Multistable Dynamics of Connected Cortical Networks: Mechanisms and Modulation

描述(由申请者提供)：认知需要大脑皮质网络之间电活动的精确协调。这种功能连接的障碍与精神分裂症和抑郁症等精神疾病的认知症状有关。单个神经元轴突形成的长程投射(LRP)可能为跨皮质网络的宏观活动模式的出现提供了机制。然而，目前尚不清楚表现出显著传播延迟的LRP如何支持跨网络的活动的临时精确协调和同步。长期目标是开发非侵入性脑刺激范例，恢复皮质区域之间受损的沟通。本研究的目的是利用大规模计算机模拟的新生物-计算机混合系统，阐明LRP在两个相互连接的皮质网络动力学中的因果作用，并识别非侵入性脑刺激范例来调节相互连接的皮质网络的动力学。工作假设是：(1)LRP的传播延迟创建了一个由同步和非同步活动状态组成的多稳态场景，以及(2)两个网络的同时经颅交流电刺激(TAC)将诱导向同步状态的转变，由于网络的多稳定性，这种状态在刺激终止后持续存在。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例，增强大规模功能网络中的同步和信息流。以下两个具体目标将被用来检验工作假说：(1)确定长程投影(LRP)在相互连接的皮质网络中宏观活动状态的出现中的作用；(2)阐明由LRP连接的两个网络同时进行的经颅交流电刺激(TAC)如何改变宏观活动状态。我们的方法是创新的，因为它结合了计算机模拟、切片电生理学、光遗传学和反馈控制，为在混合系统中研究LRP搭建了一个平台，该系统展示了生物学上的可能性，但使 对LRPS进行精确的实验控制。这项工作的意义在于，了解LRP在塑造相互连接的网络动力学中的因果作用将使Tacs范式的发展直接针对以连接中断为特征的精神和神经疾病患者的连接皮质网络相互作用动力学受损。

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.