Median Nerve Stimulation Pilot

Study Overview
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Brief Summary
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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
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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.

Official Title
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Peripheral Induction of Inhibitory Brain Circuits to Treat Tourette's: Pilot

Conditions
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Tourette Syndrome, Tic Disorders, Tic Disorder, Chronic Motor or Vocal

Intervention / Treatment
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* Device: Rhythmic median nerve stimulation
* Device: Arrhythmic median nerve stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 15-64 inclusive at initial screening visit Informed consent by adult subject; assent by child and informed consent by guardian Current Tourette's Disorder or Persistent (Chronic) Tic Disorder according to the criteria in the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 At least 1 tic per minute (average) during the first 5-min. baseline video session on the first visit (as scored during the session by the investigator) Exclusion Criteria: Unable to complete study procedures for any reason Has an implanted device that could be affected by electrical current Pregnancy known to participant or (for children) to the parent Known or suspected primary genetic syndrome (e.g. Down syndrome, Fragile X) Intellectual disability (known, or likely from history and examination) Head trauma with loss of consciousness for more than 5 minutes Significant neurologic disease, not counting TS (exceptions include febrile seizures or uncomplicated migraine) Severe or unstable systemic illness Factors (such as exaggerated signs) that in the judgment of the principal investigator make the video recording or YGTSS an inaccurate assessment of tic severity Judged by investigator to be unlikely to complete study procedures or to return for later visits Change in somatic or psychotherapeutic treatment in the 2 weeks preceding the first stimulation visit Planned change in somatic or psychotherapeutic treatment between the 2 stimulation visits

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Experimental: rhythmic MNS, then arrhythmic MNS<br>Participants will complete two stimulation sessions, at least a week apart. The first session involves rhythmic MNS and the second uses arrhythmic MNS. | Device: Rhythmic median nerve stimulation<br>* 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.<br>* Other names: Rhythmic MNS;Device: Arrhythmic median nerve stimulation<br>* 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.<br>* Other names: Arrhythmic MNS;|
| Other: Experimental: arrhythmic MNS, then rhythmic MNS<br>Participants will complete two stimulation sessions, at least a week apart. The first session involves arrhythmic MNS and the second uses rhythmic MNS. | Device: Rhythmic median nerve stimulation<br>* 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.<br>* Other names: Rhythmic MNS;Device: Arrhythmic median nerve stimulation<br>* 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.<br>* Other names: Arrhythmic MNS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Tic Frequency From When MNS is Turned Off | The number of tics per minute is assessed by an expert rater blind to condition and time point. Mean tic frequency was compared in on vs. off 1-minute stimulation epochs on the rhythmic MNS day. This analysis replicates that of Study 3 in the Morera Maiquez et al 2020 citation, who reported tics in the last 40 seconds of the block to minimize carryover effects. A Mixed Models Analysis was used to test statistical significance; it included a factor for possible within-day carryover effect and used a logarithmic transformation for tic count. Data reported here have been back-transformed to the number of tics in the last 40 s of the stimulation blocks. | During the 1-minute on and 1-minute off blocks of rhythmic MNS stimulation (total 4 blocks) | 
| Change in Tic Severity From When MNS is Turned Off | Severity is rated on a 5-point scale for each occurrence of any tic. The scale is the Intensity item from the Yale Global Tic Severity Scale [YGTSS], which uses integer scores from 0 (no tics) to 5 (severe intensity). Mean tic severity was compared in on vs. off 1-minute stimulation epochs on the rhythmic MNS day. This analysis replicates that of Study 3 in the Morera Maiquez et al 2020 citation. | During the 1-minute on and 1-minute off blocks of rhythmic MNS stimulation (total 4 blocks) | 
| Change in Tic Frequency During Rhythmic MNS (vs. Arrhythmic MNS) | The number of tics per minute is assessed by an expert rater blind to condition and time point. Change in tic frequency from baseline (stimulation off) is compared between 5-minute MNS-on epochs on the rhythmic vs. the arrhythmic day. Subjects who do not complete both stimulation visits will not be included in this analysis. The hypothesized change is greater improvement (off to on) with rhythmic vs. arrhythmic stimulation. This analysis includes the first six 5-minute blocks on each MNS day (i.e., the blocks that all participants complete). MNS was administered throughout blocks 6 and 8 only. Tic frequency in block 0 (baseline, before any stimulation) on the same day was a covariate in the statistical model. | During 5-minute MNS stimulation on or off blocks 0, 5, 6, 7, 8 and 9 | 
| Change in Tic Severity During Rhythmic MNS (vs. Arrhythmic MNS) | Overall tic severity for each 5-minute block is rated once on a 5-point scale by an expert blind to condition and time point. The scale is the Intensity item from the Yale Global Tic Severity Scale [YGTSS], which uses integer scores from 0 (no tics) to 5 (severe intensity). Change in tic severity from baseline (stimulation off) is compared between 5-minute MNS-on epochs on the rhythmic vs. the arrhythmic day. Subjects who do not complete both stimulation visits will not be included in this analysis. The hypothesized change was greater improvement (off to on) with rhythmic vs. arrhythmic stimulation. This analysis includes the first six 5-minute blocks on each MNS day (i.e., the blocks that all participants complete). MNS was administered throughout blocks 6 and 8 only. Tic frequency in block 0 (baseline, before any stimulation) on the same day was a covariate in the statistical model. | During 5-minute MNS stimulation on or off blocks 0, 5, 6, 7, 8 and 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Tic Severity After MNS Ends | We compared the change in tic frequency from baseline, during each 1-minute-long period following the end of stimulation. Here baseline means the tic frequency during the last 5 minutes of MNS from the same day (block 8). Last observation carried forward was used for participants who had less than 20 minutes of data following block 8. | up to 20 minutes after the end of stimulation at each study visit up to 1 month | 
| CGI-I, Participant | Clinical Global Impression of Improvement (CGI-I), rated by participant. The CGI-I is a 7-point scale ranging from 1 = very much improved to 7 = very much worse. | 5-25 minutes after the end of stimulation at each study visit up to 1 month | 
| CGI-I, Investigator | Clinical Global Impression of Improvement (CGI-I), rated by investigator. The CGI-I is a 7-point scale ranging from 1 = very much improved to 7 = very much worse. | 5-25 minutes after the end of stimulation at each study visit up to 1 month | 
| Rating of Therapeutic Effect Using the CGI Efficacy Index | Participant rates peak improvement experienced during the visit using the 4-point scale of the CGI (Unchanged or worse; Minimal - Slight improvement that doesn't decrease the overall impact of symptoms*; Moderate - Decided improvement. Partial remission of symptoms; Marked - Vast improvement. Complete or nearly complete remission of all symptoms). * = Minimal option anchor text slightly edited from original. The number provided is the number of participants who rated each visit as moderate or marked. | 5-25 minutes after the end of stimulation at each study visit up to 1 month | 
| VAS (Visual Analog Scale) Rating of Premonitory Urge Severity | Participant rates the maximal severity of any premonitory urges over the preceding minute, from 0=no premonitory urge to 100=maximally uncomfortable premonitory urge, using a Visual Analog Scale. | At the end of each 5-min. MNS on or off block through block 9, at each study visit | 
| Rating of Discomfort Using the CGI Efficacy Index (Edited) | Participant rates peak discomfort experienced during the visit using the 4-point scale of the CGI: Overall, today, how much DISCOMFORT did the stimulation cause? If discomfort is the wrong word, please substitute any negative effects or side effects of stimulation. (No discomfort; Discomfort noticeable, but not severe enough to concern me or to turn it off; Enough discomfort, impairment of functioning or social embarrassment that I would only keep it on if the benefit was considerable; Caused discomfort, impairment of functioning or social embarrassment to a degree that any treatment benefit was not worth leaving it on). The number provided is the number of visits where discomfort is rated as none or minimal. | 5-25 minutes after the end of stimulation at each study visit up to 1 month | 
| Blindedness Assessment | Participants guess at each study visit whether they received the active or sham MNS condition, and rate their certainty for that guess on a 0-3 scale (0 = pure guess, 3 = certain). The number reported here is the number of visits for which the participant guessed correctly (active vs. sham MNS). | 5-25 minutes after the end of stimulation at each study visit up to 1 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tourette, Tic, Transcutaneous Electric Nerve Stimulation, Median Nerve