Neuroimaging of Top-Down Control and Bottom-Up Processes in Childhood ASD

摘要 自闭症谱系障碍(ASD)的特征是普遍存在的社会情绪和认知缺陷，即使在 智力水平较高的儿童。它的神经病理生理学涉及执行功能障碍，由 前额叶皮质，但由于高度表型异质性和与 注意力和焦虑症以及在受影响的执行功能的组成部分过程中缺乏解决办法。 我们推测，自闭症儿童的症状表现有所不同，这是由于 描述共病障碍(冲动、焦虑)。考察大脑功能组织的差异 使用敏感的fMRI探针对焦虑和冲动引起的执行控制的研究将阐明表型 自闭症儿童的异质性。在发育神经解剖学模型的指导下，我们将检查 多个自上而下的控制过程和自下而上的感知过程在自适应中发挥作用 平衡服务于目标导向的行为。我们将测试特定的前额叶纹状体-- 调节适应性平衡的边缘回路在ASD中是不典型的。我们将操作组件 9-12岁自上而下(自愿、非自愿)和自下而上(注意偏向突出)加工的操作 一岁的高功能自闭症儿童与年龄、言语智商和性别匹配。群体差异 焦虑、冲动和症状严重程度的个体差异将用确认性检验 (假设驱动)和探索性(数据驱动)功能网络和潜在白质分析 微观结构。Aim I研究了注意的自愿和非自愿控制是否受 刺激性突显(即知觉新颖性、情绪)在ASD中不典型。实验1将检查附带的 (非自愿)和有意(自愿)编码显著(新奇/罕见与熟悉/重复)干扰 在一项持续任务的背景下。实验2将考察外源性(非自愿)和内源性(自愿)。 在Dot-Probe任务中，注意偏向于突出的面孔(愤怒与中性)。目标2检查是否自愿 反应的非自愿控制受刺激领域的调节(社会-情绪或非 社交)，这在ASD中并不典型。EXP 3将审查自愿反应控制(反应抑制和 干扰抑制)和在具有象征性(非社会性)的侧翼任务期间的非自愿上下文适应 刺激物。EXP 4将检查冲突期间的自愿反应控制，这些控制在不同的社会情感意义上 一项类似Stroop的任务。目标3将检查内在静息状态连接是否在ASD中是非典型的。 目前的研究表明，在行为状态和休息状态下，平行的功能组织。我们会搜索的 对于自愿和非自愿汇聚的执行控制组件操作的静止状态相关性 来自实验1-4的条件和领域(非社会、社会-情感)，并确定它们是否是非典型的 在ASD中，并因焦虑、冲动和症状严重程度而异。从这项建议中获得的新知识将得到提炼 ASD的神经病理生理学模型，并为药物和行为干预提供靶点。

ABSTRACT Autism Spectrum Disorder (ASD) is characterized by pervasive socio-emotional and cognitive deficits even in children with high intellectual function. Its neuropathophysiology involves executive dysfunction mediated by prefrontal cortex but is not well-understood, due to high phenotypic heterogeneity and comorbidity with attention and anxiety disorders and a lack of resolution in affected component processes of executive function. We postulate that symptom expression varies among ASD children due to the influence of traits that characterize comorbid disorders (impulsivity, anxiety). Examining differences in functional brain organization of executive control due to anxiety and impulsivity with sensitive fMRI probes will elucidate phenotypic heterogeneity in ASD children. Guided by developmental neuroanatomical models, we will examine multiple top-down control processes and bottom-up perceptual processes that function in adaptive balance to serve goal-directed behavior. We will test the hypothesis that specific prefrontal-striato- limbic circuits, which mediate that adaptive balance, are atypical in ASD. We will manipulate component operations of top-down (voluntary, involuntary) and bottom-up (attention bias to salience) processing in 9-12 year-old high-functioning ASD children and age, Verbal IQ, and gender matched controls. Group differences and individual variation by anxiety, impulsivity, and symptom severity will be examined with confirmatory (hypothesis-driven) and exploratory (data-driven) analysis of functional networks and underlying white-matter microstructure. Aim I examines whether voluntary and involuntary control of attention is modulated by stimulus saliency (i.e., perceptual novelty, emotion) atypically in ASD. Exp 1 will examine incidental (involuntary) and intentional (voluntary) encoding of salient (novel/infrequent vs. familiar/repeated) distracters in the context of an ongoing task. Exp 2 will examine exogenous (involuntary) and endogenous (voluntary) attentional bias to salient faces (angry vs. neutral) in the Dot-probe task. Aim 2 examines whether voluntary and involuntary control of responses is modulated by stimulus domain (social-emotional or non- social) atypically in ASD. Exp 3 will examine voluntary response control (response inhibition and interference suppression) and involuntary context adaptation during a Flanker task with symbolic (non-social) stimuli. Exp 4 will examine voluntary response control during conflict varying in socio-emotional significance in a Stroop-like task. Aim 3 will examine whether intrinsic resting-state connectivity is atypical in ASD. Current research shows parallel functional organization during behavioral and resting states. We will search for resting-state correlates of component operations of executive control pooled by voluntary and involuntary conditions and domains (non-social, socio-emotional) from Exps 1-4 and determine whether they are atypical in ASD and vary by anxiety, impulsivity, and symptom severity. New knowledge from this proposal will refine models of ASD neuropathophysiology and provide targets for pharmacological and behavioral intervention.