Long-Term Desynchronization by Coordinated Reset Stimulation in a Neural Network Model With Synaptic and Structural Plasticity.

Thanos Manos,Peter A Tass,Sandra Diaz-Pier

doi:10.3389/fphys.2021.716556

Abstract

Several brain disorders are characterized by abnormal neuronal synchronization. To specifically counteract abnormal neuronal synchrony and, hence, related symptoms, coordinated reset (CR) stimulation was computationally developed. In principle, successive epochs of synchronizing and desynchronizing stimulation may reversibly move neural networks with plastic synapses back and forth between stable regimes with synchronized and desynchronized firing. Computationally derived predictions have been verified in pre-clinical and clinical studies, paving the way for novel therapies. However, as yet, computational models were not able to reproduce the clinically observed increase of desynchronizing effects of regularly administered CR stimulation intermingled by long stimulation-free epochs. We show that this clinically important phenomenon can be computationally reproduced by taking into account structural plasticity (SP), a mechanism that deletes or generates synapses in order to homeostatically adapt the firing rates of neurons to a set point-like target firing rate in the course of days to months. If we assume that CR stimulation favorably reduces the target firing rate of SP, the desynchronizing effects of CR stimulation increase after long stimulation-free epochs, in accordance with clinically observed phenomena. Our study highlights the pivotal role of stimulation- and dosing-induced modulation of homeostatic set points in therapeutic processes.

Highlights

High-frequency deep brain stimulation (HF DBS) is the standard treatment of medically refractory movement disorders such as Parkinson’s disease (PD) (Benabid et al, 1991; Krack et al, 2003; Deuschl et al, 2006) and is being tested in other psychiatric diseases (Cleary et al, 2015)
After the first periodic stimulation (PS)-coordinated reset (CR) sequence, we turn on structural plasticity in the desynchronized state for a computational time interval corresponding to arbitrary time units
spike-timing-dependent plasticity (STDP) and structural plasticity operate at different time scales simulating biological time which ranges from milliseconds up to minutes when STDP is ON and up to several days when structural plasticity is ON

Summary

Introduction

High-frequency deep brain stimulation (HF DBS) is the standard treatment of medically refractory movement disorders such as Parkinson’s disease (PD) (Benabid et al, 1991; Krack et al, 2003; Deuschl et al, 2006) and is being tested in other psychiatric diseases (Cleary et al, 2015). HF DBS aims to permanently deliver electrical charge-balanced pulses at high frequencies (>100 Hz) to target areas such as the thalamic ventralis intermedius (VIM) nucleus or the subthalamic nucleus (STN) through chronically implanted depth electrodes (Benabid et al, 1991, 2009). Any DBS treatment regime should be minimized in duration as much as possible, in order to minimize the AEs that can result (Buhmann et al, 2017)

Objectives

Methods

Results

Conclusion