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）以普遍的社会情感和认知缺陷为特征，即使在具有高智力功能的儿童中也是如此。其神经病理生理学涉及由前额叶皮层介导的执行功能障碍，但由于高度的表型异质性和与注意力和焦虑障碍的共病，以及执行功能受影响的组成过程缺乏解决，目前尚不清楚。我们假设ASD儿童的症状表达是不同的，这是由于合并症的特征（冲动、焦虑）的影响。利用灵敏的功能磁共振成像（fMRI）探针检测由焦虑和冲动引起的执行控制的功能性脑组织的差异，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，这些过程在适应平衡中起作用，为目标导向的行为服务。我们将测试特定的前额叶-纹状体-边缘回路的假设，该回路介导适应性平衡，在ASD中是非典型的。我们将在9-12岁的高功能ASD儿童和年龄、语言智商和性别匹配的对照组中操纵自上而下（自愿、非自愿）和自下而上（注意偏向显著性）加工的组成部分。通过对功能网络和潜在白质微观结构的验证性（假设驱动）和探索性（数据驱动）分析，研究焦虑、冲动和症状严重程度引起的群体差异和个体差异。目的1研究ASD的非典型刺激显著性（即知觉新颖性、情绪）是否调节了自愿和非自愿的注意控制。实验1将检查在正在进行的任务中显著（新奇/不常见vs熟悉/重复）干扰因素的偶然（非自愿）和有意（自愿）编码。实验2将检验点探测任务中外源性（非自愿）和内源性（自愿）对显著面孔（愤怒与中性）的注意偏倚。目的2研究ASD的非典型刺激域（社会情绪或非社会）是否调节了自愿和非自愿的反应控制。实验3将考察具有符号（非社会）刺激的Flanker任务中的自愿反应控制（反应抑制和干扰抑制）和非自愿情境适应。实验4将检验在类似stroop的任务中，冲突中不同社会情感意义的自愿反应控制。目的3将检查ASD的内在静息状态连接是否不典型。目前的研究表明，在行为和休息状态下，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（非社会的，社会情感的）汇总的执行控制组件操作的静歇状态相关性，并确定它们是否在ASD中是非典型的，是否因焦虑、冲动和症状严重程度而变化。本研究的新知识将完善ASD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高级认知功能脑组织的个体差异。它将使用脑成像来检查执行功能的功能性大脑组织是否会因焦虑和冲动而变化，这些都反映在该疾病的症状中。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理学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.