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.

Median Nerve Stimulation Pilot

Tourette Syndrome

Tic Disorders

Tic Disorder, Chronic Motor or Vocal

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.

Rhythmic median nerve stimulation

Arrhythmic median nerve stimulation

Peripheral Induction of Inhibitory Brain Circuits to Treat Tourette's: Pilot

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.

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.

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.

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.

Principal Investigator

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.

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.

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.

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.

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.

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.

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).

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.

Median Nerve Stimulation Pilot

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Not accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

Location

Status