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

描述(由申请人提供)：自闭症谱系障碍(ASD)的特征是普遍存在的社会情感和认知缺陷，即使在具有高智力功能的儿童中也是如此。它的神经病理生理学涉及由前额叶皮质介导的执行功能障碍，但由于高度表型异质性和与注意力障碍和焦虑障碍的共病，以及执行功能受影响的组成部分过程缺乏解决，因此尚未被很好地理解。我们推测，ASD儿童的症状表现有所不同，这是由于共病障碍的特征(冲动、焦虑)的影响。用灵敏的fMRI探针检测由于焦虑和冲动导致的执行控制功能脑组织的差异将阐明ASD儿童的表型异质性。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，这些过程在适应性平衡中发挥作用，为目标导向行为服务。我们将检验一种假设，即调节适应性平衡的特定前额叶-纹状体-边缘环路在ASD中是非典型的。我们将操纵9-12岁高功能ASD儿童自上而下(自愿、非自愿)和自下而上(注意偏向于突出)加工的成分操作，以及年龄、言语智商和性别匹配的对照。焦虑、冲动和症状严重程度的群体差异和个体差异将通过功能网络和潜在白质微结构的验证性(假设驱动)和探索性(数据驱动)分析来检验。目的研究在自闭症患者中，注意的自愿和非自愿控制是否受到非典型的刺激突显(即知觉新颖性、情绪)的调节。实验1将在一项正在进行的任务的背景下，考察突显(新奇/不频繁与熟悉/重复)干扰因素的偶然(非自愿)和有意(自愿)编码。实验2将考察Dot-Probe任务中外源性(非自愿)和内源性(自愿)对突出面孔(愤怒与中性)的注意偏向。目的2研究ASD患者对反应的自愿和非自愿控制是否受到非典型的刺激领域(社会-情绪或非社会)的调节。实验3将考察在有象征性(非社会)刺激的侧翼任务中的自愿反应控制(反应抑制和干扰抑制)和非自愿语境适应。实验4将考察冲突期间的自愿反应控制，在类似Stroop的任务中，社会情绪意义不同。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。我们将从实验1-4中寻找由自愿和非自愿条件和领域(非社会、社会情绪)汇集的执行控制成分操作的静止状态相关性，并确定它们是否在自闭症中不典型，是否因焦虑、冲动和症状严重程度而异。这项提议的新知识将完善ASD的神经病理生理学模型，并为药物和行为干预提供靶点。公共卫生相关性：本项目旨在阐明智力功能正常的9-12岁自闭症谱系障碍儿童在高级认知功能脑组织功能上的个体差异。它将使用大脑成像来检查执行功能的大脑功能组织是否因焦虑和冲动而变化，这些焦虑和冲动反映在疾病的症状中。从拟议的研究中获得的知识将完善临床特征，并揭示自闭症谱系障碍的药物和行为治疗的新靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project aims to elucidate individual differences in functional brain organization of higher cognition in 9-12 year old children with Autism Spectrum Disorders with normal intellectual function. It will use brain imaging to examine whether functional brain organization of executive function varies by anxiety and impulsivity that are reflected in symptoms of the disorder. Knowledge gained from proposed studies will refine clinical characterization and reveal new targets for pharmacological and behavioral treatment for Autism Spectrum Disorders.