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Computationally it was shown that desynchronizing delayed feedback stimulation methods are effective closed-loop techniques for the control of synchronization in ensembles of interacting oscillators. We here computationally design stimulation signals for electrical stimulation of neuronal tissue that preserve the desynchronizing delayed feedback characteristics and comply with mandatory charge deposit-related safety requirements. For this, the amplitude of the high-frequency (HF) train of biphasic charge-balanced pulses used by the standard HF deep brain stimulation (DBS) is modulated by the smooth feedback signals. In this way we combine the desynchronizing delayed feedback approach with the HF DBS technique. We show that such a pulsatile delayed feedback stimulation can effectively and robustly desynchronize a network of model neurons comprising subthalamic nucleus and globus pallidus external and suggest this approach for desynchronizing closed-loop DBS. Intriguingly, an interphase gap introduced between the recharging phases of the charge-balanced biphasic pulses can significantly improve the stimulation-induced desynchronization and reduce the amount of the administered stimulation. In view of the recent experimental and clinical studies indicating a superiority of the closed-loop DBS to open-loop HF DBS, our results may contribute to a further development of effective stimulation methods for the treatment of neurological disorders characterized by abnormal neuronal synchronization.

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High-frequency (HF) deep brain stimulation (DBS) is the gold standard for the treatment of medically refractory movement disorders like Parkinson's disease, essential tremor, and dystonia, with a significant potential for application to other neurological diseases. The standard setup of HF DBS utilizes an open-loop stimulation protocol, where a permanent HF electrical pulse train is administered to the brain target areas irrespectively of the ongoing neuronal dynamics. Recent experimental and clinical studies demonstrate that a closed-loop, adaptive DBS might be superior to the open-loop setup. We here combine the notion of the adaptive high-frequency stimulation approach, that aims at delivering stimulation adapted to the extent of appropriately detected biomarkers, with specifically desynchronizing stimulation protocols. To this end, we extend the delayed feedback stimulation methods, which are intrinsically closed-loop techniques and specifically designed to desynchronize abnormal neuronal synchronization, to pulsatile electrical brain stimulation. We show that permanent pulsatile high-frequency stimulation subjected to an amplitude modulation by linear or nonlinear delayed feedback methods can effectively and robustly desynchronize a STN-GPe network of model neurons and suggest this approach for desynchronizing closed-loop DBS.

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In this computational study we investigate coordinated reset (CR) neuromodulation designed for an effective control of synchronization by multi-site stimulation of neuronal target populations. This method was suggested to effectively counteract pathological neuronal synchrony characteristic for several neurological disorders. We study how many stimulation sites are required for optimal CR-induced desynchronization. We found that a moderate increase of the number of stimulation sites may significantly prolong the post-stimulation desynchronized transient after the stimulation is completely switched off. This can, in turn, reduce the amount of the administered stimulation current for the intermittent ON-OFF CR stimulation protocol, where time intervals with stimulation ON are recurrently followed by time intervals with stimulation OFF. In addition, we found that the optimal number of stimulation sites essentially depends on how strongly the administered current decays within the neuronal tissue with increasing distance from the stimulation site. In particular, for a broad spatial stimulation profile, i.e., for a weak spatial decay rate of the stimulation current, CR stimulation can optimally be delivered via a small number of stimulation sites. Our findings may contribute to an optimization of therapeutic applications of CR neuromodulation.

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This computational study is devoted to the optimal parameter calibration for coordinated reset (CR) stimulation, a stimulation technique suggested for an effective desynchronization of pathological neuronal synchronization. We present a detailed study of the parameter space of the CR stimulation method and show that CR stimulation can induce cluster states, desynchronization and oscillation death. The stimulation-induced cluster states (at CR offset) cause the longest desynchronizing post-stimulus transients, which constitute an essential part of the CR stimulation effect. We discover a desynchronization-related anti-resonance response of the stimulated oscillators induced by a periodic ON-OFF CR stimulation protocol with m cycles ON stimulation followed by n cycles OFF stimulation. The undesired collective oscillations are effectively desynchronized if the stimulation is administered at resonant frequencies of the controlled ensemble, which is in complete contrast to the typical effect of the usual periodic forcing.

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We computationally study whether it is possible to stimulate a neuronal population in such a way that its mean firing rate increases without an increase of the population's net synchronization. For this, we use coordinated reset (CR) stimulation, which has previously been developed to desynchronize populations of oscillatory neurons. Intriguingly, delivered to a population of predominantly silent FitzHugh-Nagumo or Hindmarsh-Rose neurons at sufficient stimulation amplitudes, CR robustly causes a multi-frequency activation: different Arnold tongues such as 1 : 1 or n : m entrained neuronal clusters emerge, which consist of phase-shifted sub clusters. Owing to the clustering pattern the neurons' timing is well balanced, so that in total there is no synchronization. Our findings may contribute to the development of novel and safe stimulation treatments that specifically counteract cerebral hypo-activity without promoting pathological synchronization or inducing epileptic seizures.

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We present a simplified phase model for neuronal dynamics with spike timing-dependent plasticity (STDP). For asymmetric, experimentally observed STDP we find multistability: a coexistence of a fully synchronized, a fully desynchronized, and a variety of cluster states in a wide enough range of the parameter space. We show that multistability can occur only for asymmetric STDP, and we study how the coexistence of synchronization and desynchronization and clustering depends on the distribution of the eigenfrequencies. We test the efficacy of the proposed method on the Kuramoto model which is, de facto, one of the sample models for a description of the phase dynamics in neuronal ensembles.