Functional connectivity substrates of social and non-social deficits in ASD

描述（由申请人提供）：在过去的十年中，自闭症谱系障碍（ASD）是一种远程功能连接减少和局部功能连接增加的障碍的假设得到了越来越多的关注。然而，到目前为止，没有证据表明ASD的局部功能连接增加。此外，如果ASD确实是一种功能连接障碍，那么类似的异常应该在社会交流（核心/定义）和非社会交流（非核心/非定义）缺陷领域都表现出来。然而，情况是否如此，从来没有在一组参与者中进行过系统的测试。本研究的目的是确定ASD中局部和远程功能连接异常的性质，它们之间的关系，它们是否在ASD缺陷的核心社会和非核心非社会领域表现相似，以及它们与行为和结构措施的相关性。我们的中心假设是，ASD实际上是一种连通性障碍，远程连接减少，局部功能连接减少，而不是增加，是分布的，ASD的皮质范围特征，表现在所有的缺陷领域。我们进一步假设局部和远程功能连接在ASD中彼此成比例地减少。这些假设将通过研究ASD缺陷的社会沟通（Aim 1）和非社会（Aim 2）领域的局部和远程功能连接，以及它们与ASD表型的相关性（Aim 3）来验证。这些研究将利用MEG的高空间和时间分辨率来检查45名8-12岁的ASD儿童和45名正常发育的儿童的功能连通性，因为他们执行的任务涉及ASD缺陷的核心社会沟通（面部感知和语音处理）和非核心（执行控制和听觉处理）领域。我们提出的研究在概念上是创新的，因为我们的假设挑战了ASD中局部功能连接增加的流行观点，并进一步提出了局部和远程功能连接减少之间的直接关联。此外，它同时解决了同一参与者的多个缺陷领域。提出的研究在分析上是创新的，因为它使用了新的分析工具来非侵入性地研究皮层空间的相位振幅交叉频率耦合（局部功能连接的一种测量方法）。这项研究具有重要意义，因为(a)它将同时检查多个缺陷域的局部和远程功能连接异常的性质，(b)它将确定局部和远程功能连接异常是否与ASD直接相关，(c)它将为非侵入性测量皮质空间的局部功能连接提供一种新的方法。(d)它将为开发新的基于功能连接的ASD神经生理生物标志物奠定基础，这些标志物在治疗和早期诊断方面具有潜在的应用前景。

DESCRIPTION (provided by applicant): Over the past decade, the hypothesis that autism spectrum disorder (ASD) is a disorder of reduced long-range and increased local functional connectivity has been gaining traction. To date, however, there is no evidence of increased local functional connectivity in ASD. If, furthermore, ASD is indeed a disorder of functional connectivity, then similar abnormalities ought to manifest in both the social communication (core/defining) and the non-social communication (non-core/non-defining) domains of deficits. Whether this is the case, however, has never been systematically tested in one group of participants. The objectives of the current proposal are to determine the nature of local and long-range functional connectivity abnormalities in ASD, the relationship between them, whether they are manifested similarly in both the core social and non-core non-social domains of ASD deficits, and their correlations with behavioral and structural measures. Our central hypotheses are that ASD is in fact a disorder of connectivity, and that reduced long-range and reduced, not increased, local functional connectivity are distributed, cortex-wide features of ASD, manifested in all domains of deficits. We further hypothesize that local and long-range functional connectivity are reduced proportionally to one another in ASD. These hypotheses will be tested by investigating local and long-range functional connectivity in the social communication (Aim 1) and non-social (Aim 2) domains of deficits of ASD, and their correlation with the ASD phenotype (Aim 3). The proposed studies will take advantage of MEG's high spatial and temporal resolutions to examine functional connectivity in 45 ASD children, ages 8-12, and 45 matched typically developing children, as they perform tasks that tap into core social communication (face perception and speech processing) and non-core (executive control and auditory processing) domains of ASD deficits. The proposed research is conceptually innovative because our hypothesis challenges the prevailing notion that local functional connectivity is increased in ASD, and further proposes a direct correlation between the reductions in local and long-range functional connectivity. Furthermore, it addresses multiple domains of deficits simultaneously in the same participants. The proposed research is analytically innovative because it uses novel analytical tools to study phase-amplitude cross-frequency coupling (a measure of local functional connectivity) non-invasively in cortical space. The proposed research is significant because (a) it will examine the nature of both local and long-range functional connectivity abnormalities in multiple domains of deficits simultaneously, (b) it will determine whether local and long-range functional connectivity abnormalities are directly correlated in ASD, (c) it will provide a novel approach for non-invasively measuring local functional connectivity in cortical space, (d) it will set the stage for developing novel functiona-connectivity based neurophysiological biomarkers for ASD, which have potential applications for treatment and early diagnosis.