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

摘要 有大量有力的证据描述自闭症患者的小脑异常。 谱系障碍(ASD)。同时，功能连接异常也得到了广泛的记录 在自闭症患者的大脑中。虽然大多数这样的研究都集中在皮质-皮质联系上，但研究 这确实观察了皮质-小脑连接记录的ASD的多种异常，使用低颞叶 分辨率功能磁共振成像。然而，到目前为止，还没有关于大脑皮质-小脑功能连接异常的研究。 使用高时间分辨率的ASD方法。使用绘制ASD中的功能连接异常 高度的时间特异性是关键，因为功能连接异常可能会有很大的不同，并且可能 甚至表现在相反的方向，在不同的频段，正如我们小组之前所展示的那样。这一差距 这在很大程度上是由于将传感器数据从这种方法本地化到源相关的挑战 小脑。将我们对皮质-小脑功能连接异常的理解与我们的 更广泛地了解ASD的功能连接异常，有必要扩展到高 ASD患者小脑功能连接异常的时间分辨率研究。 这一提议的动机是我们的合作者和合作伙伴最近展示的事实- 调查员MSH和他的同事们认为，脑磁图传感器数据实际上可以可靠地本地化，并 在小脑的CRU I和CRU II区域，脑磁图在这方面优于EEG。 鉴于ASD中CRU I和CRU II异常的广泛证据以及CRU I和CRU II的作用 在与ASD表型相关的认知领域，这些最先进的发展创造了一个 这是一个令人兴奋的机会，可以更深入地了解自闭症患者的皮质-小脑回路异常。 我们建议使用“概念验证”设计来实现这一点，其中将应用这些新的方法 利用已有的ASD研究静息状态下皮质-小脑功能连接的异常 脑磁图静息状态数据集，由72名7-21岁和79岁的ASD患者的行为特征组成 年龄、非语言智商和惯用左撇子与典型的发展中(TD)参与者相匹配。具体来说，我们建议 为了比较TD组和ASD组在皮质-小脑功能连接方面，CRU I和CRU II在 小脑，以及已知在ASD中有异常反应的皮质区域，在theta到beta频率 频段(~3赫兹至~30赫兹)，使用相干(目标1)和相位幅度耦合(目标2A)。我们还将 检验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 个体行为评估的ASD严重程度测量是否与功能性 连接异常记录为目标1和2的一部分。

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.