Clinical trial NCT04731714: Median Nerve Stimulation Pilot
Official title: Peripheral Induction of Inhibitory Brain Circuits to Treat Tourette's: Pilot
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Tourette Syndrome
Tic Disorders
Tic Disorder, Chronic Motor or Vocal
Keywords: Tourette
Tic
Transcutaneous Electric Nerve Stimulation
Median Nerve
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Center for Advancing Translational Sciences (NCATS)
First posted: 2021-02-01
Enrollment: 34
Sex: ALL
Minimum age (years): 15
Maximum age (years): 64
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Change in Tic Frequency From When MNS is Turned Off
timeFrame: During the 1-minute on and 1-minute off blocks of rhythmic MNS stimulation (total 4 blocks)
measure: Change in Tic Severity From When MNS is Turned Off
timeFrame: During the 1-minute on and 1-minute off blocks of rhythmic MNS stimulation (total 4 blocks)
measure: Change in Tic Frequency During Rhythmic MNS (vs. Arrhythmic MNS)
timeFrame: During 5-minute MNS stimulation on or off blocks 0, 5, 6, 7, 8 and 9
measure: Change in Tic Severity During Rhythmic MNS (vs. Arrhythmic MNS)
timeFrame: During 5-minute MNS stimulation on or off blocks 0, 5, 6, 7, 8 and 9
Secondary outcomes:
measure: Change in Tic Severity After MNS Ends
timeFrame: up to 20 minutes after the end of stimulation at each study visit up to 1 month
measure: CGI-I, Participant
timeFrame: 5-25 minutes after the end of stimulation at each study visit up to 1 month
measure: CGI-I, Investigator
timeFrame: 5-25 minutes after the end of stimulation at each study visit up to 1 month
measure: Rating of Therapeutic Effect Using the CGI Efficacy Index
timeFrame: 5-25 minutes after the end of stimulation at each study visit up to 1 month
measure: VAS (Visual Analog Scale) Rating of Premonitory Urge Severity
timeFrame: At the end of each 5-min. MNS on or off block through block 9, at each study visit
measure: Rating of Discomfort Using the CGI Efficacy Index (Edited)
timeFrame: 5-25 minutes after the end of stimulation at each study visit up to 1 month
measure: Blindedness Assessment
timeFrame: 5-25 minutes after the end of stimulation at each study visit up to 1 month
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine, Movement Disorders Center
state: Missouri
Study officials:
affiliation: Washington University Medical School
name: Kevin J Black, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.