Decoupling of interacting neuronal populations by time-shifted stimulation through spike-timing-dependent plasticity

摘要

The synaptic organization of the brain is constantly modified by activity-dependent synaptic plasticity. In several neurological disorders, abnormal neuronal activity and pathological synaptic connectivity may significantly impair normal brain function. Reorganization of neuronal circuits by therapeutic stimulation has the potential to restore normal brain dynamics. Increasing evidence suggests that the temporal stimulation pattern crucially determines the long-lasting therapeutic effects of stimulation. Here, we tested whether a specific pattern of brain stimulation can enable the suppression of pathologically strong inter-population synaptic connectivity through spike-timing-dependent plasticity (STDP). More specifically, we tested how introducing a time shift between stimuli delivered to two interacting populations of neurons can effectively decouple them. To that end, we first used a tractable model, i.e., two bidirectionally coupled leaky integrate-and-fire (LIF) neurons, to theoretically analyze the optimal range of stimulation frequency and time shift for decoupling. We then extended our results to two reciprocally connected neuronal populations (modules) where inter-population delayed connections were modified by STDP. As predicted by the theoretical results, appropriately time-shifted stimulation causes a decoupling of the two-module system through STDP, i.e., by unlearning pathologically strong synaptic interactions between the two populations. Based on the overall topology of the connections, the decoupling of the two modules, in turn, causes a desynchronization of the populations that outlasts the cessation of stimulation. Decoupling effects of the time-shifted stimulation can be realized by time-shifted burst stimulation as well as time-shifted continuous simulation. Our results provide insight into the further optimization of a variety of multichannel stimulation protocols aiming at a therapeutic reshaping of diseased brain networks. Author summaryTo clinically advance different types of brain stimulation, e.g., deep brain stimulation or epicortical stimulation, in numerous clinical studies, typically only a few types of stimulus patterns have been delivered to different target areas in the midbrain or cortex. To further leverage the power of these clinical trials we here present a theoretical and numerical study demonstrating that the effects of brain stimulation may massively depend on variations of supposedly minor parameters. To this end, we introduce a time shift between stimulus trains delivered to two anatomically separate neuronal populations interacting through plastic synapses. Depending on the specific time shift, stimulation may be ineffective or induce pronounced changes of the connections between and, in turn, within the neuronal populations, ultimately causing a long-lasting unlearning of abnormal neuronal synchrony. To thoroughly understand the time shift-induced decoupling mechanism, we first consider a simple two-neuron motif of two leaky integrate-and-fire neurons. Intriguingly, our results obtained in the two-neuron motif are in excellent agreement with the two-population scenario, illustrating the predictive power of comparably simple models. Our results are important in the context of the control of plastic neuronal networks and provide testable hypotheses for the improvement of clinically used stimulation techniques.