Multistable Dynamics of Connected Cortical Networks: Mechanisms and Modulation

描述（由申请人提供）：认知需要皮层网络之间电活动的精确协调。这种功能连通性的损害与精神分裂症和抑郁症等精神疾病的认知症状有关。由单个神经元轴突形成的远程投射（lrp）可能为皮层网络宏观活动模式的出现提供了机制。然而，仍然不清楚表现出大量传播延迟的lrp如何支持跨网络活动的临时精确协调和同步。长期目标是发展非侵入性脑刺激范式，以恢复皮层区域之间受损的通信。本文的目的是通过大规模计算机模拟，阐明lrp在两个连接的皮层网络动力学中的因果作用，并确定非侵入性脑刺激范式来调节相互连接的皮层网络的动力学。工作假设是：(1)lrp的传播延迟创造了一个由同步和非同步活动状态组成的多稳态景观；(2)两个网络的同时经颅交流电刺激（tACS）将诱导过渡到同步状态，这种状态在刺激终止后由于网络的多稳定性而持续存在。这项工作的基本原理是，了解非侵入性脑刺激如何调节互联网络的同步，将使合理设计新的脑刺激范式，增强大规模功能网络的同步和信息流。为了验证这一工作假设，我们将实现以下两个具体目标：(1)确定远程投射（lrp）在相互连接的皮层网络中宏观活动状态的出现中的作用；(2)阐明由lrp连接的两个网络的同时经颅交流电刺激（tACS）如何改变宏观活动状态。我们的方法是创新的，因为它将计算机模拟、切片电生理学、光遗传学和反馈控制结合在一起，为在混合系统中研究lrp建立了一个平台，该平台既展示了生物学上的合理性，又能够实现

DESCRIPTION (provided by applicant): Cognition requires precise coordination of electric activity between cortical networks. Impairment of such functional connectivity has been associated with cognitive symptoms in psychiatric illnesses such as schizophrenia and depression. Long-range projections (LRPs) formed by axons of individual neurons likely provide the mechanism for the emergence of macroscopic activity patterns across cortical networks. Yet, it remains unknown how LRPs that exhibit substantial propagation delays can support temporally precise coordination and synchronization of activity across networks. The long-term goal is to develop non-invasive brain stimulation paradigms that reinstate impaired communication between cortical areas. The objective here is to elucidate the causal role of LRPs in the dynamics of two connected cortical networks with a novel biology-computer hybrid system motivated by large-scale computer simulations and to identify non-invasive brain stimulation paradigms to modulate the dynamics of interconnected cortical networks. The working hypothesis is that (1) the propagation delays of the LRPs create a multistable landscape composed of both synchronized and unsynchronized activity states and (2) that simultaneous transcranial alternating current stimulation (tACS) of both networks will induce transitions to synchronized states that persist after termination of stimulation due to network multistability. The rationale for this work is that understanding how non-invasive brain stimulation modulates synchronization of interconnected networks will enable the rational design of novel brain stimulation paradigms that enhance synchronization and information flow in large-scale functional networks. The following two specific aims will be pursued to test the working hypothesis: (1) to determine the role of long-range projections (LRPs) in the emergence of macroscopic activity states in interconnected cortical networks and (2) to elucidate how simultaneous transcranial alternating current stimulation (tACS) of two networks connected by LRPs alters macroscopic activity state. Our approach is innovative since it brings together computer simulations, slice electrophysiology, optogenetics, and feedback control to build a platform for the study of LRPs in a hybrid system that exhibits biological plausibility yet enables precise experimental control over the LRPs. The significance of this works is that understanding the causal role of LRPs in shaping the dynamics of interconnected networks will enable the development of tACS paradigms that directly target impaired interaction dynamics of connected cortical networks in patients with psychiatric and neurological illnesses characterized by disconnectivity.