Testing the Bottom-Up vs Top-Down Imbalance Hypothesis of ASD

摘要/项目摘要 自闭症谱系障碍(ASD)患者大脑的功能连接已经出现 作为与该疾病相关的神经异常的重要标志。然而，尽管有数百人 关于这一主题的研究，即表征该疾病的功能连接异常的特定性质 仍然悬而未决，也没有出现统一的框架来描述它。构建一致的模型 ASD背后的功能连接异常对于推进我们的 对这种疾病的神经病因学的理解。而普遍接受的模式是一种长期- 许多研究表明，ASD患者的范围功能连接性降低，而局部功能连接性增加 已经显示ASD的远程功能连接性增加或正常，并且有证据支持 关于局部功能连接增加的假设仍然很少，而且是间接的。 到目前为止，绝大多数ASD的功能连接研究都是使用功能磁共振成像进行的， 一种依靠血流动力学反应的技术，因此具有1赫兹的时间分辨率。这很好 然而，众所周知，功能连通性通常由快得多的频带来调节，通常 分为五个基频段：Delta(1-2赫兹)，θ(3-7赫兹)，阿尔法(8-12赫兹)，贝塔(13-30赫兹)， 和伽马(31-80赫兹)。最近也有证据表明，这些频段调节功能 具有首选方向性的连接。根据我们自己的初步数据和目前的研究，我们建议 测试ASD以远程自下而上(前馈)增加为特征的假设 功能连接，以及远程自上而下(反馈)功能连接减少， 伽马频段和贝塔频段分别调节这些功能连接 异常现象。 在这里，我们建议通过从两个人那里获得脑磁图数据来检验我们的假设 空间注意范式，视觉和听觉，优化为评估自下而上与自上而下的功能 连接性，50名TD和60名ASD患者，年龄14-17岁。具体来说，我们提出了以下目标：(1) 测试ASD患者自下而上功能连接性异常增强的假设 视觉领域，这主要体现在伽马频段。(2)检验以下假设： ASD患者在听觉和视觉领域的下行功能连接异常减少，这是 主要表现在贝塔频段。(3)检验神经生理功能的假设 使用脑磁图得出的连接性测量将预测ASD的严重性、诊断和行为 特征，使用健壮的相关性、规范的相关性和机器学习技术。我们期待着 这项研究的结果将导致更详细、更全面和更机械的 对于ASD中观察到的广泛的功能连接异常的激励框架。

ABSTRACT / PROJECT SUMMARY Functional connectivity in the brains of individuals with autism spectrum disorders (ASD) has emerged as an important marker of neural abnormalities associated with the disorder. However, despite hundreds of studies on the topic, the specific nature of functional connectivity abnormalities that characterize the disorder remains unresolved and no unifying framework has emerged to describe it. Constructing a consistent model of the functional connectivity abnormalities that underlie ASD is absolutely essential for advancing our understanding of the neural etiology of the disorder. While the commonly accepted model is one where long- range functional connectivity is decreased in ASD while local functional connectivity is increased, many studies have shown increased or normal long-range functional connectivity in ASD and the evidence supporting the hypothesis that local functional connectivity is increased remains scant and indirect. To date, the vast majority of studies of functional connectivity in ASD have been carried out using fMRI, a technique that relies on the hemodynamic response and thus has a temporal resolution of <1Hz. It is well known, however, that functional connectivity is usually mediated by much faster frequency bands, commonly divided into five fundamental frequency bands: delta (1-2 Hz), theta (3-7 Hz), alpha (8-12 Hz), beta (13-30 Hz), and gamma (31-80 Hz). There is also recent evidence that these frequency bands mediate functional connectivity with preferred directionality. Based on our own preliminary data and current studies, we propose to test the hypothesis that ASD is characterized by increased long-range bottom-up (feedforward) functional connectivity, alongside decreased long-range top-down (feedback ) functional connectivity, and that the gamma and beta frequency bands, respectively, mediate these functional connectivity abnormalities. Here, we propose to test our hypothesis by obtaining MEG (magnetoencephalography) data from two spatial attention paradigms, visual and auditory, optimized for assessing bottom-up versus top-down functional connectivity, in 50 TD and 60 ASD individuals, ages 14-17. Specifically, we propose the following aims: (1) Test the hypothesis that bottom-up functional connectivity is abnormally increased in ASD in the auditory and visual domains, and this is manifested primarily in the gamma frequency band. (2) Test the hypothesis that top- down functional connectivity is abnormally reduced in ASD in the auditory and visual domains, and this is manifested primarily in the beta frequency band. (3) Test the hypothesis that neurophysiological functional connectivity measures derived using MEG will be predictive of ASD severity, diagnosis, and behavioral features, using robust correlations, canonical correlations, and machine learning techniques. We expect that the results of this study will lead to a substantially more detailed, comprehensive, and mechanistically motivated framework for the wide range of functional connectivity abnormalities observed in ASD.