Anti-kindling Induced by Two-Stage Coordinated Reset Stimulation with Weak Onset Intensity

Abstract

Abnormal neuronal synchrony plays an important role in a number of brain diseases. To specifically counteract abnormal neuronal synchrony by desynchronization, Coordinated Reset (CR) stimulation, a spatiotemporally patterned stimulation technique, was designed with computational means. In neuronal networks with spike timing–dependent plasticity CR stimulation causes a decrease of synaptic weights and finally anti-kindling, i.e., unlearning of abnormally strong synaptic connectivity and abnormal neuronal synchrony. Long-lasting desynchronizing aftereffects of CR stimulation have been verified in pre-clinical and clinical proof of concept studies. In general, for different neuromodulation approaches, both invasive and non-invasive, it is desirable to enable effective stimulation at reduced stimulation intensities, thereby avoiding side effects. For the first time, we here present a two-stage CR stimulation protocol, where two qualitatively different types of CR stimulation are delivered one after another, and the first stage comes at a particularly weak stimulation intensity. Numerical simulations show that a two-stage CR stimulation can induce the same degree of anti-kindling as a single-stage CR stimulation with intermediate stimulation intensity. This stimulation approach might be clinically beneficial in patients suffering from brain diseases characterized by abnormal neuronal synchrony where a first treatment stage should be performed at particularly weak stimulation intensities in order to avoid side effects. This might, e.g., be relevant in the context of acoustic CR stimulation in tinnitus patients with hyperacusis or in the case of electrical deep brain CR stimulation with sub-optimally positioned leads or side effects caused by stimulation of the target itself. We discuss how to apply our method in first in man and proof of concept studies.

Dendritic and Axonal Propagation Delays Determine Emergent Structures of Neuronal Networks with Plastic Synapses

“…Note, in our case the phase lags are determined by the connections within the system and in the case that spikings (and their timing difference) are controlled by external stimulation, the decoupled configuration can be achieved and maintained. This result could be of importance in treatment methods for neurological disorders by external stimulation646566.…”

“…However, by the resultant weak connections the system can no longer maintain the neurons in the phase-locked state, and the fluctuations of the phase difference in this case lead to unidirectional connections. Yet, the possibility of the simultaneous depression of the reciprocal connections in a phase-locked state can shed light on how coordinated stimulation of different brain regions might lead to an unlearning of the pathological synchronized dynamics6566.…”

Computationally Developed Sham Stimulation Protocol for Multichannel Desynchronizing Stimulation

“…From previous studies (Zeitler and Tass, 2015 , 2016 ) we know that different initial network conditions and different stimulation signal realizations have an influence on the anti-kindling effects. Therefore, we draw eleven different sets of initial values from the distributions as described above at the start of the initializing period.…”

How stimulation frequency and intensity impact on the long-lasting effects of coordinated reset stimulation

“…For instance, striving for anti-kindling induced at minimal stimulation intensities led to the computational development of spaced CR stimulation [118] and two-stage CR stimulation with weak onset intensity [79]. The motivation behind these developments was to avoid side effects by substantially reducing stimulation intensities [79, 118]. Another direction is to accomplish anti-kindling at moderate stimulation duration as computationally studied in this paper.…”

“…Hpothesis #2: Different embodiments of CR stimulation may differ with respect to effect size and robustness. In a series of computational studies [39, 40, 58, 59, 75, 78, 79] and in all pre-clinical [63, 64] and clinical studies [67–72] performed so far, CR was applied either with fixed sequences or rapidly varying sequences (RVS) , where the sequence was randomly varied from cycle to cycle. In a recent computational study, it was shown that at intermediate stimulation intensities the CR-induced anti-kindling effect may significantly be improved by CR with slowly varying sequences (SVS) , i.e.…”