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

Abstract

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.

Keywords: Parkinson's disease; coordinated reset; non-invasive stimulation; non-motor symptoms; sensorimotor; study protocol; vibrotactile stimulation.

Conflict of interest statement

RD has served as a clinical trials investigator for Impax Pharmaceuticals, Pharma2B, CALA Health, Axovant and Neurocrine Biosciences. PT works as consultant for Boston Scientific Neuromodulation and Gretap AG and is inventor on a number of patents for non-invasive neuromodulation. BM is employed by Engineering Acoustics who manufacture vibrotactile systems. This study received funding from Synergic Medical Technologies, Inc., The Parkinson Alliance and John A. Blume Foundation. Synergic Medical Technologies, Inc. was not involved in the collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. We discussed the study design with Synergic Medical Technologies, Inc. and adjusted some aspects of the study design for compliance with the FDA approval process. The Parkinson Alliance and John A. Blume Foundation were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. No further disclosures. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Pfeifer, Cook, Yankulova, Mortimer, Erickson-DiRenzo, Dhall, Montaser-Kouhsari and Tass.

Figures

Figure 1

Schematic illustration of the vCR stimulation using a three cycles ON: two cycles OFF pattern (17). Single vibratory bursts (highlighted by red bars) are delivered at periodic times subjected to a jitter that is uniformly distributed within the range of ±23.5% the inter-stimulus intervals. A vCR sequence comprises four subsequent vibratory bursts, delivered (on average) within one vCR cycle. Within one vCR sequence each fingertip (two through five) is activated exactly once. The CR frequency fCR, i.e., the rate at which the CR sequences are delivered, is 1.5 Hz. Hence, the length of a CR cycle is 667 ms. Bilateral noisy vCR is administered in a mirrored manner to both hands, coincidently activating right and left fingers (two through five). Schematic shows the vCR pattern coincidently delivered to left and right hand. Vibration frequency is 250 Hz and duration of vibration bursts is 100 ms. The duration of a single vCR session is 2 h.

Figure 2

Displays the vibrotactile wearable stimulator. (A) Displays the tactors and gloves that can be adjusted via Velcro straps for the finger pad or length of finger. (B) Depicts the controller being worn and fastened by a belt. (C) Displays the part of the controller in which the tactor ends plug into. (D) Displays the LCD screen which shows battery life and time remaining of stimulation. A push button turns on, pauses, and turns off the controller. (E) Displays the charging port of the controller which is charged with a micro-USB.

Figure 3

Depicts study 1 procedures for the double-blind, sham-controlled vCR study. Patients will receive a General Health Survey which includes our inclusion/exclusion questionnaire and our dopamine dysregulation syndrome questionnaire developed for the purpose of our study via email 8–1 weeks prior to the screening visit. During the screening visit (8–4 weeks prior to baseline) patients will be consented and will arrive at Stanford off medication, to complete their physical/neurological examination and report their PD medical history. Patients will perform the MDS-UPDRS III off medication with the study's main movement disorders evaluator and then receive Parcopa (dopamine medication). Patients will then repeat the MDS-UPDRS III after 1 hour of taking medication. Patients will complete a vibratory intensity discrimination task to confirm that they do not have severe vibratory sensory abnormalities. The study's treating movement disorders neurologist will track patients for 4 weeks prior to their first clinical study visit (baseline) to confirm that their medication is stable. One to two weeks prior to every clinical study visit, patients will receive the following questionnaires/tests: MDS-UPDRS IB, II, UPSIT, PDSS, FOG, PDQ-39, and the usability/tolerability questionnaire of the vCR device. During the clinical study visits (baseline, 3, 6, and 7 months), patients will arrive to Stanford off medication and undergo the physical/ neurological examination, PD medical history, MDS-UPDRS III, EEG, VTDT, APDM, Kinesia ONE, and speech assessments. Patients are administered Parcopa and after 1 h perform the MDS-UPDRS III, IA, IV, Kinesia ONE, and APDM. After the 6-month visit, patients undergo a 1-month pause in stimulation to measure long term effects of vCR at the 7-month follow-up. During the entire length of the trial, patients will report their daily LEDD amount and starting from baseline will perform the Kinesia ONE motor evaluation at home one to three times a week for motor monitoring. *The Usability/Tolerability questionnaire is performed 1 week after the start of therapy and then 1-2 weeks before every study visit. **vCR glove administration occurs at baseline only.

Figure 4

Depicts study 2 remote procedures that detail vCR dosing techniques and clinical data obtained. At the 7-month in-person visit, patients will be reconsented and will be sent home with active vCR. Patients will be instructed to stimulate between 2 h a day (maximum) to 2 h three times a week (minimum) from months 7 to 13, report their LEDD amount and perform the Kinesia ONE motor assessment one to three times a week to monitor motor ability throughout the entire trial. One to two weeks before every remote study visit, patients take the following questionnaires: MDS-UPDRS IB, II, PDSS, FOG, PDQ-39, and the Usability/Tolerability vCR device questionnaire. Remote study visits occur at 10, 13 months, and after a 1 month (14th month) pause in stimulation to assess long-lasting effects. During these remote study visits, patients are off medication and the study's treating neurologist gathers medical history and the study's main movement disorders evaluator assesses the remote MDS-UPDRS III, IA, and IV. *The Usability/Tolerability questionnaire is performed 1 week after the start of therapy and then 1–2 weeks before every study visit.