Long-Lasting Desynchronization of Plastic Neuronal Networks by Double-Random Coordinated Reset Stimulation.

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Hypersynchrony of neuronal activity is associated with several neurological disorders, including essential tremor and Parkinson's disease (PD). Chronic high-frequency deep brain stimulation (HF DBS) is the standard of care for medically refractory PD. Symptoms may effectively be suppressed by HF DBS, but return shortly after cessation of stimulation. Coordinated reset (CR) stimulation is a theory-based stimulation technique that was designed to specifically counteract neuronal synchrony by desynchronization. During CR, phase-shifted stimuli are delivered to multiple neuronal subpopulations. Computational studies on CR stimulation of plastic neuronal networks revealed long-lasting desynchronization effects obtained by down-regulating abnormal synaptic connectivity. This way, networks are moved into attractors of stable desynchronized states such that stimulation-induced desynchronization persists after cessation of stimulation. Preclinical and clinical studies confirmed corresponding long-lasting therapeutic and desynchronizing effects in PD. As PD symptoms are associated with different pathological synchronous rhythms, stimulation-induced long-lasting desynchronization effects should favorably be robust to variations of the stimulation frequency. Recent computational studies suggested that this robustness can be improved by randomizing the timings of stimulus deliveries. We study the long-lasting effects of CR stimulation with randomized stimulus amplitudes and/or randomized stimulus timing in networks of leaky integrate-and-fire (LIF) neurons with spike-timing-dependent plasticity. Performing computer simulations and analytical calculations, we study long-lasting desynchronization effects of CR with and without randomization of stimulus amplitudes alone, randomization of stimulus times alone as well as the combination of both. Varying the CR stimulation frequency (with respect to the frequency of abnormal target rhythm) and the number of separately stimulated neuronal subpopulations, we reveal parameter regions and related mechanisms where the two qualitatively different randomization mechanisms improve the robustness of long-lasting desynchronization effects of CR. In particular, for clinically relevant parameter ranges double-random CR stimulation, i.e., CR stimulation with the specific combination of stimulus amplitude randomization and stimulus time randomization, may outperform regular CR stimulation with respect to long-lasting desynchronization. In addition, our results provide the first evidence that an effective reduction of the overall stimulation current by stimulus amplitude randomization may improve the frequency robustness of long-lasting therapeutic effects of brain stimulation.

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