High Temporal Resolution Study of Resting-State Cerebro-Cerebellar Functional Connectivity in ASD

摘要 有大量的证据表明自闭症患者小脑异常 谱系障碍（ASD）。与此同时，功能性连接异常已被广泛记录 在自闭症患者的大脑中。虽然大多数此类研究都集中在皮质-皮质连接上， 这一研究确实观察了皮质-小脑连接，使用低颞叶神经元记录了ASD的多种异常， 分辨率fMRI。然而，到目前为止，还没有研究皮质-小脑功能连接异常， ASD使用高时间分辨率方法。绘制ASD中的功能连接异常， 高时间特异性是至关重要的，因为功能连接异常可以显著不同，并且可以 甚至在相反的方向上，在不同的频带中出现，如我们小组先前所示。这一差距 主要是由于与将来自这些方法的传感器数据源定位到 小脑为了使我们对皮质-小脑功能连接异常的理解与我们的 更普遍地理解ASD中的功能连接异常，有必要扩展高 ASD与小脑异常功能连接的时间分辨率研究。 这一提议的动机是最近我们的合作者和合作者所展示的事实， 研究人员MSH和他同事认为，MEG传感器数据实际上可以可靠地定位， 脑磁图对小脑的I脚和II脚区域的影响很大，在这方面上级脑电图。 考虑到ASD中小腿I和小腿II异常的广泛证据，以及小腿I和小腿II的作用， 在与ASD表型相关的认知领域中，这些最先进的发展创造了一个 这是一个令人兴奋的机会，可以更深入地了解ASD中的皮质-小脑回路异常。 我们建议使用“概念验证”设计来实现这一点，其中将应用这些新方法 研究ASD患者静息状态下皮质-小脑功能连接异常， MEG静息状态数据集由72名行为特征的ASD参与者组成，年龄为7-21岁， 年龄，非语言智商和惯用手匹配典型发展（TD）的参与者。具体来说，我们建议 比较TD和ASD组的皮质-小脑功能连接， 小脑和皮质区域已知在ASD中具有异常反应，在θ到β频率 频带（~ 3 Hz至~ 30 Hz），使用相干性（Aim 1）和相位振幅耦合（Aim 2A）。我们还将 测试相干性和相位幅度测量之间的相关性（目标2B）。最后，我们将测试 个体行为学评估的ASD严重性测量是否与功能相关 作为目标1和2的一部分记录的连接异常。

ABSTRACT There is a substantial and robust body of evidence describing cerebellar abnormalities in autism spectrum disorder (ASD). In parallel, functional connectivity abnormalities have been extensively documented in the brains of individuals with ASD. While most such studies focused on cortico-cortical connections, studies that did look at cortico-cerebellar connections document multiple abnormalities in ASD, using low temporal resolution fMRI. Yet, to date, there are no studies of cortico-cerebellar functional connectivity abnormalities in ASD using high temporal resolution methods. Mapping out functional connectivity abnormalities in ASD with high temporal specificity is critical, as functional connectivity abnormalities can differ substantially, and may even manifest in opposite directions, in different frequency bands, as previously shown by our group. This gap is largely due to the challenges associated with source localizing the sensors data from such methods to the cerebellum. To put our understanding of cortico-cerebellar functional connectivity abnormalities on par with our understanding of functional connectivity abnormalities in ASD more generally, it is necessary to extend high temporal resolution studies of abnormal functional connectivity in ASD to the cerebellum. This proposal is motivated by the fact that has recently been shown by our collaborator and co- investigator, MSH, and his colleagues, that MEG sensor data can in fact be source localized reliably and robustly to the Crus I and Crus II areas of the cerebellum, and that MEG is superior in that aspect to EEG. Given the extensive evidence of abnormalities in Crus I and Crus II in ASD, and the roles of Crus I and Crus II in cognitive domains that are relevant to the ASD phenotype, these state-of-the-art developments create an exciting opportunity to gain a deeper insight into cortico-cerebellar circuitry abnormalities in ASD. We propose to do this using a “proof of concept” design, where these novel approaches will be applied to investigate resting state cortico-cerebellar functional connectivity abnormalities in ASD using an existing MEG resting-state dataset that consists of 72 behaviorally characterized ASD participants ages 7-21, and 79 age, non-verbal IQ, and handedness matched typically developing (TD) participants. Specifically, we propose to compare the TD and ASD group on cortico-cerebellar functional connectivity, between Crus I & II in the cerebellum, and cortical areas known to have abnormal responses in ASD, at the theta through beta frequency bands (~3Hz to ~30Hz), using both coherence (Aim 1) and phase amplitude coupling (Aim 2A). We will also test for correlations between the coherence and phase amplitude measures (Aim 2B). Lastly, we will test whether the individual behaviorally assessed ASD severity measures are correlated with the functional connectivity abnormalities documented as part of Aims 1 and 2.