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.
The proposed research is relevant to public health since a mechanistic understanding of how long- range connections enable multistable dynamics in interconnected cortical and how non-invasive brain stimulation can modulate these dynamics provides the basis for rational design of brain stimulation to enhance neural synchrony in psychiatric illnesses such as schizophrenia and autism. Thus, the proposed research is relevant to the NIH's mission to foster innovative research strategies to improve human health.