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.

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.

Designing Tactile Cues: Factors Affecting Perceived Salience and Recognition.

Two experiments were conducted to investigate effects of tactile cue characteristics on operator perception, learning, recall of assigned meaning, and interactions of recall performance given stationary versus tasks with demands on operator attention. In the first experiment, twelve multitactor cues ("tactions") represented differences in tactor actuator signal characteristics (complexity) and sequencing of cue activations (pattern location type). The second experiment replicated the first experiment, using a different task demand, and included assessments of aspects of working memory (visual, auditory) and spatial ability. Results demonstrated significant differences in operator perception of tactions and recall while stationary and during task performance, due to differences in taction complexity and pattern location type. Tactions having static locational repetitive patterns were more easily learned and remembered. Participants scoring higher in visual and audio working memory were associated significantly with higher recall accuracy of tactile cues.

Development of a planar shear sensor.

This paper describes a wearable sensor that simultaneously measures both shear and orthogonal force. The planar shear sensor is based on inductive coupling between a small target and a series of adjacent coils. Lateral movement of the target changes the coupling between a primary coil and a series of geometrically shaped and scaled sense coils. Design of the sensor and methods for calibration are investigated. The wearable sensor can be used for measurement of in-situ foot loading during ambulation and we postulate that this may be useful for biomechanical analysis including exoskeletons and balance rehabilitation applications.

Vibrotactile pattern perception as a method for the assessment of brain dysfunction.

An immediate need exists for a portable diagnostic device for the assessment of cortical function, and diagnosis of mTBI. This paper presents initial results using a vibrotactile acuity test for the objective and quantitative diagnosis of acute mTBI suspects. mTBI is hypothesized to involve derangement or damage to the underlying cortical network. In particular, fundamental building blocks of the cortex are changed in such a way as to limit the functional connectivity within and between cortical columns. Our approach is based on sensory illusions that are configured as a test of neural connectivity. Pilot clinical test data showed differences between a small healthy normal group and a concussion group using a sports concussion model.

Vibrotactile transduction and transducers.

The body's sense of touch is potentially a versatile channel for the conveyance of directional, spatial, command, and timing information. Most practical implementations of vibrotactile systems require compact, light-weight actuators that can be mounted against the body. Eccentric mass motors are widely used for this application, yet their output is limited and the effects of loading on the transducers due to the skin and mounting arrangement have been largely ignored. Conventional linear actuators are well suited as vibrotactile transducers and can provide high output, but are typically limited to laboratory research due to their large size and cost. The effect of loading on various practical vibrotactile transducers is investigated using a skin impedance phantom and measuring the transducer displacement with respect to additional mass loading. Depending on the transducer design, loading can dramatically reduce the vibratory displacement and, in the case of eccentric mass motors, also increase the operating frequency. In contrast, a new linear actuator design can be designed to be almost independent of skin loading, by considering the mechanical impedance of the load and optimizing the transducer contact area.