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.

Purpose: Children with benign epilepsy with centrotemporal spikes have rare seizures emerging from the motor cortex, which they outgrow in adolescence, and additionally may have language deficits of unclear etiology. We piloted the use of transcranial magnetic stimulation paired with EMG and EEG (TMS-EMG, TMS-EEG) to test the hypotheses that net cortical excitability decreases with age and that use-dependent plasticity predicts learning. Methods: We assessed language and motor learning in 14 right-handed children with benign epilepsy with centrotemporal spikes. We quantified two TMS metrics of left motor cortex excitability: the resting motor threshold (measure of neuronal membrane excitability) and amplitude of the N100-evoked potential (an EEG measure of GABAergic tone). To test plasticity, we applied 1 Hz repetitive TMS to the motor cortex to induce long-term depression-like changes in EMG- and EEG-evoked potentials. Results: Children with benign epilepsy with centrotemporal spikes tolerate TMS; no seizures were provoked. Resting motor threshold decreases with age but is elevated above maximal stimulator output for half the group. N100 amplitude decreases with age after controlling for resting motor threshold. Motor cortex plasticity correlates significantly with language learning and at a trend level with motor learning. Conclusions: Transcranial magnetic stimulation is safe and feasible for children with benign epilepsy with centrotemporal spikes, and TMS-EEG provides more reliable outcome measures than TMS-EMG in this group because many children have unmeasurably high resting motor thresholds. Net cortical excitability decreases with age, and motor cortex plasticity predicts not only motor learning but also language learning, suggesting a mechanism by which motor cortex seizures may interact with language development.

Electroencephalographic activity over the sensorimotor cortex has been one of the best studied targets for neurofeedback therapy. Parkinson’s disease patients display abnormal brain rhythms in the motor cortex caused by increased synchrony in the basal ganglia-cortical pathway. Few studies have examined the effects of sensorimotor-based neurofeedback therapy in humans with PD. In this pilot study, one patient, diagnosed with Parkinson’s disease 10 years prior, participated in two consecutive days of EEG neurofeedback training to increase sensorimotor rhythm (SMR) power over the motor cortex. Using a visual display connected to ongoing EEG, the patient voluntarily manipulated SMR power, and he/she was awarded with points to positively reinforce successful increases over a predefined threshold. Recorded EEG data were source localized and analyzed for the occurrence of high amplitude bursts of SMR activity as well as bursts in the beta frequency band in the precentral cortex. The rate of SMR bursts increased with each subsequent training session, while the rate of beta bursts only increased on the final session. Relative power in the beta band, a marker of PD symptom severity, decreased over the motor cortex in the later session. These results provide first evidence for the feasibility of SMR neurofeedback training as a non-invasive therapy for reducing Parkinson’s disease related activity and upregulating SMR in the human motor cortex.

The impact of repetitive magnetic stimulation (rTMS) on cortex varies with stimulation parameters, so it would be useful to develop a biomarker to rapidly judge effects on cortical activity, including regions other than motor cortex. This study evaluated rTMS-evoked EEG potentials (TEP) after 1 Hz of motor cortex stimulation. New features are controls for baseline amplitude and comparison to control groups of sham stimulation. We delivered 200 test pulses at 0.20 Hz before and after 1500 treatment pulses at 1 Hz. Sequences comprised AAA = active stimulation with the same coil for test–treat–test phases (n = 22); PPP = realistic placebo coil stimulation for all three phases (n = 10); and APA = active coil stimulation for tests and placebo coil stimulation for treatment (n = 15). Signal processing displayed the evoked EEG waveforms, and peaks were measured by software. ANCOVA was used to measure differences in TEP peak amplitudes in post-rTMS trials while controlling for pre-rTMS TEP peak amplitude. Post hoc analysis showed reduced P60 amplitude in the active (AAA) rTMS group versus the placebo (APA) group. The N100 peak showed a treatment effect compared to the placebo groups, but no pairwise post hoc differences. N40 showed a trend toward increase. Changes were seen in widespread EEG leads, mostly ipsilaterally. TMS-evoked EEG potentials showed reduction of the P60 peak and increase of the N100 peak, both possibly reflecting increased slow inhibition after 1 Hz of rTMS. TMS-EEG may be a useful biomarker to assay brain excitability at a seizure focus and elsewhere, but individual responses are highly variable, and the difficulty of distinguishing merged peaks complicates interpretation.

Acoustic coordinated reset (aCR) therapy for tinnitus aims to desynchronize neuronal populations in the auditory cortex that exhibit pathologically increased coincident firing. The original therapeutic paradigm involves fixed spacing of four low-intensity tones centered around the frequency of a tone matching the tinnitus pitch, fT, but it is unknown whether these tones are optimally spaced for induction of desynchronization. Computational and animal studies suggest that stimulus amplitude, and relatedly, spatial stimulation profiles, of coordinated reset pulses can have a major impact on the degree of desynchronization achievable. In this study, we transform the tone spacing of aCR into a scale that takes into account the frequency selectivity of the auditory system at each therapeutic tone’s center frequency via a measure called the gap index. Higher gap indices are indicative of more loosely spaced aCR tones. The gap index was found to be a significant predictor of symptomatic improvement, with larger gap indices, i.e., more loosely spaced aCR tones, resulting in reduction of tinnitus loudness and annoyance scores in the acute stimulation setting. A notable limitation of this study is the intimate relationship of hearing impairment with the gap index. Particularly, the shape of the audiogram in the vicinity of the tinnitus frequency can have a major impact on tone spacing. However, based on our findings we suggest hypotheses-based experimental protocols that may help to disentangle the impact of hearing loss and tone spacing on clinical outcome, to assess the electrophysiologic correlates of clinical improvement, and to elucidate the effects following chronic rather than acute stimulation.

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.