Cross-frequency coupling and cognition in early psychosis

描述（由申请人提供）：皮质振荡中的干扰被认为是精神分裂症中感觉和认知处理损伤的病理生理学的核心，具有γ频带（30-100 Hz）以及较低频带如θ（4-8 Hz）和α（8-12 Hz）中的损伤。越来越多的证据表明，低频带对伽马射线的调制对正常的感觉和认知过程也至关重要。因此，恢复伽马活动可能是必要的，但不足以恢复认知功能，这需要通过较低频率调制的组织影响。虽然这种交叉频率耦合（CFC）被认为是在认知服务中调节伽马振荡的核心神经计算机制，但在精神分裂症研究中，CFC在很大程度上被忽视了。目前的项目旨在解决这一重要的差距，进行第一次系统的调查CFC的干扰精神分裂症采用综合脑磁图（MEG）和计算建模方法。CFC的调查最常见的检查相幅耦合，反映了较低的频率变化膜兴奋性，系统地调制较高频率振荡的局部网络的振幅。初步研究表明，在精神分裂症中，这种相位-振幅耦合存在干扰。执行听觉稳态反应（ASSR）任务的患者，感觉皮层周期性驾驶范式，显示受损的α-γ耦合相比，控制。初步研究结果还显示，健康对照组的前额叶皮层θ-γ CFC在工作记忆表现与工作记忆能力的强相关性，证明调查CFC干扰精神分裂症患者的可行性。最后，初步的计算工作模拟了死后的调查结果的干扰快速尖峰interneurons（FSI）作为“病变”的模型FSI，再现干扰α-γ CFC。鉴于这些研究结果，我们假设，感觉和前额叶皮层CFC将在精神分裂症和FSI的干扰是足以提供一个机制帐户CFC的干扰。这些假设将通过以下具体目标来解决：（1）研究早期精神病的感觉皮层CFC障碍;（2）研究早期精神病的前额叶皮层CFC障碍;（3）研究早期精神病CFC障碍的神经计算机制。我们预计，这项研究在早期精神病将揭示CFC，一个重要的组织机制，神经活动的感觉和认知处理的障碍。总而言之，该项目的研究结果将提供一个新颖的经验和理论框架， 未来的研究将针对大脑皮层回路的特定成分，以增强精神分裂症患者的CFC和认知能力。

DESCRIPTION (provided by applicant): Disturbances in cortical oscillations are thought to be core to the pathophysiology of sensory and cognitive processing impairments in schizophrenia, with impairments in the gamma-band (30-100 Hz) as well as lower frequency-bands such as theta (4-8 Hz) and alpha (8-12 Hz). There is growing evidence that modulation of gamma by lower frequency bands is also critical for normal sensory and cognitive processing. Accordingly, restoring gamma activity may be necessary but not sufficient for restoring cognitive function, which requires the organizing influence by lower frequency modulations. While such cross-frequency coupling (CFC) is thought to be a core neurocomputational mechanism for regulating gamma oscillations in the service of cognition, CFC has been largely ignored in in schizophrenia research. The current project aims to address this important gap by conducting the first systematic investigation of CFC disturbances in schizophrenia employing an integrated magnetoencephalography (MEG) and computational modeling approach. Investigations of CFC most commonly examine phase-amplitude coupling, reflecting lower frequency changes in membrane excitability that systematically modulates the amplitude of higher frequency oscillations of the local network. Preliminary studies show evidence of disturbances in such phase-amplitude coupling in schizophrenia. Patients performing the auditory steady-state response (ASSR) task, a sensory cortical periodic driving paradigm, showed impaired alpha-gamma coupling compared to controls. Preliminary findings also show prefrontal cortical theta-gamma CFC in healthy controls during working memory performance with strong correlations with working memory capacity, demonstrating feasibility for investigating CFC disturbances in schizophrenia patients. Finally, preliminary computational work modeled post-mortem findings of disturbances in fast-spiking interneurons (FSI) as 'lesions' to the model FSI, reproducing disturbances in alpha-gamma CFC. Given these findings, we hypothesize that sensory and prefrontal cortical CFC will be disturbed in schizophrenia and that FSI disturbances are sufficient to provide a mechanistic account of CFC disturbances. These hypotheses will be addressed through the following Specific Aims: (1) To investigate sensory cortical CFC disturbances in early psychosis; (2) To investigate prefrontal cortical CFC disturbances in early psychosis; and (3) To investigate neurocomputational mechanisms of CFC disturbance in early psychosis. We anticipate that this study in early psychosis will reveal disturbances in CFC, a critical organizing mechanism for neural activity underlying sensory and cognitive processing. Together, the findings of this project will provide a novel empirical and theoretical framework for future studies that will aim to pharmacologically target specific components of cortical circuitry o enhance CFC and cognition in schizophrenia.