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.
Highlights
Several brain disorders are characterized by abnormally strong neuronal synchronized activity (Uhlhaas and Singer, 2006)
Without stimulation (K = 0.0) the average synaptic weight, Cav, does not change, but it decreases by the rapidly varying sequences (RVS) Coordinated Reset (CR) stimulation during the CR-on period (Figure 3A)
In this study we investigated if a two-stage CR-stimulation induces better anti-kindling effects than a single-stage CRstimulation for weak to intermediate stimulation intensities (K ≤ 0.25)
Summary
Several brain disorders are characterized by abnormally strong neuronal synchronized activity (Uhlhaas and Singer, 2006). Examples of such neuronal disorders are epilepsy (Wong et al, 1986; Schomer and Lopes da Silva, 2011), Parkinson’s disease (Lenz et al, 1994; Nini et al, 1995; Hammond et al, 2007), and tinnitus (Ochi and Eggermont, 1997; Llinas et al, 1999; Weisz et al, 2005; Eggermont and Tass, 2015). Computational studies were devoted to the role of gap junctions in the emergence of epileptic seizures (Volman et al, 2011) or on the impact of the interplay between gap junctions and delayed inhibitory synaptic coupling on the emergence of different patterns of neuronal synchrony (Guo et al, 2012)
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