A double‐blind, sham‐controlled, trial of home‐administered rhythmic 10‐Hz median nerve stimulation for the reduction of tics, and suppression of the urge‐to‐tic, in individuals with Tourette syndrome and chronic tic disorder

Abstract

Tourette syndrome (TS) and chronic tic disorder (CTD) are neurological disorders of childhood onset characterized by the occurrence of tics; repetitive, purposeless, movements or vocalizations of short duration which can occur many times throughout a day. Currently, effective treatment for tic disorders is an area of considerable unmet clinical need. We aimed to evaluate the efficacy of a home‐administered neuromodulation treatment for tics involving the delivery of rhythmic pulse trains of median nerve stimulation (MNS) delivered via a wearable ‘watch‐like’ device worn at the wrist. We conducted a UK‐wide parallel double‐blind sham‐controlled trial for the reduction of tics in individuals with tic disorder. The device was programmed to deliver rhythmic (10 Hz) trains of low‐intensity (1–19 mA) electrical stimulation to the median nerve for a pre‐determined duration each day, and was intended to be used by each participant in their home once each day, 5 days each week, for a period of 4 weeks. Between 18th March 2022 and 26th September 2022, 135 participants (45 per group) were initially allocated, using stratified randomization, to one of the following groups; active stimulation; sham stimulation or to a waitlist (i.e. treatment as usual) control group. Recruited participants were individuals with confirmed or suspected TS/CTD aged 12 years of age or upward with moderate to severe tics. Researchers involved in the collection or processing of measurement outcomes and assessing the outcomes, as well as participants in the active and sham groups and their legal guardians were all blind to the group allocation. The primary outcome measure used to assess the ‘offline’ or treatment effect of stimulation was the Yale Global Tic Severity Scale–Total Tic Severity Score (YGTSS–TTSS) assessed at the conclusion of 4 weeks of stimulation. The primary outcome measure used to assess the ‘online’ effects of stimulation was tic frequency, measured as the number of tics per minute (TPM) observed, based upon blind analysis of daily video recordings obtained while stimulation was delivered. The results demonstrated that after 4‐week stimulation, tic severity (YGTSS‐TTSS) had reduced by 7.1 points (35 percentile reduction) for the active stimulation group compared to 2.13/2.11 points for the sham stimulation and waitlist control groups. The reduction in YGTSS–TTSS for the active stimulation group was substantially larger, clinically meaningful (effect size = .5) and statistically significant (p = .02) compared to both the sham stimulation and waitlist control groups, which did not differ from one another (effect size = −.03). Furthermore, blind analyses of video recordings demonstrated that tic frequency (tics per minute) reduced substantially (−15.6 TPM) during active stimulation compared to sham stimulation (−7.7 TPM). This difference represents a statistically significant (p < .03) and clinically meaningful reduction in tic frequency (>25 percentile reduction: effect size = .3). These findings indicate that home‐administered rhythmic MNS delivered through a wearable wrist‐worn device has the potential to be an effective community‐based treatment for tic disorders.

Investigating neurometabolite changes in response to median nerve stimulation

“…Furthermore, the neuromodulatory effects of rhythmic and arrhythmic stimulation were similar despite the entrainment seen previously with rhythmic stimulation (Houlgreave et al, 2022). Recent evidence also suggests that both rhythmic and arrhythmic stimulation may be effective in reducing tics in Tourette Syndrome (Iverson, Arbuckle, Song, et al, 2023; Iverson, Arbuckle, Ueda, et al, 2023; Maiquez et al, 2023; Morera Maiquez et al, 2020). We suggested previously that if both rhythmic and arrhythmic stimulation were effective in reducing tic frequency in Tourette Syndrome, then the beneficial effects might be due to a sustained decrease in sensorimotor noise after stimulation, due to the synchronous firing of activated neuronal populations associated with each pulse of stimulation (Houlgreave et al, 2022).…”

“…This may make it less likely that an involuntary movement is generated during continuous stimulation. As an offline reduction in tic severity has been reported following 4-weeks of rhythmic MNS (Maiquez et al, 2023), it would be interesting to explore the offline changes in neurometabolites following prolonged periods of stimulation.…”

“…This modulation is restricted to the contralateral sensorimotor cortex and is not seen during arrhythmic stimulation (Houlgreave et al, 2022; Morera Maiquez et al, 2020). The mechanisms underpinning rhythmic MNS are of therapeutic interest as compared to periods of no stimulation, rhythmic application of 10Hz MNS has also been demonstrated to produce substantial reduction in tic frequency and the urge-to-tic in individuals with Tourette Syndrome (Iverson, Arbuckle, Song, et al, 2023; Iverson, Arbuckle, Ueda, et al, 2023; Maiquez et al, 2023; Morera Maiquez et al, 2020). In contrast to other non-invasive stimulation methods, specifically transcranial magnetic stimulation (TMS), MNS offers an attractive approach to modulating brain sensorimotor networks implicated in brain health conditions such as Tourette Syndrome, which could easily be adapted into a wearable therapeutic device.…”

Algorithm of diagnosis and treatment of Gilles de la Tourette syndrome and tic disorder, adapted for the Republic of Moldova: a review

“…In the last year there was found evidence for the median nerve stimulation in the reduction of tics' frequency [103]. The transcranial magnetic stimulation (usually of the supplementary motor area) represents an experimental treatment method whose results are variable and not usually reproducible [104][105][106][107].…”

OPM-MEG Measuring Phase Synchronization on Source Time Series: Application in Rhythmic Median Nerve Stimulation

“…It is proven that the rhythmic stimulation could induce the synchronous oscillation [36], and has widely used for the rehabilitation treatment on the diseases, such as tic disorder [37]. In this paper, the OPM-MEG was applied to measure the oscillation activity induced by the 20Hz rhythmic median nerve stimulation, then the time series of somatosensory cortex contralateral to stimulation after source reconstruction were extracted and used for the analysis of ITPS and IRPS.…”