Long-Lasting Desynchronization of Plastic Neural Networks by Random Reset Stimulation.

Excessive neuronal synchrony is a hallmark of neurological disorders such as epilepsy and Parkinson's disease. An established treatment for medically refractory Parkinson's disease is high-frequency (HF) deep brain stimulation (DBS). However, symptoms return shortly after cessation of HF-DBS. Recently developed decoupling stimulation approaches, such as Random Reset (RR) stimulation, specifically target pathological connections to achieve long-lasting desynchronization. During RR stimulation, a temporally and spatially randomized stimulus pattern is administered. However, spatial randomization, as presented so far, may be difficult to realize in a DBS-like setup due to insufficient spatial resolution. Motivated by recently developed segmented DBS electrodes with multiple stimulation sites, we present a RR stimulation protocol that copes with the limited spatial resolution of currently available depth electrodes for DBS. Specifically, spatial randomization is realized by delivering stimuli simultaneously to randomly selected stimulation sites out of a total of stimulation sites, which will be called L/M-RR stimulation. We study decoupling by L/M-RR stimulation in networks of excitatory integrate-and-fire neurons with spike-timing dependent plasticity by means of theoretical and computational analysis. We find that L/M-RR stimulation yields parameter-robust decoupling and long-lasting desynchronization. Furthermore, our theory reveals that strong high-frequency stimulation is not suitable for inducing long-lasting desynchronization effects. As a consequence, low and high frequency L/M-RR stimulation affect synaptic weights in qualitatively different ways. Our simulations confirm these predictions and show that qualitative differences between low and high frequency L/M-RR stimulation are present across a wide range of stimulation parameters, rendering stimulation with intermediate frequencies most efficient. Remarkably, we find that L/M-RR stimulation does not rely on a high spatial resolution, characterized by the density of stimulation sites in a target area, corresponding to a large . In fact, L/M-RR stimulation with low resolution performs even better at low stimulation amplitudes. Our results provide computational evidence that L/M-RR stimulation may present a way to exploit modern segmented lead electrodes for long-lasting therapeutic effects.