中ADHD症状和抑制控制的存在情况。这些儿童将完成功能磁共振成像和静息状态扫描，以检查反应抑制的功能神经解剖学和功能连接性。我们假设，我们的数据驱动的方差方法将识别出一种模式的ASD儿童和较少的ADHD症状，以及两种模式的具有明显ADHD症状的ASD亚组：一组具有类似于典型ADHD儿童的fMRI反应抑制激活模式，另一组具有与典型ADHD不同的模式。我们假设，随着ASD组ADHD症状和日常抑制控制障碍的减少，参与反应抑制的网络之间的功能连接将具有更大的网络内相关性和更低的网络间相关性。如果成功，我们将确定新的基于生物学的亚组来表征ASD，以及确定可以在未来的治疗试验中测试的ADHD症状的新治疗靶点。 公共卫生相关性：对ASD的病因和治疗的研究受到极端异质性的限制，据我们所知，没有研究试图通过检查合并ADHD症状的影响来减少神经水平上的这种异质性。此外，我们使用新的数据驱动的分析方法将识别基于生物学的ASD亚组。如果成功，这些ASD儿童的新亚群将减少未来遗传学研究的异质性，并为未来减少ASD的ADHD症状的治疗试验提供指导。

DESCRIPTION (provided by applicant): Research into the causes and treatments of Autism Spectrum Disorders (ASD) are limited by extreme heterogeneity in how children and adults present at our clinics. There is an increasing appreciation for inattention and hyperactivity/impulsivity symptoms as a contributing factor to heterogeneity in ASD. Our work shows that the presence of these symptoms leads to worse outcomes (more maladaptive behaviors and poorer daily living skills). Clinicians have adapted diagnostics and treatments from Attention Deficit/Hyperactivity Disorder (ADHD), but this approach has shown reduced efficacy of methylphenidate (i.e., ritalin) treatment in children with ASD. This suggests an alternative pathophysiology for the ADHD symptoms. The proposed study will use functional MRI and rest state MRI along with novel, data-driven methods to examine brain networks disrupted in children with ASD and ADHD symptoms. This approach has two distinct advantages: 1) a basal ganglia-thalamocortical loop tapped by response inhibition is well- defined and known to be disrupted in children with prototypical ADHD; and 2) our data-driven methods make no a priori assumptions about potential sub-groups identified or connectivity among brain regions. We will examine the presence of ADHD symptoms and inhibitory control in everyday settings in 8-10-year-old children with ASD (n=30) and typically developing controls (n=15). These children will complete fMRI and resting state scans to examine functional neuroanatomy and functional connectivity of response inhibition. We hypothesize that our data-driven variance methods will identify one pattern of children with ASD and few ADHD symptoms and two patterns of ASD subgroups with significant ADHD symptoms: one group with fMRI response inhibition activation patterns similar to prototypical ADHD children, and one group with patterns distinct from prototypical ADHD. We hypothesize that functional connectivity among networks involved in response inhibition will have greater intra-network correlations and lower inter-network correlations as ADHD symptoms and everyday inhibitory control impairments decrease in the ASD group. If successful, we will identify novel biologically- based subgroups to characterize ASD, as well as identify novel treatment targets for ADHD symptoms that can be tested in future therapeutic trials. PUBLIC HEALTH RELEVANCE: Research into the causes and treatments of ASD is limited by extreme heterogeneity, and no studies to our knowledge have attempted to reduce this heterogeneity at the neural level by examining the impact of comorbid ADHD symptoms. Also, our use of new, data-driven analysis methods will identify subgroups of ASD that is based on biology. If successful, these new subgroups of children with ASD will reduce heterogeneity for future genetic investigations and serve as a guide for future therapeutic trials for reducing ADHD symptoms in ASD.