Median Nerve Stimulation Pilot ((MNS))

• ClinicalTrials.gov Identifier: NCT04731714
• Recruitment Status: Recruiting
• First Posted: February 1, 2021
• Last Update Posted: July 16, 2021
• Sponsor: Washington University School of Medicine
• Collaborator: National Center for Advancing Translational Science (NCATS)
• Information provided by (Responsible Party): Kevin J. Black, MD, Washington University School of Medicine

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.

Condition or disease	Intervention/treatment	Phase
Tourette Syndrome; Tic Disorders; Tic Disorder, Chronic Motor or Vocal	Device: Rhythmic median nerve stimulation; Device: Arrhythmic median nerve stimulation	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 32 participants
• 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)
• 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).
• Primary Purpose: Treatment
• Official Title: Peripheral Induction of Inhibitory Brain Circuits to Treat Tourette's: Pilot
• Actual Study Start Date: July 15, 2021
• Estimated Primary Completion Date: February 28, 2022
• Estimated Study Completion Date: February 28, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: rhythmic MNS, then arrhythmic MNS; 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; 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.; Other Name: Rhythmic MNS; Device: Arrhythmic median nerve stimulation; 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 Name: Arrhythmic MNS
Experimental: arrhythmic MNS, then rhythmic MNS; 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; 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.; Other Name: Rhythmic MNS; Device: Arrhythmic median nerve stimulation; 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 Name: Arrhythmic MNS

Outcome Measures

Primary Outcome Measures :

1. Change in tic frequency from when MNS is turned off [ Time Frame: During rhythmic MNS stimulation ]
   The number of tics per minute is assessed by an expert rater blind to condition and time point. A one-tailed t test will compare mean tic frequency 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. A secondary analysis will test for carryover effects.
2. Change in tic severity from when MNS is turned off [ Time Frame: During rhythmic MNS stimulation ]
   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). A one-tailed t test will compare mean tic severity 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. A secondary analysis will test for carryover effects.
3. Change in tic frequency during rhythmic MNS (vs. arrhythmic MNS) [ Time Frame: During rhythmic MNS stimulation ]
   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. A repeated measures ANOVA will be used to compare effects of visit, order (rhythmic day first or second) and stimulation (on vs. off) on tic frequency. The hypothesized change is a significant interaction of visit, order and stimulation factors (p≤.05), showing 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).
4. Change in tic severity during rhythmic MNS (vs. arrhythmic MNS) [ Time Frame: During rhythmic MNS stimulation ]
   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. A repeated measures ANOVA will be used to compare effects of visit, order (rhythmic day first or second) and stimulation (on vs. off) on tic frequency and severity. The hypothesized change is a significant interaction of visit, order and stimulation factors (p≤.05), showing 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).

Secondary Outcome Measures :

1. Change in tic severity after MNS ends [ Time Frame: up to 20 minutes after the end of stimulation at each study visit up to 1 month ]
   Duration of benefit will be estimated as follows. A repeated measures ANOVA will compare 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.
2. CGI-I, participant [ Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month ]
   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.
3. CGI-I, investigator [ Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month ]
   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.
4. VAS rating of tic improvement [ Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month ]
   Participant rates overall tic improvement during active stimulation, from 0=no improvement to 100=complete remission of symptoms at some point, using a Visual Analog Scale (VAS).
5. VAS rating of premonitory urge severity [ Time Frame: Before MNS begins, at the end of each 5-min. MNS on or off block, and 5-25 minutes after the end of stimulation at each study visit up to 1 month ]
   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.
6. VAS rating of discomfort [ Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month ]
   Participant rates peak discomfort experienced during the session, from 0=no discomfort to 100=maximal possible discomfort, using a Visual Analog Scale.
7. Blindedness assessment [ Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month ]
   Participants guess 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).

Eligibility Criteria

• Ages Eligible for Study: 15 Years to 64 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Emily Bihun, MEd; 314-362-2083; emilybihun@wustl.edu

Contact: Samantha A Ranck, MSW, MA; 314-362-6514; blankens@wustl.edu

Locations

United States, Missouri

Washington University School of Medicine, Movement Disorders Center; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Emily C. Bihun, M.Ed. 314-362-2083 EmilyBihun@wustl.edu

Contact: Kevin J Black, MD 314-362-5041 kevin@WUSTL.edu

Principal Investigator: Kevin J. Black, MD

Sponsors and Collaborators

Washington University School of Medicine

National Center for Advancing Translational Science (NCATS)

Investigators

• Principal Investigator: Kevin J Black, MD; Washington University Medical School

More Information

Additional Information:

Study protocol (follow link under "Protocol") 

Study Data/Documents: Individual Participant Data Set 

Identifier: mtbzf
IPD, study protocol, SAP, and ICF will all be posted at this location.

Publications:

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.

• Responsible Party: Kevin J. Black, MD, Principal Investigator, Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT04731714
• Other Study ID Numbers: 202011092; UL1TR002345 ( U.S. NIH Grant/Contract )
• First Posted: February 1, 2021
• Last Update Posted: July 16, 2021
• Last Verified: July 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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/).
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• Time Frame: The study protocol is available now (https://osf.io/mtbzf/). Statistical Analysis Plan (SAP) will be available before enrolling the first participant.
• 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/).
• URL: https://osf.io/mtbzf/

• 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

Keywords provided by Kevin J. Black, MD, Washington University School of Medicine:

Tourette; Tic; Transcutaneous Electric Nerve Stimulation; Median Nerve

Additional relevant MeSH terms:

Tourette Syndrome; Tics; Tic Disorders; Disease; Pathologic Processes; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Neurodevelopmental Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations