Coordinated reset stimulation of plastic neural networks with spatially dependent synaptic connections.

Background: Abnormal neuronal synchrony is associated with several neurological disorders, including Parkinson's disease (PD), essential tremor, dystonia, and epilepsy. Coordinated reset (CR) stimulation was developed computationally to counteract abnormal neuronal synchrony. During CR stimulation, phase-shifted stimuli are delivered to multiple stimulation sites. Computational studies in plastic neural networks reported that CR stimulation drove the networks into an attractor of a stable desynchronized state by down-regulating synaptic connections, which led to long-lasting desynchronization effects that outlasted stimulation. Later, corresponding long-lasting desynchronization and therapeutic effects were found in animal models of PD and PD patients. To date, it is unclear how spatially dependent synaptic connections, as typically observed in the brain, shape CR-induced synaptic downregulation and long-lasting effects. Methods: We performed numerical simulations of networks of leaky integrate-and-fire neurons with spike-timing-dependent plasticity and spatially dependent synaptic connections to study and further improve acute and long-term responses to CR stimulation. Results: The characteristic length scale of synaptic connections relative to the distance between stimulation sites plays a key role in CR parameter adjustment. In networks with short synaptic length scales, a substantial synaptic downregulation can be achieved by selecting appropriate stimulus-related parameters, such as the stimulus amplitude and shape, regardless of the employed spatiotemporal pattern of stimulus deliveries. Complex stimulus shapes can induce local connectivity patterns in the vicinity of the stimulation sites. In contrast, in networks with longer synaptic length scales, the spatiotemporal sequence of stimulus deliveries is of major importance for synaptic downregulation. In particular, rapid shuffling of the stimulus sequence is advantageous for synaptic downregulation. Conclusion: Our results suggest that CR stimulation parameters can be adjusted to synaptic connectivity to further improve the long-lasting effects. Furthermore, shuffling of CR sequences is advantageous for long-lasting desynchronization effects. Our work provides important hypotheses on CR parameter selection for future preclinical and clinical studies.

Simulated dataset on coordinated reset stimulation of homogeneous and inhomogeneous networks of excitatory leaky integrate-and-fire neurons with spike-timing-dependent plasticity.

We present simulated data on coordinated reset stimulation (CRS) of plastic neuronal networks. The neuronal network consists of excitatory leaky integrate-and-fire neurons and plasticity is implemented as spike-timing-dependent plasticity (STDP). A synchronized state with strong synaptic connectivity and a desynchronized state with weak synaptic connectivity coexist. CRS may drive the network from the synchronized state into a desynchronized state inducing long-lasting desynchronization effects that persist after cessation of stimulation. This is used to model brain stimulation-induced transitions between a pathological state, with abnormally strong neuronal synchrony, and a physiological state, e.g., in Parkinson's disease. During CRS, a sequence of stimuli is delivered to multiple stimulation sites - called CR sequence. We present simulated data for the analysis of long-lasting desynchronization effects of CRS with shuffled CR sequences versus non-shuffled CR sequences in which the order of stimulus deliveries to the sites remains unchanged throughout the entire stimulation period. Such data are presented for networks with homogeneous synaptic connectivity and networks with inhomogeneous synaptic connectivity. Homogeneous synaptic connectivity refers to a network in which the probability of a synaptic connection does not depend on the pre- and postsynaptic neurons' locations. In contrast, inhomogeneous synaptic connectivity refers to a network in which the probability of a synaptic connection depends on the neurons' locations. The presented neuronal network model was used to analyse the impact of the CR sequences and their shuffling on the long-lasting effects of CRS [1].

Emerging wearable technologies for multisystem monitoring and treatment of Parkinson's disease: a narrative review.

Parkinson's disease (PD) is a chronic movement disorder characterized by a variety of motor and nonmotor comorbidities, including cognitive impairment, gastrointestinal (GI) dysfunction, and autonomic/sleep disturbances. Symptoms typically fluctuate with different settings and environmental factors and thus need to be consistently monitored. Current methods, however, rely on infrequent rating scales performed in clinic. The advent of wearable technologies presents a new avenue to track objective measures of PD comorbidities longitudinally and more frequently. This narrative review discusses and proposes emerging wearable technologies that can monitor manifestations of motor, cognitive, GI, and autonomic/sleep comorbidities throughout the daily lives of PD individuals. This can provide more wholistic insight into real-time physiological versus pathological function with the potential to better assess treatments during clinical trials and allow physicians to optimize treatment regimens. Additionally, this narrative review briefly examines novel applications of wearables as therapy for PD patients.

Synaptic network structure shapes cortically evoked spatio-temporal responses of STN and GPe neurons in a computational model.

Introduction: The basal ganglia (BG) are involved in motor control and play an essential role in movement disorders such as hemiballismus, dystonia, and Parkinson's disease. Neurons in the motor part of the BG respond to passive movement or stimulation of different body parts and to stimulation of corresponding cortical regions. Experimental evidence suggests that the BG are organized somatotopically, i.e., specific areas of the body are associated with specific regions in the BG nuclei. Signals related to the same body part that propagate along different pathways converge onto the same BG neurons, leading to characteristic shapes of cortically evoked responses. This suggests the existence of functional channels that allow for the processing of different motor commands or information related to different body parts in parallel. Neurological disorders such as Parkinson's disease are associated with pathological activity in the BG and impaired synaptic connectivity, together with reorganization of somatotopic maps. One hypothesis is that motor symptoms are, at least partly, caused by an impairment of network structure perturbing the organization of functional channels. Methods: We developed a computational model of the STN-GPe circuit, a central part of the BG. By removing individual synaptic connections, we analyzed the contribution of signals propagating along different pathways to cortically evoked responses. We studied how evoked responses are affected by systematic changes in the network structure. To quantify the BG's organization in the form of functional channels, we suggested a two-site stimulation protocol. Results: Our model reproduced the cortically evoked responses of STN and GPe neurons and the contributions of different pathways suggested by experimental studies. Cortical stimulation evokes spatio-temporal response patterns that are linked to the underlying synaptic network structure. Our two-site stimulation protocol yielded an approximate functional channel width. Discussion/conclusion: The presented results provide insight into the organization of BG synaptic connectivity, which is important for the development of computational models. The synaptic network structure strongly affects the processing of cortical signals and may impact the generation of pathological rhythms. Our work may motivate further experiments to analyze the network structure of BG nuclei and their organization in functional channels.

Perspectives on adaptive dynamical systems.

Adaptivity is a dynamical feature that is omnipresent in nature, socio-economics, and technology. For example, adaptive couplings appear in various real-world systems, such as the power grid, social, and neural networks, and they form the backbone of closed-loop control strategies and machine learning algorithms. In this article, we provide an interdisciplinary perspective on adaptive systems. We reflect on the notion and terminology of adaptivity in different disciplines and discuss which role adaptivity plays for various fields. We highlight common open challenges and give perspectives on future research directions, looking to inspire interdisciplinary approaches.

Asymmetric adaptivity induces recurrent synchronization in complex networks.

Rhythmic activities that alternate between coherent and incoherent phases are ubiquitous in chemical, ecological, climate, or neural systems. Despite their importance, general mechanisms for their emergence are little understood. In order to fill this gap, we present a framework for describing the emergence of recurrent synchronization in complex networks with adaptive interactions. This phenomenon is manifested at the macroscopic level by temporal episodes of coherent and incoherent dynamics that alternate recurrently. At the same time, the dynamics of the individual nodes do not change qualitatively. We identify asymmetric adaptation rules and temporal separation between the adaptation and the dynamics of individual nodes as key features for the emergence of recurrent synchronization. Our results suggest that asymmetric adaptation might be a fundamental ingredient for recurrent synchronization phenomena as seen in pattern generators, e.g., in neuronal systems.

Decoupling of interacting neuronal populations by time-shifted stimulation through spike-timing-dependent plasticity.

The synaptic organization of the brain is constantly modified by activity-dependent synaptic plasticity. In several neurological disorders, abnormal neuronal activity and pathological synaptic connectivity may significantly impair normal brain function. Reorganization of neuronal circuits by therapeutic stimulation has the potential to restore normal brain dynamics. Increasing evidence suggests that the temporal stimulation pattern crucially determines the long-lasting therapeutic effects of stimulation. Here, we tested whether a specific pattern of brain stimulation can enable the suppression of pathologically strong inter-population synaptic connectivity through spike-timing-dependent plasticity (STDP). More specifically, we tested how introducing a time shift between stimuli delivered to two interacting populations of neurons can effectively decouple them. To that end, we first used a tractable model, i.e., two bidirectionally coupled leaky integrate-and-fire (LIF) neurons, to theoretically analyze the optimal range of stimulation frequency and time shift for decoupling. We then extended our results to two reciprocally connected neuronal populations (modules) where inter-population delayed connections were modified by STDP. As predicted by the theoretical results, appropriately time-shifted stimulation causes a decoupling of the two-module system through STDP, i.e., by unlearning pathologically strong synaptic interactions between the two populations. Based on the overall topology of the connections, the decoupling of the two modules, in turn, causes a desynchronization of the populations that outlasts the cessation of stimulation. Decoupling effects of the time-shifted stimulation can be realized by time-shifted burst stimulation as well as time-shifted continuous simulation. Our results provide insight into the further optimization of a variety of multichannel stimulation protocols aiming at a therapeutic reshaping of diseased brain networks.

Synaptic reshaping of plastic neuronal networks by periodic multichannel stimulation with single-pulse and burst stimuli.

Synaptic dysfunction is associated with several brain disorders, including Alzheimer's disease, Parkinson's disease (PD) and obsessive compulsive disorder (OCD). Utilizing synaptic plasticity, brain stimulation is capable of reshaping synaptic connectivity. This may pave the way for novel therapies that specifically counteract pathological synaptic connectivity. For instance, in PD, novel multichannel coordinated reset stimulation (CRS) was designed to counteract neuronal synchrony and down-regulate pathological synaptic connectivity. CRS was shown to entail long-lasting therapeutic aftereffects in PD patients and related animal models. This is in marked contrast to conventional deep brain stimulation (DBS) therapy, where PD symptoms return shortly after stimulation ceases. In the present paper, we study synaptic reshaping by periodic multichannel stimulation (PMCS) in networks of leaky integrate-and-fire (LIF) neurons with spike-timing-dependent plasticity (STDP). During PMCS, phase-shifted periodic stimulus trains are delivered to segregated neuronal subpopulations. Harnessing STDP, PMCS leads to changes of the synaptic network structure. We found that the PMCS-induced changes of the network structure depend on both the phase lags between stimuli and the shape of individual stimuli. Single-pulse stimuli and burst stimuli with low intraburst frequency down-regulate synapses between neurons receiving stimuli simultaneously. In contrast, burst stimuli with high intraburst frequency up-regulate these synapses. We derive theoretical approximations of the stimulation-induced network structure. This enables us to formulate stimulation strategies for inducing a variety of network structures. Our results provide testable hypotheses for future pre-clinical and clinical studies and suggest that periodic multichannel stimulation may be suitable for reshaping plastic neuronal networks to counteract pathological synaptic connectivity. Furthermore, we provide novel insight on how the stimulus type may affect the long-lasting outcome of conventional DBS. This may strongly impact parameter adjustment procedures for clinical DBS, which, so far, primarily focused on acute effects of stimulation.

Dynamics of phase oscillator networks with synaptic weight and structural plasticity.

We study the dynamics of Kuramoto oscillator networks with two distinct adaptation processes, one varying the coupling strengths and the other altering the network structure. Such systems model certain networks of oscillatory neurons where the neuronal dynamics, synaptic weights, and network structure interact with and shape each other. We model synaptic weight adaptation with spike-timing-dependent plasticity (STDP) that runs on a longer time scale than neuronal spiking. Structural changes that include addition and elimination of contacts occur at yet a longer time scale than the weight adaptations. First, we study the steady-state dynamics of Kuramoto networks that are bistable and can settle in synchronized or desynchronized states. To compare the impact of adding structural plasticity, we contrast the network with only STDP to one with a combination of STDP and structural plasticity. We show that the inclusion of structural plasticity optimizes the synchronized state of a network by allowing for synchronization with fewer links than a network with STDP alone. With non-identical units in the network, the addition of structural plasticity leads to the emergence of correlations between the oscillators' natural frequencies and node degrees. In the desynchronized regime, the structural plasticity decreases the number of contacts, leading to a sparse network. In this way, adding structural plasticity strengthens both synchronized and desynchronized states of a network. Second, we use desynchronizing coordinated reset stimulation and synchronizing periodic stimulation to induce desynchronized and synchronized states, respectively. Our findings indicate that a network with a combination of STDP and structural plasticity may require stronger and longer stimulation to switch between the states than a network with STDP only.

Pilot study of responsive nucleus accumbens deep brain stimulation for loss-of-control eating.

Cravings that precede loss of control (LOC) over food consumption present an opportunity for intervention in patients with the binge eating disorder (BED). In this pilot study, we used responsive deep brain stimulation (DBS) to record nucleus accumbens (NAc) electrophysiology during food cravings preceding LOC eating in two patients with BED and severe obesity (trial registration no. NCT03868670). Increased NAc low-frequency oscillations, prominent during food cravings, were used to guide DBS delivery. Over 6 months, we observed improved self-control of food intake and weight loss. These findings provide early support for restoring inhibitory control with electrophysiologically-guided NAc DBS. Further work with increased sample sizes is required to determine the scalability of this approach.

Spike-Timing-Dependent Plasticity Mediated by Dopamine and its Role in Parkinson's Disease Pathophysiology.

Parkinson's disease (PD) is a multi-systemic neurodegenerative brain disorder. Motor symptoms of PD are linked to the significant dopamine (DA) loss in substantia nigra pars compacta (SNc) followed by basal ganglia (BG) circuit dysfunction. Increasing experimental and computational evidence indicates that (synaptic) plasticity plays a key role in the emergence of PD-related pathological changes following DA loss. Spike-timing-dependent plasticity (STDP) mediated by DA provides a mechanistic model for synaptic plasticity to modify synaptic connections within the BG according to the neuronal activity. To shed light on how DA-mediated STDP can shape neuronal activity and synaptic connectivity in the PD condition, we reviewed experimental and computational findings addressing the modulatory effect of DA on STDP as well as other plasticity mechanisms and discussed their potential role in PD pathophysiology and related network dynamics and connectivity. In particular, reshaping of STDP profiles together with other plasticity-mediated processes following DA loss may abnormally modify synaptic connections in competing pathways of the BG. The cascade of plasticity-induced maladaptive or compensatory changes can impair the excitation-inhibition balance towards the BG output nuclei, leading to the emergence of pathological activity-connectivity patterns in PD. Pre-clinical, clinical as well as computational studies reviewed here provide an understanding of the impact of synaptic plasticity and other plasticity mechanisms on PD pathophysiology, especially PD-related network activity and connectivity, after DA loss. This review may provide further insights into the abnormal structure-function relationship within the BG contributing to the emergence of pathological states in PD. Specifically, this review is intended to provide detailed information for the development of computational network models for PD, serving as testbeds for the development and optimization of invasive and non-invasive brain stimulation techniques. Computationally derived hypotheses may accelerate the development of therapeutic stimulation techniques and potentially reduce the number of related animal experiments.

Long-Lasting Desynchronization of Plastic Neuronal Networks by Double-Random Coordinated Reset Stimulation.

Hypersynchrony of neuronal activity is associated with several neurological disorders, including essential tremor and Parkinson's disease (PD). Chronic high-frequency deep brain stimulation (HF DBS) is the standard of care for medically refractory PD. Symptoms may effectively be suppressed by HF DBS, but return shortly after cessation of stimulation. Coordinated reset (CR) stimulation is a theory-based stimulation technique that was designed to specifically counteract neuronal synchrony by desynchronization. During CR, phase-shifted stimuli are delivered to multiple neuronal subpopulations. Computational studies on CR stimulation of plastic neuronal networks revealed long-lasting desynchronization effects obtained by down-regulating abnormal synaptic connectivity. This way, networks are moved into attractors of stable desynchronized states such that stimulation-induced desynchronization persists after cessation of stimulation. Preclinical and clinical studies confirmed corresponding long-lasting therapeutic and desynchronizing effects in PD. As PD symptoms are associated with different pathological synchronous rhythms, stimulation-induced long-lasting desynchronization effects should favorably be robust to variations of the stimulation frequency. Recent computational studies suggested that this robustness can be improved by randomizing the timings of stimulus deliveries. We study the long-lasting effects of CR stimulation with randomized stimulus amplitudes and/or randomized stimulus timing in networks of leaky integrate-and-fire (LIF) neurons with spike-timing-dependent plasticity. Performing computer simulations and analytical calculations, we study long-lasting desynchronization effects of CR with and without randomization of stimulus amplitudes alone, randomization of stimulus times alone as well as the combination of both. Varying the CR stimulation frequency (with respect to the frequency of abnormal target rhythm) and the number of separately stimulated neuronal subpopulations, we reveal parameter regions and related mechanisms where the two qualitatively different randomization mechanisms improve the robustness of long-lasting desynchronization effects of CR. In particular, for clinically relevant parameter ranges double-random CR stimulation, i.e., CR stimulation with the specific combination of stimulus amplitude randomization and stimulus time randomization, may outperform regular CR stimulation with respect to long-lasting desynchronization. In addition, our results provide the first evidence that an effective reduction of the overall stimulation current by stimulus amplitude randomization may improve the frequency robustness of long-lasting therapeutic effects of brain stimulation.

Clinical Efficacy and Dosing of Vibrotactile Coordinated Reset Stimulation in Motor and Non-motor Symptoms of Parkinson's Disease: A Study Protocol.

Enhanced neuronal synchronization of the subthalamic nucleus (STN) is commonly found in PD patients and corresponds to decreased motor ability. Coordinated reset (CR) was developed to decouple synchronized states causing long lasting desynchronization of neural networks. Vibrotactile CR stimulation (vCR) was developed as non-invasive therapeutic that delivers gentle vibrations to the fingertips. A previous study has shown that vCR can desynchronize abnormal brain rhythms within the sensorimotor cortex of PD patients, corresponding to sustained motor relief after 3 months of daily treatment. To further develop vCR, we created a protocol that has two phases. Study 1, a double blinded randomized sham-controlled study, is designed to address motor and non-motor symptoms, sensorimotor integration, and potential calibration methods. Study 2 examines dosing effects of vCR using a remote study design. In Study 1, we will perform a 7-month double-blind sham-controlled study including 30 PD patients randomly placed into an active vCR or inactive (sham) vCR condition. Patients will receive stimulation for 4 h a day in 2-h blocks for 6 months followed by a 1-month pause in stimulation to assess long lasting effects. Our primary outcome measure is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III off medication after 6 months of treatment. Secondary measures include a freezing of gait (FOG) questionnaire, objective motor evaluations, sensorimotor electroencephalography (EEG) results, a vibratory temporal discrimination task (VTDT), non-motor symptom evaluations/tests such as sleep, smell, speech, quality of life measurements and Levodopa Equivalent Daily Dose (LEDD). Patients will be evaluated at baseline, 3, 6, and 7 months. In the second, unblinded study phase (Study 2), all patients will be given the option to receive active vCR stimulation at a reduced dose for an additional 6 months remotely. The remote MDS-UPDRS part III off medication will be our primary outcome measure. Secondary measures include sleep, quality of life, objective motor evaluations, FOG and LEDD. Patients will be evaluated in the same time periods as the first study. Results from this study will provide clinical efficacy of vCR and help validate our investigational vibrotactile device for the purpose of obtaining FDA clearance. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT04877015.

Long-Lasting Desynchronization Effects of Coordinated Reset Stimulation Improved by Random Jitters.

Abnormally strong synchronized activity is related to several neurological disorders, including essential tremor, epilepsy, and Parkinson's disease. Chronic high-frequency deep brain stimulation (HF DBS) is an established treatment for advanced Parkinson's disease. To reduce the delivered integral electrical current, novel theory-based stimulation techniques such as coordinated reset (CR) stimulation directly counteract the abnormal synchronous firing by delivering phase-shifted stimuli through multiple stimulation sites. In computational studies in neuronal networks with spike-timing-dependent plasticity (STDP), it was shown that CR stimulation down-regulates synaptic weights and drives the network into an attractor of a stable desynchronized state. This led to desynchronization effects that outlasted the stimulation. Corresponding long-lasting therapeutic effects were observed in preclinical and clinical studies. Computational studies suggest that long-lasting effects of CR stimulation depend on the adjustment of the stimulation frequency to the dominant synchronous rhythm. This may limit clinical applicability as different pathological rhythms may coexist. To increase the robustness of the long-lasting effects, we study randomized versions of CR stimulation in networks of leaky integrate-and-fire neurons with STDP. Randomization is obtained by adding random jitters to the stimulation times and by shuffling the sequence of stimulation site activations. We study the corresponding long-lasting effects using analytical calculations and computer simulations. We show that random jitters increase the robustness of long-lasting effects with respect to changes of the number of stimulation sites and the stimulation frequency. In contrast, shuffling does not increase parameter robustness of long-lasting effects. Studying the relation between acute, acute after-, and long-lasting effects of stimulation, we find that both acute after- and long-lasting effects are strongly determined by the stimulation-induced synaptic reshaping, whereas acute effects solely depend on the statistics of administered stimuli. We find that the stimulation duration is another important parameter, as effective stimulation only entails long-lasting effects after a sufficient stimulation duration. Our results show that long-lasting therapeutic effects of CR stimulation with random jitters are more robust than those of regular CR stimulation. This might reduce the parameter adjustment time in future clinical trials and make CR with random jitters more suitable for treating brain disorders with abnormal synchronization in multiple frequency bands.

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

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.

Multistability in a star network of Kuramoto-type oscillators with synaptic plasticity.

We analyze multistability in a star-type network of phase oscillators with coupling weights governed by phase-difference-dependent plasticity. It is shown that a network with N leaves can evolve into [Formula: see text] various asymptotic states, characterized by different values of the coupling strength between the hub and the leaves. Starting from the simple case of two coupled oscillators, we develop an analytical approach based on two small parameters [Formula: see text] and [Formula: see text], where [Formula: see text] is the ratio of the time scales of the phase variables and synaptic weights, and [Formula: see text] defines the sharpness of the plasticity boundary function. The limit [Formula: see text] corresponds to a hard boundary. The analytical results obtained on the model of two oscillators are generalized for multi-leaf star networks. Multistability with [Formula: see text] various asymptotic states is numerically demonstrated for one-, two-, three- and nine-leaf star-type networks.

Coordinated Reset Vibrotactile Stimulation Induces Sustained Cumulative Benefits in Parkinson's Disease.

BACKGROUND: Abnormal 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. METHODS: Study 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. RESULTS: Clinically, 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. CONCLUSION: In 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.