Noninvasive neuromodulation in essential tremor demonstrates relief in a sham‐controlled pilot trial

Although the precise mechanisms are uncertain, essential tremor (ET) is thought to be caused by tremulous activity within a central tremor neural network, which involves the ventral intermediate nucleus (VIM) of the thalamus. Clinical evidence supports targeting the VIM to treat tremor symptoms in ET with various methods. Previous studies have shown that electrical median nerve stimulation evokes activity within the VIM and other regions of the central tremor network. Based on these reports, we hypothesized that median and radial nerve stimulation at the wrist could reduce hand tremor. The objective of this study was to evaluate the efficacy of median and radial nerve stimulation as a noninvasive, nonpharmacological treatment to aid in the symptomatic relief of hand tremor in individuals with ET. Twenty-three blinded subjects were examined at a single site under an institutional review board-approved protocol (Fig. S1, Table S1). Subjects were randomized to treatment or sham groups. For stimulation, hydrogel electrodes were positioned on the wrist over the median and radial nerves (Fig. 1A; see Supporting Information). Efficacy was measured as the change in the Tremor Research Group’s Essential Tremor Rating Assessment Scale (TETRAS) Archimedes spiral drawing task following stimulation compared with prestimulation (Fig. 1B,C). The response in the treatment group was significant compared with both baseline and sham. In the treatment group, blinded rater scores significantly improved following stimulation (1.77 6 0.21) compared with prestimulation (2.77 6 0.22; P 5 0.01; Fig. 1D). This response was achieved without the risks of surgical or pharmacological intervention, such as the risk of hemorrhage or infection with DBS implantation, or side effects of ET medications, including the first-line therapies propranolol and primidone. In the sham group, scores did not change significantly following stimulation (2.37 6 0.22) compared with prestimulation (2.62 6 0.14; P 5 0.37; Fig. 1E). The response to treatment corresponded to an estimated hand tremor amplitude reduction of 60% 6 8.4% and was significantly greater in the treatment than in the sham group (P 5 0.02; Fig. 1F). Three subjects experienced transient redness and/or itchiness under the hydrogel electrodes that resolved without intervention. No unanticipated device effects occurred during the study. This was a pilot study with too few subjects for subanalyses of the effects of age, medication status, or medical history. Future studies should expand the subject count, investigate the response rate, repeatability, durability, and effects of chronic use, and add assessments of quality of life. This therapeutic approach was inspired by the idea that peripheral stimulation evokes central activity in brain regions such as the VIM, a thalamic target widely accepted to improve tremor with DBS. Although our data support this idea, other potential mechanisms are possible, including circuitry modulated in previous studies demonstrating tremor reduction by manipulation of peripheral sensory input. Future studies that are able to better characterize the precise mechanism may facilitate improvements to therapy. Nonetheless, this randomized, sham-controlled pilot study suggests that noninvasive neuroperipheral therapy may offer clinically meaningful symptomatic relief from hand tremor in ET with a favorable side effect profile compared with other available therapies.