Median Nerve Stimulation Pilot (MNS)
Primary Purpose
Tourette Syndrome, Tic Disorders, Tic Disorder, Chronic Motor or Vocal
Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Rhythmic median nerve stimulation
Arrhythmic median nerve stimulation
Sponsored by
About this trial
This is an interventional treatment trial for Tourette Syndrome focused on measuring Tourette, Tic, Transcutaneous Electric Nerve Stimulation, Median Nerve
Eligibility Criteria
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
Sites / Locations
- Washington University School of Medicine, Movement Disorders Center
Arms of the Study
Arm 1
Arm 2
Arm Type
Other
Other
Arm Label
Experimental: rhythmic MNS, then arrhythmic MNS
Experimental: arrhythmic MNS, then rhythmic MNS
Arm Description
Participants will complete two stimulation sessions, at least a week apart. The first session involves rhythmic MNS and the second uses arrhythmic MNS.
Participants will complete two stimulation sessions, at least a week apart. The first session involves arrhythmic MNS and the second uses rhythmic MNS.
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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).
Full Information
NCT ID
NCT04731714
First Posted
January 13, 2021
Last Updated
September 11, 2023
Sponsor
Washington University School of Medicine
Collaborators
National Center for Advancing Translational Sciences (NCATS)
1. Study Identification
Unique Protocol Identification Number
NCT04731714
Brief Title
Median Nerve Stimulation Pilot
Acronym
MNS
Official Title
Peripheral Induction of Inhibitory Brain Circuits to Treat Tourette's: Pilot
Study Type
Interventional
2. Study Status
Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
July 15, 2021 (Actual)
Primary Completion Date
April 27, 2022 (Actual)
Study Completion Date
April 27, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Washington University School of Medicine
Collaborators
National Center for Advancing Translational Sciences (NCATS)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tourette Syndrome, Tic Disorders, Tic Disorder, Chronic Motor or Vocal
Keywords
Tourette, Tic, Transcutaneous Electric Nerve Stimulation, Median Nerve
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
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
ParticipantInvestigatorOutcomes Assessor
Masking Description
The stimulation pulses will be triggered by a computer program which will provide either rhythmic or arrhythmic MNS at the same mean rate throughout a given study session. A programmer who does not interact with the participants uses a stimulation order table created by a true random number generator to select the "day 1" and "day 2" program for each participant in advance. Participants and the investigator are blind to stimulation order and stimulation type. Audiovisual recordings of tics will be rated by a reviewer who will additionally be blind to time (first vs. second stimulation session).
Allocation
Randomized
Enrollment
34 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Experimental: rhythmic MNS, then arrhythmic MNS
Arm Type
Other
Arm Description
Participants will complete two stimulation sessions, at least a week apart. The first session involves rhythmic MNS and the second uses arrhythmic MNS.
Arm Title
Experimental: arrhythmic MNS, then rhythmic MNS
Arm Type
Other
Arm Description
Participants will complete two stimulation sessions, at least a week apart. The first session involves arrhythmic MNS and the second uses rhythmic MNS.
Intervention Type
Device
Intervention Name(s)
Rhythmic median nerve stimulation
Other Intervention Name(s)
Rhythmic MNS
Intervention Description
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.
Intervention Type
Device
Intervention Name(s)
Arrhythmic median nerve stimulation
Other Intervention Name(s)
Arrhythmic MNS
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in Tic Frequency From When MNS is Turned Off
Description
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.
Time Frame
During the 1-minute on and 1-minute off blocks of rhythmic MNS stimulation (total 4 blocks)
Title
Change in Tic Severity From When MNS is Turned Off
Description
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.
Time Frame
During the 1-minute on and 1-minute off blocks of rhythmic MNS stimulation (total 4 blocks)
Title
Change in Tic Frequency During Rhythmic MNS (vs. Arrhythmic MNS)
Description
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.
Time Frame
During 5-minute MNS stimulation on or off blocks 0, 5, 6, 7, 8 and 9
Title
Change in Tic Severity During Rhythmic MNS (vs. Arrhythmic MNS)
Description
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.
Time Frame
During 5-minute MNS stimulation on or off blocks 0, 5, 6, 7, 8 and 9
Secondary Outcome Measure Information:
Title
Change in Tic Severity After MNS Ends
Description
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.
Time Frame
up to 20 minutes after the end of stimulation at each study visit up to 1 month
Title
CGI-I, Participant
Description
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.
Time Frame
5-25 minutes after the end of stimulation at each study visit up to 1 month
Title
CGI-I, Investigator
Description
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.
Time Frame
5-25 minutes after the end of stimulation at each study visit up to 1 month
Title
Rating of Therapeutic Effect Using the CGI Efficacy Index
Description
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.
Time Frame
5-25 minutes after the end of stimulation at each study visit up to 1 month
Title
VAS (Visual Analog Scale) Rating of Premonitory Urge Severity
Description
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.
Time Frame
At the end of each 5-min. MNS on or off block through block 9, at each study visit
Title
Rating of Discomfort Using the CGI Efficacy Index (Edited)
Description
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.
Time Frame
5-25 minutes after the end of stimulation at each study visit up to 1 month
Title
Blindedness Assessment
Description
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).
Time Frame
5-25 minutes after the end of stimulation at each study visit up to 1 month
10. Eligibility
Sex
All
Minimum Age & Unit of Time
15 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kevin J Black, MD
Organizational Affiliation
Washington University Medical School
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University School of Medicine, Movement Disorders Center
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Video recordings will not be shared, as they cannot feasibly be de-identified. All other individual participant data (excluding PHI) will be collected and stored on REDCap (redcap.wustl.edu) and will be shared on the Open Science Framework (OSF, at https://osf.io/mtbzf/).
IPD Sharing Time Frame
The study protocol is available now (https://osf.io/mtbzf/). Statistical Analysis Plan (SAP) will be available before enrolling the first participant.
IPD Sharing Access Criteria
Individual participant data (IPD) will be freely available under a CC0 license (Creative Commons public domain dedication, https://creativecommons.org/publicdomain/zero/1.0/).
IPD Sharing URL
https://osf.io/mtbzf/
Citations:
PubMed Identifier
32502412
Citation
Morera Maiquez B, Sigurdsson HP, Dyke K, Clarke E, McGrath P, Pasche M, Rajendran A, Jackson GM, Jackson SR. Entraining Movement-Related Brain Oscillations to Suppress Tics in Tourette Syndrome. Curr Biol. 2020 Jun 22;30(12):2334-2342.e3. doi: 10.1016/j.cub.2020.04.044. Epub 2020 Jun 4.
Results Reference
background
Links:
URL
https://osf.io/mtbzf/
Description
Study protocol (follow link under "Protocol")
Available IPD and Supporting Information:
Available IPD/Information Type
Individual Participant Data Set
Available IPD/Information URL
https://osf.io/mtbzf/
Available IPD/Information Identifier
mtbzf
Available IPD/Information Comments
IPD, study protocol, SAP, and ICF will all be posted at this location.
Learn more about this trial
Median Nerve Stimulation Pilot
We'll reach out to this number within 24 hrs