Long-Term Desynchronization by Coordinated Reset Stimulation in a Neural Network Model With Synaptic and Structural Plasticity.
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ABSTRACT:
SUBMITTER: Manos T
PROVIDER: S-EPMC8455881 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAbnormal synchronization of neuronal activity in dopaminergic circuits is related to motor impairment in Parkinson's disease (PD). Vibrotactile coordinated reset (vCR) fingertip stimulation aims to counteract excessive synchronization and induce sustained unlearning of pathologic synaptic connectivity and neuronal synchrony. Here, we report two clinical feasibility studies that examine the effect of regular and noisy vCR stimulation on PD motor symptoms. Additionally, in one clinical study (study 1), we examine cortical beta band power changes in the sensorimotor cortex. Lastly, we compare these clinical results in relation to our computational findings.MethodsStudy 1 examines six PD patients receiving noisy vCR stimulation and their cortical beta power changes after 3 months of daily therapy. Motor evaluations and at-rest electroencephalographic (EEG) recordings were assessed off medication pre- and post-noisy vCR. Study 2 follows three patients for 6+ months, two of whom received daily regular vCR and one patient from study 1 who received daily noisy vCR. Motor evaluations were taken at baseline, and follow-up visits were done approximately every 3 months. Computationally, in a network of leaky integrate-and-fire (LIF) neurons with spike timing-dependent plasticity, we study the differences between regular and noisy vCR by using a stimulus model that reproduces experimentally observed central neuronal phase locking.ResultsClinically, in both studies, we observed significantly improved motor ability. EEG recordings observed from study 1 indicated a significant decrease in off-medication cortical sensorimotor high beta power (21-30 Hz) at rest after 3 months of daily noisy vCR therapy. Computationally, vCR and noisy vCR cause comparable parameter-robust long-lasting synaptic decoupling and neuronal desynchronization.ConclusionIn these feasibility studies of eight PD patients, regular vCR and noisy vCR were well tolerated, produced no side effects, and delivered sustained cumulative improvement of motor performance, which is congruent with our computational findings. In study 1, reduction of high beta band power over the sensorimotor cortex may suggest noisy vCR is effectively modulating the beta band at the cortical level, which may play a role in improved motor ability. These encouraging therapeutic results enable us to properly plan a proof-of-concept study.
| S-EPMC8055937 | biostudies-literature
Project description:Several brain diseases are characterized by abnormally strong neuronal synchrony. Coordinated Reset (CR) stimulation was computationally designed to specifically counteract abnormal neuronal synchronization processes by desynchronization. In the presence of spike-timing-dependent plasticity (STDP) this may lead to a decrease of synaptic excitatory weights and ultimately to an anti-kindling, 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. 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 the first computational study on the dependence of the acute and long-term outcome on the CR stimulation frequency in neuronal networks with STDP. For this purpose, CR stimulation was applied with Rapidly Varying Sequences (RVS) as well as with Slowly Varying Sequences (SVS) in a wide range of stimulation frequencies and intensities. Our findings demonstrate that acute desynchronization, achieved during stimulation, does not necessarily lead to long-term desynchronization after cessation of stimulation. By comparing the long-term effects of the two different CR protocols, the RVS CR stimulation turned out to be more robust against variations of the stimulation frequency. However, SVS CR stimulation can obtain stronger anti-kindling effects. We revealed specific parameter ranges that are favorable for long-term desynchronization. For instance, RVS CR stimulation at weak intensities and with stimulation frequencies in the range of the neuronal firing rates turned out to be effective and robust, in particular, if no closed loop adaptation of stimulation parameters is (technically) available. From a clinical standpoint, this may be relevant in the context of both invasive as well as non-invasive CR stimulation.
| S-EPMC5963814 | biostudies-other
Project description:Pathological synchronization in the basal ganglia network has been considered an important component of Parkinson's disease pathophysiology. An established treatment for some patients with Parkinson's disease is deep brain stimulation, in which a tonic high-frequency pulse train is delivered to target regions of the brain. In recent years, a novel neuromodulation paradigm called coordinated reset stimulation has been proposed, which aims to reverse the pathological synchrony by sequentially delivering short high-frequency bursts to distinct sub-regions of the pathologically synchronized network, with an average intra-burst interval for each sub-region corresponding to period of the pathological oscillation. It has further been proposed that the resultant desynchronization can be enhanced when stimulation is interrupted periodically, and that it is particularly beneficial to precisely tune the stimulation ON and OFF time-windows to the underlying pathological frequency. Pre-clinical and clinical studies of coordinated reset stimulation have relied on these proposals for their stimulation protocols. In this study, we present a modified ON-OFF coordinated reset stimulation paradigm called periodic flashing and study its behavior through computational modeling using the Kuramoto coupled phase oscillator model. We demonstrate that in contrast to conventional coordinated reset stimulation, the periodic flashing variation does not exhibit a need for precise turning of the ON-OFF periods to the pathological frequency, and demonstrates desynchronization for a wide range of ON and OFF periods. We provide a mechanistic explanation for the previously observed sensitivities and demonstrate that they are an artifact of the specific ON-OFF cycling paradigm used. As a practical consequence, the periodic flashing paradigm simplifies the tuning of optimal stimulation parameters by decreasing the dimension of the search space. It also suggests new, more flexible ways of delivering coordinated reset stimulation.
| S-EPMC6128645 | biostudies-literature
Project description:In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long-term desynchronization at comparably short stimulation duration and low integral stimulation duration. Currently, clinical proof of concept is available for deep brain CR stimulation for Parkinson's therapy and acoustic CR stimulation for tinnitus therapy. Promising first in human data is available for vibrotactile CR stimulation for Parkinson's treatment. For the clinical development of these treatments it is mandatory to perform dose-finding studies to reveal optimal stimulation parameters and dosage regimens. Our findings can straightforwardly be tested in human dose-finding studies.
| S-EPMC5906576 | biostudies-literature
Project description:Experience-dependent synaptic plasticity is a fundamental feature of neural networks involved in the encoding of information, and the capability of synapses to express plasticity is itself activity-dependent. Here, we introduce a "low-frequency burst stimulation" protocol, which can readily induce both long-term potentiation (LTP) and long-term depression (LTD) at in vivo medial perforant path-dentate gyrus synapses. By varying stimulation parameters, we were able to build a stimulus-response map of synaptic plasticity as a LTP-LTD continuum. The response curve displayed a bidirectional shift toward LTP and LTD, depending on the degree and timing of neural activity of the basolateral amygdala. The range of this plastic modulation was also modified by past activity of the basolateral amygdala, suggesting that the amygdala can arrange its ability to regulate the dentate plastic responses. The effects of the BLA activation were replicated by stimulation of the lateral perforant path and, hence, BLA stimulation may recruit the lateral entorhinal cortex. These results represent a high-order dimension of heterosynaptic modulations of hippocampal synaptic plasticity.
| S-EPMC521145 | biostudies-literature
Project description:Plasticity of cortical responses in vivo involves activity-dependent changes at synapses, but the manner in which different forms of synaptic plasticity act together to create functional changes in neurons remains unknown. We found that spike timing-induced receptive field plasticity of visual cortex neurons in mice is anchored by increases in the synaptic strength of identified spines. This is accompanied by a decrease in the strength of adjacent spines on a slower time scale. The locally coordinated potentiation and depression of spines involves prominent AMPA receptor redistribution via targeted expression of the immediate early gene product Arc. Hebbian strengthening of activated synapses and heterosynaptic weakening of adjacent synapses thus cooperatively orchestrate cell-wide plasticity of functional neuronal responses.
| S-EPMC6366621 | biostudies-literature
Project description:Electrical synapses between interneurons contribute to synchronized firing and network oscillations in the brain. However, little is known about how such networks respond to excitatory synaptic input. To investigate this, we studied electrically coupled Golgi cells (GoC) in the cerebellar input layer. We show with immunohistochemistry, electron microscopy, and electrophysiology that Connexin-36 is necessary for functional gap junctions (GJs) between GoC dendrites. In the absence of coincident synaptic input, GoCs synchronize their firing. In contrast, sparse, coincident mossy fiber input triggered a mixture of excitation and inhibition of GoC firing and spike desynchronization. Inhibition is caused by propagation of the spike afterhyperpolarization through GJs. This triggers network desynchronization because heterogeneous coupling to surrounding cells causes spike-phase dispersion. Detailed network models predict that desynchronization is robust, local, and dependent on synaptic input properties. Our results show that GJ coupling can be inhibitory and either promote network synchronization or trigger rapid network desynchronization depending on the synaptic input.
| S-EPMC2954316 | biostudies-literature
Project description:Short-term synaptic plasticity strongly affects the neural dynamics of cortical networks. The Tsodyks and Markram (TM) model for short-term synaptic plasticity accurately accounts for a wide range of physiological responses at different types of cortical synapses. Here, we report a route to chaotic behavior via a Shilnikov homoclinic bifurcation that dynamically organizes some of the responses in the TM model. In particular, the presence of such a homoclinic bifurcation strongly affects the shape of the trajectories in the phase space and induces highly irregular transient dynamics; indeed, in the vicinity of the Shilnikov homoclinic bifurcation, the number of population spikes and their precise timing are unpredictable and highly sensitive to the initial conditions. Such an irregular deterministic dynamics has its counterpart in stochastic/network versions of the TM model: The existence of the Shilnikov homoclinic bifurcation generates complex and irregular spiking patterns and--acting as a sort of springboard--facilitates transitions between the down-state and unstable periodic orbits. The interplay between the (deterministic) homoclinic bifurcation and stochastic effects may give rise to some of the complex dynamics observed in neural systems.
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Project description:In this work we study the detection of weak stimuli by spiking (integrate-and-fire) neurons in the presence of certain level of noisy background neural activity. Our study has focused in the realistic assumption that the synapses in the network present activity-dependent processes, such as short-term synaptic depression and facilitation. Employing mean-field techniques as well as numerical simulations, we found that there are two possible noise levels which optimize signal transmission. This new finding is in contrast with the classical theory of stochastic resonance which is able to predict only one optimal level of noise. We found that the complex interplay between adaptive neuron threshold and activity-dependent synaptic mechanisms is responsible for this new phenomenology. Our main results are confirmed by employing a more realistic FitzHugh-Nagumo neuron model, which displays threshold variability, as well as by considering more realistic stochastic synaptic models and realistic signals such as poissonian spike trains.
| S-EPMC3050837 | biostudies-literature
Project description:Synaptic efficacy is subjected to activity-dependent changes on short- and long time scales. While short-term changes decay over minutes, long-term modifications last from hours up to a lifetime and are thought to constitute the basis of learning and memory. Both plasticity mechanisms have been studied extensively but how their interaction shapes synaptic dynamics is little known. To investigate how both short- and long-term plasticity together control the induction of synaptic depression and potentiation, we used numerical simulations and mathematical analysis of a calcium-based model, where pre- and postsynaptic activity induces calcium transients driving synaptic long-term plasticity. We found that the model implementing known synaptic short-term dynamics in the calcium transients can be successfully fitted to long-term plasticity data obtained in visual- and somatosensory cortex. Interestingly, the impact of spike-timing and firing rate changes on plasticity occurs in the prevalent firing rate range, which is different in both cortical areas considered here. Our findings suggest that short- and long-term plasticity are together tuned to adapt plasticity to area-specific activity statistics such as firing rates.
| S-EPMC7549837 | biostudies-literature