Specifying and Treating the Anxiety Phenotype in Autism Spectrum Disorder

项目摘要-项目1 40%到80%的自闭症谱系障碍（ASD）儿童和青少年表现出临床症状， 显著的焦虑症状，与社交缺陷、抑郁、易怒和 刻板和自我伤害的行为。虽然很明显，焦虑症状是一个严重的问题， 对于那些患有ASD的人来说，可以指导治疗的重要问题仍然没有得到解决。例如：1）有一个 缺乏关于如何区分ASD和焦虑症状的明确性，2）关于焦虑如何影响自闭症的认识很少。 ASD和智力残疾（ID）患者的焦虑水平较低; 3）ASD患者焦虑的神经基础较差 4）目前还不清楚采用何种治疗方法来帮助受影响的个人， research.在自闭症谱系表型治疗发展中心的项目1中， 我们在132名参与者（年龄8-12岁）中进行了一项神经影像学疗效比较试验， ASD和临床上显著的焦虑来解决其中的一些问题。在具体目标1中，我们试图更好地 描述患有ASD的儿童和青春期前儿童中表现出焦虑的亚组。我们使用 临床医生管理的金标准测量以及父母报告的重叠结构，如坚持 关于相同性，感觉处理问题，以及使焦虑复杂化的情绪调节问题， ASD中的表型我们实施多元统计分析，以揭示焦虑的子类型。然后我们检查 焦虑患病率估计值是否因医生管理或共同父母而异 使用问卷调查来查看后者是否对ASD和ID患者产生较低的结果。在具体目标2中， 我们进行了一项为期16周的严格的随机对照治疗试验， (CBT)自闭症儿童焦虑行为干预（BIACA），舍曲林和安慰剂， 患有ASD的年轻人，IQ>50，并且至少有一种临床显著的焦虑症。我们比较了 的：（1）BIACA与药丸安慰剂和舍曲林与药丸安慰剂在减少焦虑症状，（2）BIACA与药丸 安慰剂和舍曲林与安慰剂相比，降低ASD症状的严重程度，以及（3）BIACA与舍曲林相比 在减少焦虑症状的亚型。我们预测这两种疗法都是有效的，但BIACA 在治疗ASD症状方面有优势。在具体目标3中，我们使用功能磁共振成像来研究神经预测因子 治疗效果、治疗引起的变化的标志物和焦虑亚型的特征。这里我们 假设舍曲林和BIACA治疗期间焦虑评分的降低将通过以下因素预测： 腹内侧和腹外侧皮质的治疗前募集，沿着减少的基于任务的功能性 这些前额叶区域和杏仁核之间的连接在功能磁共振成像任务。总而言之， 项目1是更好地描述ASD中的焦虑，严格测试药物和CBT疗法， 研究焦虑和治疗变化的神经机制，以使干预更加精确 并可能促进积极的结果。

PROJECT SUMMARY – PROJECT 1 Forty to eighty percent of children and preadolescents with autism spectrum disorder (ASD) exhibit clinically significant anxiety symptoms, which are associated with increased social deficits, depression, irritability, and stereotyped and self-injurious behaviors. While it is clear that anxiety symptoms represent a substantial problem for those with ASD, important issues that could inform treatment remain unresolved. For example: 1) there is a lack of clarity about how to differentiate ASD and anxiety symptoms, 2) little is known about how anxiety manifests in those with ASD and intellectual disability (ID), 3) the neural substrates of anxiety in ASD are poorly understood, and 4) it is unclear what treatment(s) to employ to help affected individuals given the early stage of research. In Project 1 of the Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder, we conduct a comparative efficacy trial with neuroimaging in n=132 participants (ages 8-12 years) with ASD and clinically significant anxiety to resolve some of these issues. In Specific Aim 1, we attempt to better characterize the sub-group of children and preadolescents with ASD that exhibit anxiety. We use clinician-administered gold standard measurements as well as parent reports of overlapping constructs such as insistence on sameness, sensory processing issues, and emotion regulation problems that complicate the anxiety phenotype in ASD. We implement multivariate statistical analyses to reveal anxiety sub-types. We then examine whether anxiety prevalence estimates differ depending on whether clinician-administered or common parent questionnaires are used to see if the latter produce lower results for those with ASD and ID. In Specific Aim 2, we conduct a rigorous 16-week randomized, comparative treatment trial of a form of cognitive behavior therapy (CBT) called Behavioral Intervention for Anxiety in Children with Autism (BIACA), sertraline, and pill placebo in youth with ASD, IQ>50, and at least one clinically significant anxiety disorder. We compare the relative efficacy of: (1) BIACA vs. pill placebo and sertraline vs. pill placebo in reducing anxiety symptoms, (2) BIACA vs. pill placebo and sertraline vs. pill placebo in reducing the severity of ASD symptoms, and (3) BIACA vs. sertraline in reducing anxiety symptoms across sub-types. We predict that both therapies will be effective, but that BIACA will have advantages in treating ASD symptoms. In Specific Aim 3, we use fMRI to investigate neural predictors of treatment efficacy, markers of treatment-induced change, and signatures of the anxiety sub-types. Here, we hypothesize that reductions in anxiety scores during sertraline and BIACA treatment will be predicted by pre-treatment recruitment of the ventromedial and ventrolateral cortices, along with reduced task-based functional connectivity between these prefrontal regions and the amygdala during the fMRI task. In summary, the goal of Project 1 is to better characterize anxiety in ASD, to rigorously test medication and CBT therapies, and to examine neural mechanisms of anxiety and of treatment change in an effort to make interventions more precise and likely to promote positive outcomes.