Open-label MNS for Tourette Syndrome

Study Overview
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Brief Summary
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A recent report (Morera Maiquez et al 2020) described reduced tic severity in people with Tourette syndrome during 1-minute epochs of median nerve stimulation (MNS) at 10 Hz. Among the various questions still to be answered is the question of whether a device to administer MNS is practical for use in a chronic, real-world setting. This study will recruit participants who complete the clinic-based, blinded, randomized controlled trial, https://clinicaltrials.gov/ct2/show/NCT04731714, to determine the real-world usage and apparent utility of median nerve stimulation in people with chronic tics.

Detailed Description
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Chronic tic disorders (CTD), including Tourette syndrome (TS), are associated with a substantially reduced quality of life (Evans et al 2016). Medication treatments are no more than 50-60% effective in randomized, controlled trials (RCTs), and are often discontinued due to unacceptable side effects (Thomas and Cavanna 2013). Behavioral therapies require ability to participate in therapy and a specially trained therapist (Scahill et al 2013), but weekly visits to psychologists are impractical for many Americans, especially in rural areas (Lin et al 2016). Patients strongly desire new treatment options (Cuenca et al 2015). 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 (Morera Maiquez et al 2020). 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 [personal correspondence]. 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. Among the various questions still to be answered is the question of whether such a device would be practical for use in the real world. This study will supply participants with a commercially available transcutaneous electrical nerve stimulation (TENS) units to use for median nerve stimulation as described in the Nottingham study. Participants will be told to use the device as much or as little as desired to see how such stimulation might be utilized in the real world. Here the investigators propose (a) to determine the real-world usage and apparent utility of stimulation in people with chronic tics, and (b) to determine momentary self-rated efficacy and side effects of stimulation. The investigators will also compare results from this study to those from the Peripheral induction of inhibitory brain circuits to treat Tourette's: pilot study, from which participants will be drawn, in order to compare laboratory and real-world efficacy. Aim 1. Determine the real-world usage and apparent utility of stimulation in people with chronic tics. Participants will be allowed to choose when and for how long to use the stimulation, thus simulating how patients would use the stimulation in their daily lives. Aim 2. Determine momentary self-rated efficacy and side effects of stimulation, using surveys taken at the beginning and end of stimulation periods, as well as twice daily when prompted. Aim 3. Compare results of this trial with those from Peripheral induction of inhibitory brain circuits to treat Tourette's: pilot. Participants in this study will have been drawn from completers of the peripheral induction blinded RCT, allowing for clear comparisons between the laboratory conditions of the first study and the real-world conditions of the second. Completion of these Aims will provide practical information that can inform a future, controlled clinical trial of chronic MNS delivered by a portable device.

Official Title
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Open Trial of Median Nerve Stimulation for Treatment of Tourette Syndrome

Conditions
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Tourette Syndrome, Tic Disorder, Chronic Motor or Vocal

Intervention / Treatment
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* Device: Active, self-directed electrical stimulation of the median nerve


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completed participation in the study called Peripheral induction of inhibitory brain circuits to treat Tourette's: pilot Informed consent by adult participant, or assent by child and informed consent by guardian Exclusion Criteria: Has an implanted device that could be affected by electrical current Pregnancy known to participant or (for children) to the parent Severe or unstable systemic illness Factors (such as exaggerated symptom report) that in the judgment of the principal investigator may make the outcome measures inaccurate Judged by investigator to be unlikely to complete study procedures

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Interventional Model Description: All participants will receive MNS at 12 Hz, pulse width 200µs. After initial threshold determination and training on device usage, individual participants will choose duration and intensity of treatment depending on their momentary symptom severity and history of response to treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active MNS<br>Active, self-directed electrical stimulation of the right median nerve | Device: Active, self-directed electrical stimulation of the median nerve<br>* Electrical stimulation of the median nerve (12 Hz, pulse width 200µs), initially at the threshold needed to see movement of the right thumb with stimulation. After initial training with the device and education in the rationale for suprathreshold stimulation, participants will choose timing and intensity of stimulation based on their momentary symptom severity and their experience with the treatment since the beginning of the study. Participant can choose right or left median nerve (we will suggest their nondominant hand to minimize interference with daily activities).<br>* Other names: Rhythmic MNS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Spent Using the Device Per Day of Use | Number of minutes per day the device was used, only counting days in which the device was turned on, over the four-week period after the initial visit | At study conclusion, up to 4 weeks | 
| Time Spent Using the Device (Days Per Week) | Number of days per week the device was used | At study conclusion, up to 4 weeks | 
| Plan to Continue MNS (Median Nerve Stimulation) | Answered yes (from options yes / no / maybe) to the question, Do you expect to continue to use the stimulator? | At study conclusion, up to 1 month | 
| Change in Tic Frequency With Stimulation | Change in self-reported tic frequency on the frequency item (score range from 0 = no tics [better] to 5 = always [worse]) from the Yale Global Tic Severity Scale (YGTSS) from the beginning to the end of each stimulation period. Participants were instructed to answer this question every time they turned on the device and every time they turned it off, every day for 4 weeks. The difference between the turning off score and the previous turning on score was averaged across all ratings completed during the 4 weeks of the trial. The wording of the score anchors is provided at https://osf.io/7pjk4 . | Recorded every time the device was turned on and every time it was turned off, up to 4 weeks | 
| Change in Tic Intensity With Stimulation | Change in self-reported tic intensity on the intensity item (score range from 0 = no tics [better] to 5 = severe intensity [worse]) from the Yale Global Tic Severity Scale (YGTSS) from the beginning to the end of each stimulation period. Participants were instructed to answer this question every time they turned on the device and every time they turned it off, every day for 4 weeks. The difference between the turning off score and the previous turning on score was averaged across all ratings completed during the 4 weeks of the trial. | Recorded every time the device was turned on and every time it was turned off, up to 4 weeks | 
| Discomfort | Mean discomfort while using the stimulator, on a 0-3 scale adapted from the Clinical Global Impression - Improvement [CGI-I] Efficacy Index. Specifically, the prompt was How much DISCOMFORT did the stimulation cause?, and the participant selected one of the following responses: 0 = 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 Higher values represent a worse outcome. Discomfort was reported at the end of each stimulation period, and at random times twice daily between 9a.m. and 9p.m. when prompted by text message, if the device was on when the text was received. | Recorded every time the device was turned off, and every time the participant was prompted by a text to fill out the survey if the device was on when the text was received, up to 4 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CGI-I (Clinical Global Impression--Improvement) | Overall impact of the stimulation on symptoms throughout the study period: = Very much improved - nearly all better; good level of functioning; minimal symptoms; represents a very substantial change = Much improved - notably better with significant reduction of symptoms; increase in the level of functioning but some symptoms remain = Minimally improved - slightly better with little or no clinically meaningful reduction of symptoms. Represents very little change in basic clinical status, level of care, or functional capacity = No change - symptoms remain essentially unchanged = Minimally worse - slightly worse but may not be clinically meaningful; may represent very little change in basic clinical status, level of care, or functional capacity = Much worse - clinically significant increase in symptoms and diminished functioning = Very much worse - severe exacerbation of symptoms and loss of functioning On this scale, lower numbers indicate a better outcome. | At study conclusion, up to 4 weeks | 
| CGI Efficacy Index: Side Effects | Overall discomfort from stimulation throughout the study period. The prompt for this survey question was: On average, over the course of the study, how much DISCOMFORT did the stimulation cause? (If discomfort is the wrong word, please substitute any negative effects or side effects of stimulation.) Participants chose one of the following answers: 0 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 On this scale, lower numbers represent a better outcome. | At study conclusion, up to 4 weeks | 
| Mean Therapeutic Effect During Stimulator Use | Mean self-rated therapeutic effect (from the modified CGI Efficacy Index) when device is on, reported at the end of the study. Specifically, the prompt for this question was On average, over the course of the study, how much did your tics IMPROVE during stimulation? Participants chose one of the following answers: 0 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 On this scale, higher numbers represent a better outcome. | At study conclusion, up to 4 weeks | 
| Change in Self-reported Tic Severity | Self-rated tic severity over the past week using the Adult Tic Questionnaire (ATQ), first rating at (or within 2 weeks prior to) the beginning of study participation and second rating at the end of study participation. Higher ATQ scores reflect a worse outcome. For each tic present in the past week, its severity score is the sum of its frequency score (0-4, 4 worst, occurring almost all the time during the day) and its intensity score (0-4, 4 worst). The ATQ severity score is the sum of the severity score for each of up to 27 tics present in the past week. The minimum possible severity score on the ATQ is 0, indicating that no tics were present in the past week. The maximum possible severity score on the ATQ indicates is 216, indicating that a tic of each of the 27 types listed was present in the past week, each with an item severity score of 8 = 4 + 4. | At beginning of study participation or up to 2 weeks prior, and again at end of study participation up to 4 weeks | 
| Self-reported Duration of MNS Benefit, in Minutes | On the survey at the end of study participation, the relevant question asked: On average, over the course of the study, how long do you think the improvement in your tics lasted after you turned off the device? Give answer in minutes. Enter 0 (zero) if improvement with stimulation stopped immediately when you turned the device off. On this item, higher answers indicate a better outcome. | Monitored over the entire period of study participation, up to 4 weeks | 

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