Median Nerve Stimulation Pilot
Condition: Tourette Syndrome; Tic Disorders; Tic Disorder, Chronic Motor or Vocal
MeSH terms: Tourette Syndrome; Tics; Tic Disorders
Study type: Interventional

Summary: 
      Results from the University of Nottingham suggested that rhythmic median nerve stimulation
      (MNS) improves tic symptoms in Tourette syndrome (TS). The investigators will (1) provide a
      first replication of their study, (2) test the hypothesized electrophysiological mechanism
      and rule out a placebo effect as cause for the symptomatic benefit, and (3) gather
      information on the duration of effect after the end of stimulation and on individual
      characteristics that predict improvement with simulation. Completion of these Aims will give
      a clear go/no-go signal for a future clinical trial of chronic MNS delivered by a
      yet-to-be-developed wristwatch-style device.

      NOTE: This study is not intended to evaluate a specific device for future use. Rather it is a
      study to determine the action of pulsed electrical stimulation on tic symptoms and to gain
      early evidence of effectiveness. This is a non-significant risk device study.
    

Detailed description: 
      Chronic tic disorders (CTD), including Tourette syndrome (TS), are associated with a
      substantially reduced quality of life. Medication treatments are no more than 50-60%
      effective in randomized controlled trials, and are often discontinued due to unacceptable
      side effects. Behavioral therapies require ability to participate in therapy and a specially
      trained therapist, but weekly visits to psychologists are impractical for many Americans,
      especially in rural areas. Patients strongly desire new treatment options.

      In June, 2020, Stephen Jackson's group at the University of Nottingham published a
      fascinating report in Current Biology on a potential novel treatment for tics. The radical
      new idea arose from observations associating movement inhibition with 8-14 Hz activity in
      motor cortex. They first showed that rhythmic 12 Hz peripheral stimulation of the median
      nerve evoked synchronous contralateral EEG activity over primary sensorimotor cortex, whereas
      arrhythmic stimulation at the same mean rate did not. As hypothesized, median nerve
      stimulation (MNS) at 12 Hz created small but statistically significant effects on initiation
      of voluntary movements. Importantly, they also demonstrated that this stimulation did not
      meaningfully impair concentration, suggesting that the effect did not operate through simple
      distraction. They went on to test 10 Hz MNS in 19 TS patients, and demonstrated using blinded
      video ratings a significant reduction in tic number and severity during 1-minute stimulation
      epochs vs 1-minute no-stimulation epochs. They noted that in some participants, benefit
      lasted beyond the end of the stimulation epoch. Videos accompanying the publication showed
      dramatic benefit during MNS in some subjects. Although the authors appropriately noted the
      steps needed to generalize these results to clinical practice, news reports already have led
      a number of TS patients to contact them asking for treatment. The Nottingham group has
      referred such inquiries from the U.S. to me as leader of our Wash.U. Tourette Association of
      America (TAA) Center of Excellence.

      The hypotheses of this project are that the tic benefits reported by the Nottingham
      investigators are replicable, that they are specific to rhythmic stimulation, which alone
      entrained cortical activity, rather than to a placebo effect, and that they endure past the
      end of stimulation.

      This project (a) will replicate the Nottingham findings using identical methods, and (b) will
      test rhythmic MNS against a placebo treatment (arrhythmic MNS at the same mean frequency). It
      also will gather additional preliminary data needed for a future R01 application, including
      response and tolerability with longer (5-minute) stimulation blocks, and the duration of
      benefit after the end of a stimulation block.
    

Intervention name(s): Rhythmic median nerve stimulation; Arrhythmic median nerve stimulation
Intervention type(s): Device; Device
Intervention description(s): Square-wave 200 µs pulses triggered by computer at 12 Hz, at the threshold for thumb movement (expected ~2-15mA), applied to surface electrodes over the median nerve at the right wrist (conductive gel, 30 mm apart center-to-center, anode distal). This is a non-significant risk device study.; Square-wave 200 µs pulses triggered by computer at random intervals with a mean rate of 12 Hz (as described in Morera Maiquez et al., 2020), at the threshold for thumb movement (expected ~2-15mA), applied to surface electrodes over the median nerve at the right wrist (conductive gel, 30 mm apart center-to-center, anode distal). This is a non-significant risk device study.
Other intervention name(s): Rhythmic MNS; Arrhythmic MNS
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: After screening and characterizing symptoms and other demographic and clinical features, all participants will complete two stimulation sessions, at least a week apart. These are identical except that one session uses rhythmic and one uses arrhythmic MNS with the same number of total pulses per minute. Session order is randomized and participants are blinded to order. Biological carryover effects are very unlikely. Tics before, during and after stimulation epochs are video recorded for later analysis blind to time, stimulation (on vs. off), and stimulation type (rhythmic vs. arrhythmic).
NOTE: This study is not intended to evaluate a specific device for future use. Rather it is a study to determine the action of pulsed electrical stimulation on tic symptoms and to gain early evidence of effectiveness. This is a non-significant risk device study.
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Tourette; Tic; Transcutaneous Electric Nerve Stimulation; Median Nerve