Specifying and Treating the Anxiety Phenotype in Autism Spectrum Disorder

项目摘要--项目1 40%至80%的患有自闭症谱系障碍(ASD)的儿童和青春期前儿童表现为临床症状 明显的焦虑症状，与社交缺陷、抑郁、易怒和 刻板印象和自我伤害的行为。虽然焦虑症状显然代表着一个实质性的问题 对于ASD患者来说，可能影响治疗的重要问题仍未解决。例如：1)有一个 对于如何区分自闭症和焦虑症状缺乏明确性，2)关于焦虑是如何产生的知之甚少 ASD和智力残疾(ID)患者的表现，3)ASD患者焦虑的神经基础较差 理解，以及4)尚不清楚应该采用什么治疗方法(S)来帮助受影响的个人，因为在疾病的早期阶段 研究。在自闭症谱系表型治疗发展中心项目1中 我们对132名参与者(年龄8-12岁)进行了一项神经成像的疗效比较试验 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 描述患有自闭症的儿童和青春期前群体表现出焦虑的特征。我们用 临床医生实施的黄金标准测量以及父母对重叠结构的报告，如坚持 关于使焦虑复杂化的同质性、感觉加工问题和情绪调节问题 ASD的表型。我们进行了多元统计分析，以揭示焦虑的亚型。然后我们检查 焦虑症患病率的估计是否取决于临床医生管理或共同父母 问卷被用来观察后者是否对患有ASD和ID的人产生更低的结果。 我们对一种认知行为疗法进行了为期16周的严格的随机对照治疗试验。 (CBT)被称为自闭症儿童焦虑的行为干预(BIACA)、舍曲林和安慰剂 患有自闭症、智商50和至少一种临床显著焦虑症的年轻人。我们比较了它们的相对疗效 比较：(1)BIACA与安慰剂比较，舍曲林与安慰剂比较，(2)BIACA与安慰剂比较 安慰剂和舍曲林与服用安慰剂相比可以减轻ASD症状的严重程度，以及(3)BIACA与舍曲林的比较 在减少不同类型的焦虑症状方面。我们预测这两种疗法都会有效，但BIACA 将在治疗ASD症状方面具有优势。在特定的目标3中，我们使用fmri来研究神经预测因子。 治疗效果、治疗诱导变化的标志物以及焦虑亚型的特征。在这里，我们 假设舍曲林和BIACA治疗期间焦虑分数的降低将通过以下方式预测 治疗前重新招募腹内侧和腹外侧皮层，并减少基于任务的功能 在功能磁共振任务中，这些前额叶区域和杏仁核之间的连接。总而言之， 项目1是为了更好地描述自闭症患者的焦虑，严格测试药物和CBT疗法，并 检查焦虑和治疗变化的神经机制，以努力使干预更精确 并有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.