Median Nerve Stimulation Pilot

NCT ID: NCT04731714

Last Updated: 2023-10-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 34 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-15
• Study Completion Date: 2022-04-27

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: OTHER

Rhythmic median nerve stimulation

Intervention Type: DEVICE

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.

Arrhythmic median nerve stimulation

Intervention Type: DEVICE

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.

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.

Group Type: OTHER

Rhythmic median nerve stimulation

Intervention Type: DEVICE

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.

Arrhythmic median nerve stimulation

Intervention Type: DEVICE

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DEVICE

Other Intervention Names

Rhythmic MNS; Arrhythmic MNS

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

• Minimum Eligible Age: 15 Years
• Maximum Eligible Age: 64 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Center for Advancing Translational Sciences (NCATS)

NIH

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Kevin J. Black, M.D.

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Kevin J Black, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University Medical School

Locations

Washington University School of Medicine, Movement Disorders Center

St Louis, Missouri, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 32502412 (View on PubMed)

Iverson AM, Arbuckle AL, Ueda K, Song DY, Bihun EC, Koller JM, Wallendorf M, Black KJ. Median Nerve Stimulation for Treatment of Tics: Randomized, Controlled, Crossover Trial. J Clin Med. 2023 Mar 27;12(7):2514. doi: 10.3390/jcm12072514.

Reference Type: DERIVED

PMID: 37048598 (View on PubMed)

Iverson AM, Arbuckle AL, Ueda K, Song DY, Bihun EC, Koller JM, Wallendorf M, Black KJ. Peripheral nerve induction of inhibitory brain circuits to treat Tourette syndrome: A randomized crossover trial. medRxiv [Preprint]. 2023 Feb 6:2023.02.01.23285304. doi: 10.1101/2023.02.01.23285304.

Reference Type: DERIVED

PMID: 36778375 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Study Documents

Document Type: Individual Participant Data Set

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

View Document

Related Links

https://osf.io/mtbzf/

Study protocol (follow link under "Protocol")

Other Identifiers

UL1TR002345

Identifier Type: NIH

Identifier Source: secondary_id

View Link

202011092

Identifier Type: -

Identifier Source: org_study_id