Improving long lasting anti-kindling effects via coordinated reset stimulation frequency mild modulation

Several brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation [1,2] was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike timing-dependent plasticity (STDP) [3] this leads to a decrease of synaptic weights and ultimately to an anti-kindling [4], i.e. unlearning of abnormal synaptic connectivity and abnormal neuronal synchrony. The long-lasting desynchronizing impact of CR stimulation has been verified in pre-clinical and clinical proof of concept studies (e.g. [5]). However, as yet it is unclear how to optimally choose the CR stimulation frequency, i.e. the repetition rate at which the CR stimuli are delivered.

This work presents a first computational study on the dependence of the long-term outcome on the CR stimulation frequency in neuronal networks with STDP. From a clinical standpoint, it is desirable to achieve an anti-kindling already with stimulation durations as small as possible. For this reason and due to CPU time constraints, we have chosen a certain range of stimulation durations, where we were able to achieve a reasonable success rate (i.e. anti-kindling) at least for suitable stimulation frequencies. For a representative stimulation duration of this kind, we have thoroughly varied the stimulation frequency while we have preliminary evidence that even for longer stimulation durations the picture does not change much. For this purpose, CR stimulation was applied with Rapidly Varying Sequences (RVS) [4] in a wide range of stimulation frequencies and intensities.

A similar survey was also performed with a different type of CR signal, i.e. the Slowly Varying Sequences (SVS) [6]. We show that when comparing the two different CR signals, the RVS turn out to be more robust against stimulation frequencies; however, the SVS can obtain stronger anti-kindling effects [7]. In cases where the initial combination of CR intensity and frequency did not perform efficiently for the majority of different network initializations, we implement three plausible therapy-like stimulation protocols, which aim to ameliorate the long-lasting effects. The first one prolongs the CR on period before ceasing it completely, the second one consists of repetition of CR on and off trial-periods with the same fixed CR frequency while the third one incorporates a control mechanism monitoring the degree of synchronization at the end of the CR off period and adjust CR’s period for the following trials via a mild modulation. When comparing these three approaches, the last one not only manages to induce global (for all networks) desynchronization but also shows very good robustness among different signals and network dependent variations [8]. These findings can be implemented into stimulation protocols for first in man and proof of concept studies aiming at further improvement of CR stimulation.