Non-invasive electrical stimulation of peripheral nerves for the management of tremor

Abstract

Pathological tremor in patients with essential tremor and Parkinsons disease is typically treated using medication or neurosurgical interventions. There is a widely recognized need for new treatments that avoid the side effects of current medications and do not carry the risks of surgical interventions. Building on decades of research and engineering development, non-invasive electrical stimulation of peripheral nerves has emerged as a safe and effective strategy for reducing pathologic tremor in essential tremor. This review surveys the peripheral electrical stimulation (PES) literature and summarizes effectiveness, safety, clinical translatability, and hypothesized tremor-reduction mechanisms of various PES approaches. The review also proposes guidelines for assessing tremor in the context of evaluating new therapies that combine the strengths of clinician assessments, patient evaluations, and novel motion sensing technology. The review concludes with a summary of future directions for PES, including expanding clinical access for patients with Parkinson's disease and leveraging large, at-home datasets to learn more about tremor physiology and treatment effect that will better characterize the state of tremor management and accelerate discovery of new therapies. Growing evidence suggests that non-invasive electrical stimulation of afferent neural pathways provides a viable new option for management of pathological tremor, with one specific PES therapy cleared for prescription and home use, suggesting that PES be considered along with medication and neurosurgical interventions for treatment of tremor. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

Keywords: Afferent pathways; Essential tremor; Neuromodulation; Parkinson's disease; Pathological tremor; Tremor treatment.

Figure 1.. Stimulation control strategies.

Black curves conceptually represent a tremor measurement trace (e.g., wrist displacement or electromyography) and vertical lines represent application of stimulation pulses. (A) Open-loop stimulation is continuously delivered with no relationship to tremor features. (B) Closed-loop stimulation delivers pulses of stimulation that are synchronized with real-time tremor oscillation measurements. If tremor ceases, then stimulation is not applied. (C) Calibrated stimulation is tuned to tremor features, such as tremor frequency, but does not incorporate real-time measures of changing tremor motion. As a result, stimulation may be applied even when tremor ceases.

Figure 2.. Landscape of strategies for tremor management.

PES strategies were classified by effectiveness and clinical development phase, and the visualized landscape represents a gross placement of these strategies. Effectiveness was estimated as “High”, “Medium”, or “Low” based on reported tremor reductions, with vertical bar heights loosely representing the range of tremor reductions reported in the listed references. Color of vertical bars indicate clinical evidence in ET (green) and PD (blue). Clinical development phase was determined based on study designs and regulatory status. Treatment guidelines (e.g., “first line”, etc.) for clinically available therapies were determined from International ET Foundation (IETF) guidelines [29]. Abbreviations: PES, peripheral electrical stimulation; FES, functional electrical stimulation; TAPS, transcutaneous afferent patterned stimulation; DBS, deep brain stimulation; MRgFUS, magnetic resonance guided focused ultrasound.

Figure 3.. Motion sensor tremor assessment.

(A) Example wrist accelerometry measurements and corresponding tremor power are shown for a patient with severe postural tremor (left) and moderate postural tremor (right). (B) Postural tremor power, computed from accelerometry data, are correlated with simultaneous clinical ratings, suggesting that motion sensors provide a way to remotely monitor tremor severity in free-living settings at many time points. (C) Patients have substantial temporal (within- and across-day) variability in tremor severity. This intra-patient variability limits the ability of a single assessment, whether gold-standard clinical assessment (left) or objective motion sensor assessment (right), to provide a representative quantification of a patient’s tremor (across-day correlation coefficients of r=0.56 and r=0.53, respectively). (D) In contrast, repeated daily measurements using motion sensors aggregated over a two-week period at home provide a more robust, quantitative assessment of tremor severity as demonstrated by the higher correlation coefficient (r=0.84). All data are derived from a 3-month clinical study of TAPS [54], which included 263 patients with ET performing a series of three postural holds that were each simultaneously measured by a triaxial accelerometer and rated by clinicians on a 4-point TETRAS scale (A, B), multiple in-person clinical assessments over the 90 days with six assessed TETRAS tasks (for a total clinical assessment score of 0 – 24), and daily at-home motion sensor measurements (C, D). Panels (A) and (B) adapted from [54].

Figure 4.. Schematic of tremor reduction mechanism hypotheses after afferent PES.

(A) The afferent fibers activated through PES reach the tremor sources located at the brain, primarily the cerebellum and the ventral intermediate nucleus (VIM), and disrupt tremorgenic activity. (B) The recruited afferent fibers make connections with inhibitory interneurons at the spinal cord, mainly involved in spinal reflexes circuits and/or the propriospinal system, which modulates the supraspinal tremorgenic input and prevents it from reaching the muscles.