Linking Local Activity and Functional Connectivity in Autism

描述（由申请人提供）：虽然在过去的自闭症研究往往致力于一个单一的核心缺陷或局部脑缺陷，越来越多的证据表明，自闭症是一个“分布式障碍”，涉及许多基因和神经解剖位点，许多神经功能和行为系统。由此产生的网络组织和大脑连接的研究需求受到阻碍，我们缺乏（i）对自闭症功能连接受损（“连接不足”）的精确理解，以及（ii）将异常局部皮层结构的证据与“连接不足”的证据相结合的模型。自闭症儿童（年龄13-17岁）和匹配的正常发育儿童将参加神经心理学测试，扩散张量成像（DTI）和功能性MRI（fMRI）实验，在两个简单的感觉任务（视觉，听觉）和一个更复杂的词汇语义语言任务。事件相关功能磁共振成像设计将使我们能够识别初级视觉和听觉皮层，初级运动皮层和左下额叶皮层的激活峰值。这些激活峰值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，减少激活一致性（反映受损的局部皮层组织）将与减少区域间连接（功能，解剖），减少白色物质的完整性，并与受损的神经心理学表现自闭症。四个具体目标将测试自闭症组的假设（i）减少核心激活位点（fMRI）活动的一致性，（ii）功能连接（fcMRI）和激活一致性之间的相关性，（iii）解剖连接和白色完整性（DTI）与局部激活一致性和功能连接的相关性，以及（iv）成像之间的相关性。（一致性，连通性）和神经心理学测量。在认知行为障碍、局部皮质损害、功能连接和解剖连接之间建立联系将至少在两个方面具有翻译相关性。首先，它有望将目前几个独立的自闭症神经发育研究线结合起来，这可能是治疗进展的基础;其次，它将提供一种方法来表征神经功能定义的自闭症内表型，以支持识别人群中遗传风险的亚型。

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.