Linking Local Activity and Functional Connectivity in Autism

描述(申请人提供)：虽然过去的自闭症研究通常致力于单一的核心缺陷或局限性的大脑缺陷，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置以及许多神经功能和行为系统的“分布式障碍”。由此产生的对网络组织和大脑连通性研究的需求受到以下因素的阻碍：(I)我们缺乏对自闭症功能连通性受损(“连通性不足”)的准确理解，以及(Ii)一个将局部皮质结构异常的证据与“连通性不足”证据相结合的模型。自闭症儿童(13-17岁)和与之匹配的典型发育儿童将在两个简单的感觉任务(视觉、听觉)和更复杂的词汇-语义语言任务中进行神经心理测试、扩散张量成像(DTI)和功能磁共振(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质、初级运动皮质和左下额叶皮质的激活峰。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)将与区域间连通性降低(功能、解剖)、白质完整性降低以及自闭症患者的神经心理表现受损有关。四个特定的目标将测试自闭症组的假设：(I)核心激活部位活动的一致性降低(FMRI)，(Ii)功能连通性(FcMRI)和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的相关性，以及(Iv)成像(一致性，连通性)和神经心理学指标之间的相关性。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至少在两个方面具有翻译相关性。首先，它承诺联合目前几个独立的自闭症神经发育研究，这可能是治疗进展的基础；第二，它将提供一种方法来表征自闭症神经功能定义的内表型，以支持识别人群中的遗传风险亚型。

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.