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

摘要 自闭症谱系障碍（ASD）的特点是普遍的社会情感和认知缺陷，即使在 高智力功能的儿童。其神经病理生理学涉及执行功能障碍， 前额叶皮层，但由于高表型异质性和共病， 注意力和焦虑障碍以及执行功能的受影响组件过程中缺乏解决方案。 我们假设，ASD儿童的症状表现不同，这是由于以下特征的影响， 表征共病障碍（冲动、焦虑）。检查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进行研究将阐明表型 ASD儿童的异质性。在发育神经解剖学模型的指导下，我们将研究 多个自上而下的控制过程和自下而上的感知过程， 平衡以服务于目标导向的行为。我们将检验特定的前额叶纹状体- 调节适应性平衡边缘回路在ASD中是非典型的。我们将操纵组件 自上而下（自愿，非自愿）和自下而上（注意力偏向于显著性）的加工操作9-12 岁的高功能ASD儿童和年龄，言语智商和性别匹配的对照。群体差异 焦虑、冲动和症状严重程度的个体差异将用确证性 （假设驱动）和探索性（数据驱动）分析功能网络和潜在的白质 微观结构目的I检验注意力的自愿和非自愿控制是否受到 刺激显著性（即，知觉新奇感、情感）在ASD中的作用。实验1将检查附带的 （非自愿）和有意（自愿）编码的显着（新的/不常见的与熟悉/重复）干扰 在一个正在进行的任务的背景下。实验2将检查外源性（非自愿）和内源性（自愿） 点探测任务中对显著面孔（愤怒与中性）的注意偏向。目标2审查是否自愿 和无意识控制的反应是调制的刺激域（社会情绪或非- 在ASD中的社会性。实验3将检查自愿反应控制（反应抑制和 干扰抑制）和无意识的上下文适应过程中的侧卫任务与符号（非社会） 刺激。实验4将考察冲突中的自愿反应控制在社会情感意义上的变化， 一个类似Stroop的任务。目的3将研究是否内在的静息状态连接是非典型的ASD。 目前的研究表明，在行为和静息状态下的平行功能组织。我们会搜查 对于由自愿和非自愿汇集的执行控制的组件操作的静息状态相关性， 条件和领域（非社会，社会情感）从实验1-4，并确定他们是否是非典型的 在ASD中，并因焦虑、冲动和症状严重程度而异。这项提案中的新知识将使 ASD神经病理生理学模型，并提供药理学和行为干预的目标。

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.