Peripheral Induction of Inhibitory Brain Circuits to Treat Tourette's: Pilot
Phase: NA
Conditions: Tourette Syndrome, Tic Disorders, Tic Disorder, Chronic Motor or Vocal
Sponsor: Washington University School of Medicine

 
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STUDY IDENTIFICATION 
 
Project title 
Peripheral induction of inhibitory brain circuits to treat Tourette’s: 
pilot 
Short title 
MNS pilot 
 
 
IRB 
Washington University Human Research Protection Office 
IRB title 
Peripheral induction of inhibitory brain circuits to treat Tourette’s: 
pilot 
IRB ID # 
202011092 
 
 
Grant support 
The Washington University Institute of Clinical and Translational 
Sciences (NIH CTSA grant UL1TR002345). 
Grant title 
Peripheral induction of inhibitory brain circuits to treat Tourette’s: 
pilot 
 
 
IDE status 
Non-significant risk device study  
 
 
ClinicalTrials.gov 
Identifier 
NCT04731714 
 
 
Protocol version 
(revision date) 
Version 20220120 
(January 20, 2022) 
 
 

 
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OBJECTIVES 
Chronic tic disorders (CTD), including Tourette syndrome (TS), are associated with a substantially 
reduced quality of life [1]. Medication treatments are no more than 50-60% effective in RCTs, and are 
often discontinued due to unacceptable side effects [2]. Behavioral therapies require ability to 
participate in therapy and a specially trained therapist [3], but weekly visits to psychologists are 
impractical for many Americans, especially in rural areas [4]. Patients strongly desire new treatment 
options [5]. 
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 [6]. 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 [personal correspondence]. 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.  
We hypothesize that the tic benefits reported by our Nottingham colleagues 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.  
Here we propose (a) to replicate the Nottingham findings using identical methods, and (b) to test 
rhythmic MNS against a placebo treatment (arrhythmic MNS at the same mean frequency). At the 
same time, we 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. 
Aim 1. Replicate the Nottingham MNS results in a new sample of people with TS. We have been in 
frequent contact with the Nottingham group to ensure that we can match their methods. 
Aim 2. Test the hypothesized electrophysiological mechanism and rule out a placebo effect as 
cause for the symptomatic benefit, using randomized allocation of rhythmic stimulation to a control 
condition, namely random (not rhythmic) stimulation.  
Aim 3. Gather additional preliminary information for a future clinical efficacy trial and NIH grant 
application. This information will include (a) the duration of effect after the end of stimulation, which 
is crucial information for designing chronic treatment, and (b) preliminary information on individual 

 
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characteristics that predict improvement with simulation, e.g. demographics, tic severity, 
premonitory urges, sensory hypersensitivity, ADHD, tic suppression ability, and tic phenomenology. 
Completion of these Aims will give a clear go/no-go signal for a future clinical trial of chronic MNS 
delivered by a portable, wristwatch-style device.  
STUDY DESIGN 
Overall study timeline 
The study will complete enrollment within 11 months and complete all human subjects procedures 
within 1 year.  
Overview of each subject’s participation 
First we screen potential participants to ensure they meet criteria for study enrollment, and 
characterize their symptoms and other demographic and clinical features. They then participate in 2 
stimulation sessions, at least a week apart, which 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).  
Recruitment 
Sources may include clinical referrals, online advertising, and word of mouth. We will also involve 
the local chapter of the Tourette Association of America, which is a key part of our TAA Center of 
Excellence 
Prior to first visit 
1. REDCap presents an informed consent document to parents of potential child participants 
explaining the study, risks and benefits of participation and that participation is voluntary. 
The ICD will be provided online prior to the in-person visit. Adult participants will provide 
their own informed consent. For child participants, consent from one parent or guardian is 
sufficient, as the study is minimal risk. Children must assent to participate.  
2. Participants may optionally consent to share video of their tics and response to stimulation 
with the general public (as did some participants in the Current Biology report [6]). 
3. REDCap provides questionnaires online prior to the visit, after the participant (and guardian) 
review the ICD. These include: 
a. Age, sex 
b. Self-reported race and ethnicity  
c. Handedness (Edinburgh Handedness Inventory) 
d. Health history 
i. Medical history 
ii. Family history of tics and related symptoms 
iii. Treatment history: Lifetime neurosurgery, lifetime adequate behavior therapy for 
tics or OCD, changes in treatment within the past 2 weeks, plans to change 
treatment between the 2 stimulation visits 

 
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iv. Current treatment 
e. TS symptom history  
i. Lifetime tic list reported by participant or parent (list from Yale Global Tic 
Severity Scale [YGTSS]) [7] 
f. Current symptom status 
i. Past week tic list from the YGTSS 
ii. Adult Tic Questionnaire (ATQ) tic rating [8,9] 
iii. Premonitory Urge for Tics Scale (PUTS) [10] 
g. Other / comorbid symptoms 
i. Self-rated current Y-BOCS [11] 
ii. Self-rated current ADHD Rating Scale [12] 
iii. Quantitative autistic traits by Social Responsiveness Scale (SRS-2) [13] 
First visit 
1. Potential subjects will review the informed consent document with the investigator or 
designee and will have opportunity to resolve questions or concerns. The investigator will 
document that a child understands the procedures and assents. 
2. We review the online questionnaires and collect the following additional measures:  
a. TS symptom history  
i. Diagnostic Confidence Index [14] 
b. A TS clinician will review the history with the participant and perform a neurological 
and psychiatric examination as appropriate. 
c. Current symptom status 
i. YGTSS, performed by expert clinician 
ii. 5-minute observation, staff in room quiet, to count tics at baseline [performed 
during “stimulation protocol,” below] 
d. Disease-related outcome data, healthcare utilization, and global functioning 
i. “Marked distress” or impairment in a life role: ever, and in the past week 
(clinical judgment) 
e. Tic disorder diagnosis by DSM-5, DSM-IV-TR and DSM-IV  
3. Proceed to “stimulation protocol”  
Stimulation protocol 
See MNS section below for technical details on all procedures  
1. Clean skin at right wrist. Apply conductive gel. 
2. Attach electrodes (so they’re visible in the baseline video for optimal blinding).  
3. Check resistance through electrodes. If < 100 Ω, look for a short and correct it. If resistance 
remains out of range, do not proceed without specific approval from PI. Record resistance. 
4. Optional but recommended bathroom stop 
5. Procedures below are performed in a quiet room with only participant and study staff present 
but not conversing 
6. All videos are recorded from the elbows up for later blinded ratings of tics 
7. 5-min video-recorded baseline session, also rated live at the first visit to record baseline tic 

 
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frequency 
8. At this point, the PI or designate will review the inclusion and exclusion criteria (including 
mean baseline tic frequency ≥ 1/min.) and document eligibility for the study before additional 
procedures 
9. Determine stimulation threshold for a train of 8 pulses (12 Hz, pulse width 200µs), starting at 
1mA and increasing until a twitch of the thumb is seen, to a maximum of 20mA (expected 
range 2-15 mA, personal communication, B. Morera Maiquez to KJB).  Some subjects may wish to 
withdraw at this point if suprathreshold stimulation is too uncomfortable, but in the 
Nottingham report, participants age 15 and up found the stimulation tolerable. Since electrode 
placement can change slightly between visits, on the second visit the threshold is verified and 
adjusted as needed. We record the threshold at each visit. 
10. Resume video recording  
11. Synchronize clocks for video, urge rating software, and stimulation  
12. MNS stimulation on or off blocks as follows, without planned breaks (total 29-44 min.) 
a. Two 1-min. blocks of MNS on and two 1-min. sessions off, the order of these 4 sessions 
randomized (this design matches the Nottingham study) 
b. 5-min. block MNS off 
c. 5-min. block MNS on 
d. 5-min. block MNS off 
e. 5-min. block MNS on 
f. 5-minute stimulation off blocks until tics return to baseline frequency (min. 1 block, 
max. 4 blocks) 
13. Stop video recording 
14. CGI-I (Clinical Global Impression of Improvement) rating for tics by participant and 
investigator 
15. Debrief  
a. ratings of tic improvement and discomfort using the CGI Efficacy Index 
b. ask for comments on benefit, tolerability, side effects 
c. participant and staff guess whether this was active or control stimulation day (to test 
adequacy of blinding) 
d. ask if they think they would use a portable stimulator 
16. First visit: confirm scheduling for second visit 
Prior to second visit 
1. Participants repeat the following measures online: 
a. Health history 
i. Change in medical history since first visit 
ii. Current treatment 
b. Current symptom status 
i. Past week tic list from the YGTSS 
ii. Adult Tic Questionnaire (ATQ) tic rating [8,9] 
c. Other / comorbid symptoms 
i. Self-rated current Y-BOCS [11]  

 
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ii. Self-rated current ADHD Rating Scale [12] 
Second visit 
1. We review the online questionnaires and collect the following additional measures:  
a. TS symptom history  
i. Diagnostic Confidence Index 
b. Current symptom status 
i. YGTSS, performed by expert clinician [7] 
ii. 5-minute observation, staff in room quiet, to count tics at baseline [performed 
during “stimulation protocol”] 
c. A TS clinician will review the history with the participant and perform a neurological 
and psychiatric examination as appropriate. 
d. Disease-related outcome data, healthcare utilization, and global functioning 
i. “Marked distress” or impairment in a life role: past week (clinical judgment) 
ii. Record any change in treatment since the first visit 
e. Tic diagnosis by DSM-5, DSM-IV-TR and DSM-IV  
2. Proceed to “stimulation protocol”  
MNS procedure 
We will apply square-wave 200 µs pulses triggered by computer at the threshold for thumb 
movement (expected ~2-15mA) to surface electrodes over the median nerve at the right wrist 
(conductive gel, 30 mm apart center-to-center, anode distal).  
Video analysis 
An investigator blind to treatment order (rhythmic MNS first or second), stimulation condition (on 
vs. off), visit number, and order (of the 1-minute or 5-minute blocks) uses a derivative of our TicTimer 
Web software [15,16] to mark each occurrence of any tic and to provide a rating of tic severity for the 
full 5-minute block or (for the 1-minute blocks) for each tic occurrence. 
Subject payments 
Subjects will receive $15 or the equivalent value on a gift card at the end of the first visit, and an 
additional $25 at the end of the second visit, to help compensate for their loss of time. Travel costs to 
study visits may be reimbursed. 
Clinical vs. research purposes 
All procedures in this study are done for research purposes. 
POTENTIAL RISKS 
(The language below, in this section, is addressed to the patient, as in an informed consent document.) 
You may experience one or more of the risks indicated below from being in this study. In addition to 
these, there may be other unknown risks, or risks that we did not anticipate, associated with being in 
this study. You will be told of any new information that may affect your willingness to participate in 
this study. Dr. Black will answer any questions you have about these risks.  

 
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MNS 
Likely: 
 Discomfort in the forearm, wrist or hand during active stimulation 
 Mild skin irritation from applying or removing the surface electrodes 
Other study procedures 
Likely: 
 The questionnaires and interview may be slightly boring, fatiguing or challenging.  
 The video recordings may be slightly boring 
Rare: 
 The questions that you are asked during this study could make you feel uncomfortable. If any 
question makes you feel uncomfortable, you may choose not to answer it. 
 Confidential information about you may be accidentally disclosed. However, we think the risk of 
accidental disclosure is small. The information we gather during the course of the study is coded 
only by a study number and is kept separately from your name, address, etc.  
LOCATIONS / SITES OF STUDY 
Data collection: 
Washington University in St. Louis 
Data analysis: 
Washington University in St. Louis 
STUDY DURATION 
Anticipated duration of entire research activity per participant:    
 2-4* days, usually over the course of 1-2 weeks  
* Planned participation includes a screening visit followed by two stimulation sessions, the first of 
which may occur on the same day as the first stimulation session. The maximum of 4 days rather 
than 3 allows one additional make-up MNS session for each participant in the event of technical 
problems that prevent completion of the procedures. 
Anticipated duration of entire research activity:   
One year 
SAMPLE SIZE 
N = 32 (study completers) 
Power considerations 
We can estimate variance from the Nottingham tic frequency results. Fig. 5 in ref. [6] shows the SD of 
the improvement in tic frequency between the MNS on and off conditions to be ~81 (total tics per 
condition). The mean difference between conditions was ~41, corresponding to a nearly 30% mean 
decrease in tic frequency. A 25% decrease in tic severity using the YGTSS Total Tic Score (TTS) is 
highly predictive of clinically meaningful clinical improvement [17], and the TTS is highly correlated to 
tic frequency on video recordings [18,19].  

 
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From these data, a sample size of 32 will have 81% power to find a statistically significant result for 
Aim 1 (two tails) assuming the population mean response is the 30% reported by our colleagues in 
Nottingham. This sample size provides 75% power to detect clinically meaningful (−25%) 
improvement (one tailed). 
Estimating screen failures and dropouts at a total rate of 27%, we will plan to enroll up to 44 
participants to arrive at 32 who complete the entire study. 
INCLUSION CRITERIA 
Inclusion criteria for all subjects:  
 Age 15-64 inclusive at initial screening visit 
 Informed consent by adult subject; assent by child and informed consent by guardian 
 Current DSM-5 Tourette’s Disorder or Persistent (Chronic) Tic Disorder  
 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 
Exclusion criteria for all subjects:  
 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 
CONCOMITANT MEDICATIONS 
Required: none 
PROHIBITED MEDICATIONS 
none 
TREATMENTS AND DOSAGE 
Rhythmic 
 10 Hz for 1-minute epochs (to replicate Current Biology report) 

 
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 12 Hz for 5-minute epochs 
Arrhythmic 
 Same number of pulses per minute as in the rhythmic condition, but with a random inter-
pulse interval, as implemented by the Nottingham group in the Current Biology report 
Both 
 Square-wave 200 µs pulses triggered by computer at the threshold for thumb movement 
(expected ~2-15mA) to surface electrodes over the median nerve at the right wrist (conductive 
gel, 30 mm apart center-to-center, anode distal) 
ANALYSIS PLAN/APPROACH/METHODOLOGY 
Outcome measures 
The primary outcome measures are derived from audiovisual recordings (head to elbows), later 
broken into 1-min. or 5-min. clips, then rated in random order by an experienced movement 
disorders physician blind to stimulation conditions (on vs. off, rhythmic vs. arrhythmic) and order 
(rhythmic at first or second visit), who will record tic frequency and rate severity. For the 1-min. MNS 
on/off blocks, severity is rated on a 5-point scale (from the YGTSS severity item) for each occurrence 
of any tic, to replicate the methods of the Nottingham group. For the 5-min. blocks, overall tic 
severity is rated on the same scale once for each 5-min. block. This choice dramatically reduces rater 
time without sacrificing validity. Analysis for each participant can begin after his/her second 
stimulation visit is complete and all other data from that participant is checked. 
Primary Outcome Measures: 
1.  Change in tic frequency compared to when MNS is off 
An expert rater blind to condition and time point assesses the number of tics per minute. A one-tailed 
t test will compare mean tic frequency in the last 40 s of 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. 
[Time Frame: During rhythmic MNS stimulation] 
 
2. Change in tic severity compared to when MNS is 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). A one-tailed t test will compare mean tic severity in the last 40 s of 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. 
[Time Frame: During rhythmic MNS stimulation] 
 
3. Change in tic frequency during rhythmic MNS (vs. arrhythmic MNS) 
An expert rater blind to condition and time point assesses the number of tics per minute. 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), 

 
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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). 
[Time Frame: During rhythmic MNS stimulation] 
 
4. 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). For this analysis, we will 
define tic severity as max{phonic tic intensity score, motor tic intensity score}. 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). 
 [Time Frame: During rhythmic MNS stimulation] 
  
Secondary Outcome Measures: 
5. Change in tic severity after MNS ends 
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. 
[Time Frame: up to 20 minutes after the end of stimulation at each study visit up to 1 month] 
 
6. 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. 
[Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month] 
 
7. CGI-I, investigator 
Clinical Global Impression of Improvement (CGI-I), rated by investigator.  
[Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month] 
 
8. VAS 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. 
[Time Frame: Before MNS begins and at the end of each 5-min. MNS on or off block, at each study visit 
up to 1 month] 
 
9. 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 

 
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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 
[Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month] 
 
10. 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). 
[Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month] 
 
11. Blindedness assessment 
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). 
[Time Frame: 5-25 minutes after the end of stimulation at each study visit up to 1 month]  
 
12. Interest in a portable stimulator 
Participants answer the question, “If you had a portable device (about the size of a deck of cards) that 
delivered stimulation in your daily life like you received either today or at your previous visit, 
would you expect to use it?” 
[Time Frame: Once at the end of the second study visit] 
Data analysis 
Data storage, sharing and management. Phenotypic data will be collected and stored on REDCap 
(redcap.wustl.edu). This data will not contain PHI and will be shared on the Open Science 
Framework. Video recordings will be shared only with explicit optional informed consent. 
Overall statistical approach. To prevent “HARKing” (hypothesizing after results are known) [20], we 
have registered our hypotheses and analysis strategy on OSF.io prior to initiating enrollment. For 
this pilot study, all statistical tests will be reported independently. Aim 1 and Aim 2 test a small 
number of hypotheses, and Aim 3 results, which are primarily hypothesis-generating, will be 
presented with a warning about multiplicity of tests. 
Aim 1 (replicating the Nottingham results). The analysis will replicate that of Study 3 in the Current 
Biology report [6], with blinded ratings of tic frequency and severity based on the last 40 s of each 
60-s MNS on or off block. A one-tailed t test will compare mean tic frequency in on vs. off 1-minute 
stimulation epochs on the rhythmic MNS day. The analysis will be repeated for tic severity. 
Aim 2 (testing whether benefit from rhythmic stimulation exceeds that from the active control, 
arrhythmic stimulation). Change in tic frequency and severity from baseline are compared between 
MNS-on epochs on rhythmic vs. arrhythmic days. 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 

 
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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. The 
primary analysis will focus on the first six 5-minute blocks (i.e., the ones that all participants 
complete). A secondary analysis examines the last 40 s of the four 1-minute blocks in the same way. 
Paired t tests will compare CGI-I ratings between stimulation conditions (rhythmic vs. arrhythmic). 
Aim 2 interpretation: We chose arrhythmic stimulation as the control condition (“placebo”) because it 
did not increase stimulation-frequency EEG power in the sensorimotor cortex. However, we note that 
arrhythmic stimulation may itself possibly confer active benefit, which may produce a non-significant 
result for Aim 2. In that case a different control condition may be required for subsequent study, such 
as sub-motor-threshold stimulation current or a wait list condition. Additionally, this pilot study will 
not address the specificity of the stimulation site—as stimulation of another peripheral nerve may 
prove equally effective—nor the specificity of the 10-12 Hz stimulation frequency. Finally, other 
modifications may provide greater benefit; e.g. bilateral stimulation may be more effective than 
unilateral. All of these possibilities are reasonable goals of future study, but this pilot study focuses 
on the methods used in the published work. 
Aim 3. The duration of benefit analysis will use a repeated measures ANOVA for tic scores from each 
1-minute segment after the end of stimulation. A secondary approach may be to fit the tic scores from 
each participant after the end of each stimulation block to an exponential decay model. The analysis 
of individual characteristics that predict improvement with simulation will use a 2-tailed t test or 
correlation, as appropriate, for each measured demographic and clinical feature. These will include 
age, sex, baseline YGTSS, baseline OCD severity rating, baseline ADHD severity rating, history of 
complex tic(s), history of phonic tic(s), and motor and phonic tic frequency and severity at baseline 
(blinded ratings of the 5-minute block before stimulation on the first study visit). Other outcome 
variables, such as discomfort, adequacy of blinding, and interest in a portable stimulator, will be 
summarized descriptively. 
Additional analysis details. Outliers will be determined at the level of the individual variables before 
the main analyses. If the distribution clearly deviates from a normal distribution on visual inspection 
because of outlying values, after transformation if appropriate, we will use a nonparametric analysis. 
SAFETY MONITORING 
We anticipate no adverse events other than possible mild, transient discomfort related to the 
stimulation.  However, we will report any adverse events to the Institutional Review Board according 
to its regulations, including an annual summary.   
No serious adverse events (SAEs) are expected. The PI will monitor for unanticipated problems, life-
threatening events or deaths. If contrary to expectations any SAE occurs that the investigator 
considers possibly, probably or definitely related to participation in the study, we will confer with the 
IRB before continuing enrollment. 
 
 

 
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Scahill L, Woods DW, Himle MB, Peterson AL, Wilhelm S, Piacentini JC, McNaught K, 
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