Linking Local Activity and Functional Connectivity in Autism

描述（由申请人提供）：虽然过去的自闭症研究通常致力于单一核心缺陷或局部脑缺陷，但越来越多的证据表明，自闭症是一种涉及许多基因和神经解剖位点以及许多神经功能和行为系统的“分布式疾病”。因此，由于我们缺乏(1)对自闭症中功能连接受损（“连接不足”）的准确理解，以及(2)将局部皮质结构异常证据与“连接不足”证据整合在一起的模型，对网络组织和大脑连接的研究需求受到了阻碍。自闭症儿童（13-17岁）和匹配的正常发育儿童在完成两个简单的感官任务（视觉、听觉）和一个更复杂的词汇语义语言任务时参加神经心理测试、弥散张量成像（DTI）和功能磁共振成像（fMRI）实验。事件相关的fMRI设计将使我们能够识别初级视觉和听觉皮层、初级运动皮层和左额叶下皮层的激活峰值。这些激活峰将进一步用于功能连接（fcMRI）分析，测试整个大脑的时间序列相关性。根据我们的总体假设，激活一致性降低（反映局部皮质组织受损）将与自闭症患者区域间连通性（功能、解剖）降低、白质完整性降低以及神经心理表现受损有关。四个具体目标将测试自闭症组的假设：(i)核心激活位点活动一致性降低（fMRI）， （ii）功能连通性（fcMRI）与激活一致性之间的相关性，（iii）解剖连通性和白质完整性（DTI）与局部激活一致性和功能连通性之间的相关性，以及（iv）成像（一致性，连通性）和神经心理学测量之间的相关性。在认知行为障碍、局部皮质损伤、功能连接和解剖连接之间建立联系，至少在两个方面具有翻译相关性。首先，它有望整合目前自闭症神经发育研究的几个不同方向，这可能是治疗进步的基础；其次，它将提供一种方法来描述自闭症的神经功能定义的内表型，以支持识别人群中遗传风险的亚型。公共卫生相关性：叙述性自闭症是一个日益紧迫的儿科健康问题。遗传方法需要识别生物学上定义的亚型（内表型），该项目将通过使用几种类型的磁共振成像检查自闭症儿童的局部皮质组织、大脑连通性和认知之间的联系，对此做出贡献。

DESCRIPTION (provided by applicant): While in the past autism research has often been dedicated to a single core deficit or localized brain defect, growing evidence suggests that autism is a "distributed disorder" involving many genes and neuroanatomical loci, and many neurofunctional and behavioral systems. The resulting need for studies of network organization and brain connectivity is hampered by our lack of (i) a precise understanding of what impaired functional connectivity ("underconnectivity") in autism means, and (ii) a model integrating evidence of abnormal local cortical architecture with evidence of "underconnectivity". Children with autism (ages 13-17 years) and matched typically developing children will participate in neuropsychological testing, diffusion tensor imaging (DTI), and functional MRI (fMRI) experiments during performance on two simple sensory tasks (visual, auditory) and a more complex lexico-semantic language task. Event-related fMRI designs will allow us to identify activation peaks in primary visual and auditory cortices, primary motor cortex, and left inferior frontal cortex. These activation peaks will be further used for functional connectivity (fcMRI) analyses, testing for time series correlations across the brain. According to our overarching hypothesis, reduced activation concordance (reflecting compromised local cortical organization) will be associated with reduced interregional connectivity (functional, anatomical), reduced white matter integrity, and with impaired neuropsychological performance in autism. Four specific aims will test hypotheses for the autism group of (i) reduced concordance of activity in core activation sites (fMRI), (ii) correlation between functional connectivity (fcMRI) and activation concordance, (iii) correlations of anatomical connectivity and white matter integrity (DTI) with local activation concordance and functional connectivity, and (iv) correlations between imaging (concordance, connectivity) and neuropsychological measures. Establishing links between cognitive-behavioral impairment, local cortical compromise, functional connectivity, and anatomical connectivity will have translational relevance in at least two respects. First, it promises to unite several currently separate lines of neurodevelopmental research in autism that may be the foundation for therapeutic advances; and second, it will provide an approach to characterizing neurofunctionally defined endophenotypes of autism, in support of identifying subtypes of genetic risk within the population. PUBLIC HEALTH RELEVANCE: Narrative Autism is a pediatric health issue of growing urgency. Genetic approaches require the identification of biologically defined subtypes (endophenotypes), to which this project will contribute by examining links between local cortical organization, brain connectivity, and cognition in children with autism, using several types of magnetic resonance imaging.