Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
Phase: NA
Conditions: Tic Disorders, Tics, Tic, Motor, Tic Disorder, Childhood, Tourette Syndrome, Tourette Syndrome in Children, Tourette Syndrome in Adolescence
Sponsor: University of Minnesota

MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
PROTOCOL COVER PAGE 
Protocol Title
Transcranial Magnetic Stimulation to Augment Behavior 
Therapy for Tics
Principal 
Investigator/Faculty 
Advisor
Name: Christine Conelea, Ph.D., L.P.
Department: Psychiatry and Behavioral Sciences 
Telephone Number: 612-626-6773
Email Address: cconelea@umn.edu 
Student Investigator
Name: N/A
Current Academic Status (Student, Fellow, Resident): N/A 
 
Department: N/A
Telephone Number: N/A
Institutional Email Address: N/A
Scientific 
Assessment
HRPP Scientific Assessment
IND/IDE # (if 
applicable)
G200176
IND/IDE Holder
Christine Conelea, PhD
Investigational Drug 
Services # (if 
applicable)
N/A
Version Number/
Date:
Version 1 – 07/14/2020 
Version 2 – 12/15/2020 
Version 3 – 4/8/2021 
Version 4 – 7/20/2021 
Version 5 – 10/26/2021 
Version 6 – 2/24/2022 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
ANCILLARY REVIEWS 
Which ancillary reviews do I need and when do I need them? 
Refer to HRP-309 for more information about these ancillary reviews.
Select yes 
or no
Does your study…
If yes…
Impact on 
IRB 
☐ Yes 
☒ No 
Include Gillette resources, 
staff or locations
Gillette Scientific review and 
Gillette Research 
Administration approval is 
required.  Contact: 
Required 
prior to 
IRB 
submissio
☐ Yes 
☒ No
Involve Epic, or Fairview 
patients, staff, locations, or 
resources?
The Fairview ancillary review 
will be assigned to your study 
by IRB staff 
Contact: 
Approval 
must be 
received 
prior to 
IRB 
committe
e/ 
designate
d review.   
Consider 
seeking 
approval 
prior to 
IRB 
submissio
n.
☒ Yes 
☐ No
Include evaluation of 
drugs, devices, biologics, 
tobacco, or dietary 
supplements or data 
subject to FDA inspection?
The regulatory ancillary review 
will be assigned to your study 
by IRB staff 
Contact: medreg@umn.edu  
See: https://policy.umn.edu/
☐ Yes 
☐No
Require Scientific 
Review? Not sure? See 
guidance on next page. 
Documentation of scientific 
merit must be provided.   
Contact: hrpp@umn.edu 
☐ Yes 
☒ No
Relate to cancer patients, 
cancer treatments, cancer 
screening/prevention, or 
Complete the CPRC application 
process.  
Contact: ccprc@umn.edu 
☐ Yes 
☒ No
Include the use of 
radiation? 
(x-ray imaging, 
radiopharmaceuticals, 
external beam or 
Complete the AURPC Human 
Use Application and follow 
instructions on the form for 
submission to the AURPC 
committee. 
Approval 
from 
these 
committe
es must 
be 
received 
prior to 
IRB
☒ Yes 
☐ No
Use the Center for 
Magnetic Resonance 
Research (CMRR) as a 
Complete the CMRR pre-IRB 
ancillary review  
Contact: ande2445@umn.edu 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
☐ Yes 
☒ No
Include the use of 
recombinant or synthetic 
nucleic acids, toxins, or 
Complete the IBC application 
via eprotocol.umn.edu 
Contact:
IRB 
approval;  
These 
groups 
each have 
their own 
applicatio
n process. 
☐ Yes 
☒ No
Include the use of human 
fetal tissue, human 
embryos, or embryonic 
Contact OBAO for submission 
instructions and guidance
☒ Yes 
☐ No
Include PHI or are you 
requesting a HIPAA 
If yes, HIPCO will conduct a 
review of this protocol. 
Contact: privacy@umn.edu 
☐ Yes 
☒ No
Use data from the 
Information Exchange 
(IE)?
The Information Exchange 
ancillary review will be 
assigned to your study by IRB 
staff 
Approval 
must be 
received 
prior to 
IRB 
approval. 
These 
groups do 
not have 
a 
separate 
applicatio
n process 
but 
additional 
informati
on from 
the study 
team may 
☐ Yes 
☒ No
Use the Biorepository and 
Laboratory Services to 
collect tissue for research?
The BLS ancillary review will 
be assigned to your study by 
IRB staff. 
☐ Yes 
☒ No
Have a PI or study team 
member with a conflict of 
interest?
The CoI ancillary review will be 
assigned to your study by IRB 
staff 
☒ Yes 
☐ No
Need to be registered on 
clinicaltrials.gov?
If you select “No” in ETHOS, 
the clinicaltrials.gov ancillary 
review will be assigned to your 
study by IRB staff 
Contact: kmmccorm@umn.edu 
☒ Yes 
☐ No
Require registration in 
OnCore?
If you select “No” or “I Don’t 
Know” in ETHOS, the OnCore 
ancillary review will be 
assigned to your study by IRB 
staff 
Does not 
affect 
IRB 
approval. 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
REVISION HISTORY 
Revision #
Version Date
Summary of Changes
Consent Change?
1
12/15/2020
Added emergent unblinding 
procedures
no
2
4/08/2021
Updating screening process, 
randomization stratification 
procedures, monitoring entity, and 
online consent procedures.
Yes
3
7/20/2021
Adding recruitment strategies and 
adverse events monitoring in 
follow-up visits
No
4
10/26/2021
Added recruitment strategies and 
optional accommodations. Updated 
locations for study procedures
Yes
5
2/24/2022
Added recruitment strategies and 
transportation information
No
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
Table of Contents 
1.0 
Objectives 
7 
2.0 
Background 
7 
3.0 
Study Endpoints/Events/Outcomes 
7 
4.0 
Study Intervention(s)/Investigational Agent(s) 
7 
5.0 
Procedures Involved 
7 
6.0 
Data and Specimen Banking 
8 
7.0 
Sharing of Results with Participants 
8 
7.1 
Sharing Results: 
8 
7.2 
Sharing Genetic Results: 
8 
7.2.1 Disclosure of Results: 
8 
8.0 
Study Population 
8 
9.0 
Vulnerable Populations 
8 
10.0 Local Number of Participants 
10 
11.0 Local Recruitment Methods 
10 
12.0 Withdrawal of Participants 
10 
13.0 Risks to Participants 
11 
14.0 Potential Benefits to Participants 
11 
15.0 Statistical Considerations 
11 
16.0 Health Information and Privacy Compliance 
11 
16.1 Select which of the following is applicable to your research: 
11 
17.0 Confidentiality 
13 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
13 
19.0 Provisions to Protect the Privacy Interests of Participants 
13 
20.0 Compensation for Research-Related Injury 
14 
21.0 Consent Process 
14 
22.0 Setting 
14 
23.0 Multi-Site Research 
15 
24.0 Coordinating Center Research 
15 
25.0 Resources Available 
15 
26.0 References 
15 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
ABBREVIATIONS/DEFINITIONS 
CBIT/Comprehensive Behavioral Intervention for Tics 
SMA/ Supplementary Motor Area 
rTMS/TMS/ repetitive Transcranial Magnetic Stimulation 
ADHD/ Attention Deficit Hyperactivity Disorder 
OC/OCD/ Obsessive Compulsive/Disorder 
TST/ Tic Suppression Task 
M1/ Primary Motor Cortex  
CSTC/ Cortico-striatal-thalamo-cortical circuit 
fMRI/MRI/ Functional/Magnetic Resonance Imaging 
MEG/ Magnetoencephalography  
DBS/ Deep Brain Stimulation 
DLS/ Dorsolateral Striatal 
cTBS/ continuous Theta Burst Stimulation  
FT/ Free-to-tic 
CMRR/ Center for Magnetic Resonance Research  
MT/ Motor Threshold 
FEM/ Finite Element Method 
YGTSS/ Yale Global Tic Severity Scale 
CNBD/ Center for Neurobehavioral Development 
NDCT/ National Database for Clinical Trials  
NIMH/ National Institute of Mental Health  
GUID/ Global Unique Identifier 
DUC/ Data Use Certification 
FWA/ Federalwide Assurance 
MINI/ Mini International Neuropsychiatric Interview  
FIND/ Focus in NeuroDevelopment (Network) 
NIBS/ Noninvasive Brain Stimulation Techniques  
tDCS/ transcranial Direct Current Stimulation 
ASD/ Autism Spectrum Disorders  
ASAP/ Adjunctive Services and Attrition Prevention 
RCTs/ Randomized Controlled Trial(s) 
ITT/ Intent-to-treat 
PMT/ Premature Terminators 
MICE/ Multiple Imputation by Chained Equations 
MSI/ Minnesota Supercomputing Institute  
CAN Lab/ Converging Approaches to Neurodevelopment Lab  
CTSI/ Clinical and Translational Science Institute   
MAR/ Missing at Random  
MNAR/ Missing Not At Random  
RSFC/ Resting State fMRI Connectivity  
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
ROI/ Region of Interest  
GLM/ General Linear Model  
LME/ Linear Mixed Effects  
REDCap/ Research Electronic Data Capture  
SAE/ Serious Adverse Events  
PO/ Project Officer  
NNL/ Noninvasive Neuromodulation Laboratory  
MIDB/ Masonic Institute for the Developing Brain 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
1.
Objectives 
1.1. Purpose: The study will examine whether combining Comprehensive 
Behavioral Intervention for Tics (CBIT) with inhibition of the 
supplementary motor area (SMA) using transcranial magnetic stimulation 
(TMS) normalizes activity in the SMA-connected circuits, improves tic 
suppression ability, and enhances CBIT outcomes in young people with tic 
disorder. The study will also examine different TMS dosing strategies. 
2.
Background 
2.1. Significance of Research Question/Purpose:  
Chronic tics are a disabling neuropsychiatric symptom associated with multiple 
child-onset mental disorders. Chronic tics affect 1-3% of youth1 and are 
associated with impaired functioning, emotional and behavioral problems, 
physical pain, diminished quality of life, peer victimization, and a fourfold 
increased risk of suicide compared to the general population.2–4 Chronic tics are 
the primary symptom of Tourette Syndrome and Persistent Motor/Vocal Tic 
Disorders.5 About 80% of those with tics have additional psychiatric disorders, 
most commonly Attention Deficit Hyperactivity Disorder (ADHD) and obsessive 
compulsive (OC) spectrum disorders.1 High co-occurrence is attributed to shared 
dysfunction within cortico-striatal circuits. 
CBIT is a manualized treatment program focused on tic management skills. 
Current American Academy of Neurology practice guidelines recommend CBIT 
as a first-line treatment relative to medications and other therapies.6 Meta-
analyses show comparable effect sizes for CBIT and medication.7 Large 
randomized trials have demonstrated the superiority of CBIT over supportive 
therapy in child8 and adult9 patients. However, in these trials, only 52% of 
children and 38% of adults showed clinically meaningful tic improvement, 
meaning that 50-60% of patients do not benefit from CBIT. 
CBIT success relies on an ability to suppress tics that many youth lack. The 
central aim of CBIT is to enhance voluntary tic suppression. Better tic 
suppression ability drives CBIT improvement10 and predicts lower tic burden over 
the course of illness.11 During the core CBIT procedure, competing response 
training, patients learn to inhibit tics by engaging in a competing motor action. 
However, research shows that many youth lack this fundamental tic suppression 
ability that CBIT aspires to enhance. Tic suppression ability has been assessed in 
our laboratory and others using the Tic Suppression Task (TST), which quantifies 
tics using direct observation methods.12 Data show minimal changes in tic 
frequency when youth are instructed to suppress tics (e.g., reduction from a mean 
tic frequency of 4 tics per minute during “free to tic” baseline to 3 tics per minute 
during attempted suppression13). Under the most ideal suppression context--in 
which immediate reward is given for successful suppression--only 20% of youth 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
can suppress tics to near-zero levels, and another 20% show no detectable tic 
decrease or even tic worsening when attempting suppression.12 Enhancing tic 
suppression ability is likely to enhance the efficacy of CBIT. 
2.2. Preliminary Data: Our preliminary data show that tic suppression ability can 
be enhanced with inhibitory, noninvasive stimulation of supplementary 
motor area (SMA), an approach built upon established knowledge of tic 
neurocircuitry. Tics result from dysfunctional activity in cortico-striatal-
thalamo-cortical circuits (CSTC).14,15  
Tic generation involves the combined effects of excessive activity in 
sensorimotor pathways and reduced activity in cognitive control portions of 
CSTC circuits. SMA is a key CSTC cortical node, and SMA hyperactivity 
and hyperconnectivity is strongly implicated in tics. SMA links contextual 
cues to motor actions and plays a strong role in motor inhibition.16 In 
healthy controls, excitatory stimulation of SMA with TMS produces tic-like 
movements and urges to move.17 Similarly, direct stimulation of SMA with 
subdural electrodes produced urges to move in patients with epilepsy.18 In 
those with tics, there is enhanced functional connectivity between SMA and 
successive nodes of the CSTC sensorimotor circuit.14 SMA activation and 
functional connectivity abnormalities are significantly correlated with tic 
severity and complexity19 and tic premonitory urge severity.20 SMA activity 
is abnormally elevated prior to tic expression14,21,22 and during periods of 
higher tic frequency.22,23 Increased functional connectivity between SMA 
and primary motor cortex (M1; SMA-M1) has been shown in tic patients 
using fMRI22 and MEG.24 SMA shows strong resting state functional 
connectivity with striatal deep brain stimulation (DBS) sites most effective 
for treating tics25 and with dorsolateral striatal (DLS) regions thought to 
normalize with CBIT treatment (i.e., putamen; SMA-DLS).26 One small 
study (n = 8) examined neural correlates of CBIT using a visuospatial 
priming task and found normalization (reduced activation) in putamen 
following CBIT,26 suggesting that CBIT engages striatal regions connected 
to SMA. 
SMA’s extensive connectivity with regions implicated in motor control and 
its role in tic pathology have made it a leading brain target candidate for 
noninvasive brain stimulation (NIBS) trials.27 Repetitive TMS (rTMS) has 
been explored as a tic treatment in small trials,28–31 some of which included 
children.32–34 Early rTMS trials targeting premotor and motor cortex showed 
no effect.30,31 In contrast, inhibitory stimulation of SMA using 1Hz rTMS 
has been associated with reduced tic severity in case reports28 and open label 
trials.32,34,35 Small randomized trials targeting SMA inhibition with 1Hz 
rTMS,36 deep TMS with the HBDL coil,29 and continuous theta burst 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
stimulation (cTBS) did not find group-level clinically meaningful change, 
although an extended dose (total of 6 weeks daily) did improve outcomes 
with 1Hz.36 Importantly, in the only study measuring neural correlates of 
treatment, Wu et al.33 detected significant decreases in activation of SMA 
and functionally connected CSTC nodes (i.e., bilateral M1) after only a 2 
day course of cTBS, leading to continued interest in using TMS to alter tic-
related neural pathology. 
Our recent research suggests rTMS improves tic suppression ability more 
robustly than it reduces baseline tic frequencies. PI Conelea measured acute 
effects of 1 Hz vs. sham rTMS over SMA using the TST (K23MH103617; 
for detail see “Preliminary Data” below) and found that active 1Hz rTMS 
enhances tic suppression ability. Notably, reduction in tic frequency was 
more robust in conditions measuring tic suppression ability compared to a 
“free to tic” baseline. These data suggest that inhibitory stimulation of SMA 
with rTMS may benefit those with tics by enhancing their capacity to 
voluntarily inhibit tics. 
2.3. Existing Literature: Taken together, the existing literature and our 
preliminary data suggest that augmenting CBIT with inhibitory stimulation 
of SMA using TMS may boost tic suppression ability, which in turn may 
increase the efficacy of CBIT. This synergistic approach aligns with 
converging evidence suggesting that combining brain stimulation with 
targeted therapy is a potentially powerful approach for treating 
neuropsychiatric disorders.37 
3.
Study Endpoints/Events/Outcomes 
3.1. Primary Endpoint/Event/Outcome:  
1) Neural target engagement: Within-subject change in resting state fMRI 
connectivity of SMA-mediated brain circuits. 
2) Behavioral target engagement: Within subject change in tic suppression 
ability as measured by the Tic Suppression Task (TST). 
3.2. Secondary Endpoint(s)/Event(s)/Outcome(s):  
1) Two TMS procedures, both intended to inhibit activity in SMA, will be 
compared using data from our safety and feasibility measures. 
2) Between group differences on secondary measures of clinical and neural 
function. 
4.
Study Intervention(s)/Investigational Agent(s) 
4.1. Description: All participants will receive 10 daily sessions of CBIT, a well-
established behavioral treatment that is considered by the American 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
Academy of Neurology to be the first-line intervention for tics.6 
Immediately prior to each CBIT session, participants will undergo TMS 
targeting the SMA. The specific type of TMS procedure will be randomly 
assigned between subjects and be either: 1 Hz repetitive TMS (rTMS), 
continuous theta burst stimulation (cTBS), or sham stimulation. 
4.2. Drug/Device Handling:  
TMS device. Stimulation will be delivered using a Magstim Super Rapid2 
stimulator (Magstim Company Ltd, UK). The device will be used to deliver 
electromagnetic stimulation through a small coil positioned over a targeted 
area on the scalp. The manufacturer's indication for use is to stimulate 
peripheral nerves and the human cortex for diagnostic and research 
purposes.    
We will use a Magstim air-cooled 70mm ﬁgure-eight coil for motor 
threshold determination and active TMS conditions. Sham stimulation will 
use the Magstim sham air-cooled coil, which produces auditory signals 
identical to an active coil but contains a mu-metal shield that diverts the 
majority of the magnetic ﬂux such that a minimal (<3%) magnetic ﬁeld is 
delivered to the cortex. 
The device is installed and set-up at the University of Minnesota  Non-
Invasive Neuromodulation Laboratory (NINL). The device will only be able 
to be administered by trained personnel. The device is located in a locked, 
access controlled room. 
Operation of the TMS device (MAGSTIM Super Rapid 2) will follow the 
procedures outlined in the attached “Operating Manual.” 
4.3. Biosafety: N/A 
 
4.4. Stem Cells: N/A 
4.5. Fetal Tissue: N/A 
5.
Procedures Involved 
5.1. Study Design: The study is a double-blinded 
randomized control trial that will examine whether 
combining Comprehensive Behavioral 
Intervention for Tics (CBIT) with inhibition of the 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
supplementary motor area (SMA) using transcranial magnetic stimulation 
(TMS) normalizes activity in the SMA-connected circuits, improves tic 
suppression ability, and enhances CBIT outcomes in young people with tic 
disorder. We will compare two rTMS procedures, 1 Hz rTMS and 
continuous theta burst stimulation (cTBS), against sham stimulation. Youth 
with chronic tics (n = 60) will complete 10 daily sessions of CBIT plus 
randomly assigned TMS procedure, with fMRI, behavioral, and clinical 
assessments before and after treatment and at 1 and 3 month follow-ups 
(figure 1).  
5.2. Study Procedures: Overall, study procedures include (a) pre-screening for 
eligibility determination, (b) four assessment sessions (pre-treatment, post-
treatment, 1-month and 3-month follow ups), and (c) ten daily sessions of 
CBIT+TMS. Consent and assent will be obtained prior to the start of the 
pre-treatment assessment visit (figure 1).  
●Eligibility Assessment will occur prior to study enrollment. 
Parents/participants who contact study staff expressing interest in 
the study will be given a brief description of study procedures and 
asked to complete a phone or video chat (via Zoom) screen to 
determine preliminary eligibility. This screen is expected to take 25 
minutes. Those potentially eligible will be asked to provide 
documentation of current medications. A signed release of 
information for medical record documents will be requested if 
necessary for eligibility determination.   
o
Optional detailed eligibility assessment: In some cases, it 
is possible that phone screening outcome is unclear but 
could be clarified with an abbreviated version of the pre-
treatment assessment visit focused on the specific 
eligibility question (e.g., whether tics meet minimum 
severity threshold). In these cases, we will conduct a 
focused eligibility assessment via Zoom. Consent/assent 
will occur at this visit. Measures will be selected from the 
list of approved measures for the pre-treatment assessment 
(Table 2, column 1). This assessment is expected to take no 
more than 1 hour. For participants deemed eligible, we will 
carry-forward data when possible and accordingly shorten 
the next assessment visit to reduce participant burden. 
o
Optional accommodations: In order to ease participant 
burden, parent-report and self-report measures can be 
completed outside of the assessment or follow-up visit. All 
surveys must be completed within the 5 days following the 
visit date. 
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
●Study Assessment Measures: Assessment procedures include a 
structured diagnostic interview, a clinician-administered rating 
scale for tic severity, parent-report and self-report measures for tic 
symptoms and other related emotional symptoms, and safety 
screening for MRI and TMS. Specific measures and the timing of 
administration are below in Table 1. 
o
Timing: Consent/assent will be obtained at the first point 
of formal assessment (optional detailed eligibility 
assessment or pre-treatment assessment visit) (Step 2). 
Daily sessions of CBIT+TMS (Step 4) will begin within 10 
calendar days of the pre-treatment assessment. Participants 
will complete 10 CBIT+TMS visits within 13 business 
days. The post-treatment visit will be completed within the 
10 calendar days following the last CBIT+TMS visit. The 
1-month assessment will be completed 4-6 weeks after the 
last CBIT+TMS visit, and the 3-month assessment will be 
completed 12-14 weeks after the last CBIT+TMS visit. 
Table 1. Study measures
 
Steps in Fig 1
Time 
(min)
Steps in ﬂow chart (Figure 1) 
1
2
4
5
6,7 
MEASURE
DETAILS
Phone Screening
Eligibility, TMS safety screen38,39
x
x
 
 
 
20
Medical records
Last doctor visit, current medicaSons, 
relevant/available documents; used for 
eligibility determinaSon
x
 
 
 
 
 
MRI safety screen
Eligibility
x
x
 
 x
5
Demographics
Sample characterisScs
 
x
 
 
 
10
IQ
Eligibility
x
15
MINI 7 KID40 or adult41
Structured diagnosSc interview
 
x
 
 
 
30
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
●MINI 7: The Mini International Neuropsychiatric Interview 
(MINI) is a short, structured diagnostic interview, and is the most 
widely used neuropsychiatric diagnostic assessment tool in the 
world. The MINI is a tool used to conduct neuropsychiatric 
screening, diagnostic interviews, and outcome tracking for the 
most common adult and childhood DSM-5 and ICD-10 psychiatric 
Yale Global Tic Severity Scale, 
YGTSS42
Gold-standard, clinician-administered Sc 
severity scale. Includes symptom checklist of 
speciﬁc Sc types.
 
x
 
x
x
30
Tic Suppression Task12,43
Direct observaSon measure of Sc 
suppression ability
 
x
x
x
x
10
Parent/Adult Tic 
QuesSonnaire44,45
Adult-self or parent-report measure of Sc 
symptoms and severity
 
x
 
x
x
5
Premonitory Urge for Tics 
Scale46,47
Self-report measure of intensity of urges to 
Sc
 
x
 
x
x
5
Child/Adult Behavior 
Checklist48,49
Parent- or adult-self report measuring broad 
emoSonal and behavioral funcSoning
 
x
 
x
x
15
Sheehan Disability Scale50
Self- and parent measure of funcSonal 
impairment
 
x
 
x
x
10
Tic Impact quesSons
Self- and parent-rated measures of how Scs 
impact daily funcSon
x
x
x
5
Behavior RaSng Inventory of 
ExecuSve FuncSon51
Self- and parent-rated measure of 
impairment of execuSve funcSon
 
x
 
x
x
15
Ask Suicide-Screening QuesSons 
(ASQ)
Clinician-administered screen of suicidality
x
x
x
5
TMS Adverse Eﬀects 
QuesSonnaire39
Tracks side eﬀects of TMS
 
 
x
 x
 x
5
Clinical Global Impressions (CGI)
Clinician, paSent, parent-rated global 
measure of illness severity and improvement
x
x
x
2
SSmulaSon context tracking form
TMS operator completed form to track 
behavior and parScipant self-reported 
emoSonal state during rTMS sSmulaSon
 
 
x
 
 
2
Blinding form (parent, staﬀ, and 
child)
Assess belief about whether parScipant got 
acSve or placebo TMS
 
 
 
x
 x
2
Concurrent Treatment Tracking 
Form
Record of all medicaSons and dosages, 
psychotherapy
 
x
x
x
x
5
Client SaSsfacSon 
Quesitonnaire52
Assess paSent saSsfacSon with the 
intervenSon
 
 
 
x
2
MRI
T1 and T2 structural, rs-fMRI, ﬁnger tapping 
task for TMS coil placement
 
x
 
x
 
60
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MEDICAL PROTOCOL (HRP-590)
PROTOCOL TITLE: Transcranial Magnetic Stimulation to Augment Behavior Therapy for Tics
VERSION DATE: 2/24/2022
disorders. The MINI has been validated against the longer 
Structured Clinical Interview for DSM diagnoses (SCID-P) and 
against the longer Composite International Diagnostic Interview 
for ICD-10 (CIDI), and has been used in clinical care and research 
for more than 25 years. A digital version of the MINI 7 by Nview 
is available to researchers in the Department of Psychiatry & 
Behavioral Sciences and will be used. This program allows access 
to the MINI via web browser and stores data in HIPPA-safe Nview 
servers. Participant IDs will be indicated on MINI digital forms. 
●IQ assessment: If subjects have not completed an IQ test within 
the previous 24 months from Step 2, they will complete a brief IQ 
test to determine eligibility for the study using either the Wechsler 
Abbreviated Scale of Intelligence, version 2 (WASI-2) or the 
Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) (15 min). 
●Pregnancy testing: Females who could potentially be pregnant 
will be tested for pregnancy and, if positive, will not be allowed to 
participate. If testing is refused, participation will not be allowed. 
●Tic Suppression Task (TST) procedures: The TST will be our 
primary measure of behavioral target engagement. In this 
paradigm, a participant is seated alone in a room in front of a 
computer capturing a video recording of tic occurrences for later 
coding by independent raters. TST will consist of  two 3-min 
conditions: 1) free-to-tic (FT): youth is instructed to stay seated 
and tic freely, a measure of naturally occurring tic frequency (tics 
per minute) ; 2) suppression: youth is instructed to suppress tics. 
Videos will be coded to establish tic frequencies using a 
computerized behavioral coding program.  
●Neuroimaging procedures. MRI and fMRI data acquisition:A 
Siemens Prisma 3T scanner located at the Center for Magnetic 
Resonance Research (CMRR) will be used for image acquisition. 
To minimize motion artifact, we will immobilize the participant’s 
head with foam wedges that fit snugly between the head and 32-
channel receive only head coil. As needed, we will re-run scans or 
bring back participants for a repeat scan session. We will acquire 
the following data: 3D T1 ME-MPRAGE, 3D T2 SPACE, resting 
fMRI, spin Echo fMRI reverse phase encode scan pair, finger 
tapping task. The Finger Tapping Task will be used for functional 
localization of SMA. This task is used to isolate neural activity in 
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motor planning and execution areas, including SMA, and is a 
highly reliable, well-established fMRI task used for motor 
mapping53 and for TMS targeting of motor cortex and SMA by our 
group and others.33 A whole-brain activation map showing the 
contrast of rest vs. active tapping will be created for each person to 
determine the precise placement of the TMS coil.  
●Randomization: Randomization will occur after pre-treatment 
assessments. Randomization will be stratified on baseline TST 
performance (tic suppressibility below or above 50%) and 
medication status (on vs. off).
●Intervention Protocol: 
CBIT+TMS. TMS will be 
delivered immediately prior to 
the start of CBIT sessions (see 
ﬁgure 2).
●CBIT Protocol will follow the 
published CBIT manual54 tested 
in the large trials that 
established CBIT efﬁcacy in 
children and adults.8,9 
Participants will receive 10 
sessions of CBIT, 1 session per 
day across 10-13 business days. CBIT consists of the following 
components: 1) psychoeducation about tics; 2) functional 
interventions (behavioral strategies to decrease the impact of tic-
exacerbating factors); 3) competing response training; and 4) social 
support to bolster skills use. Session 1 will include 
psychoeducation and creation of the tic hierarchy and sessions 
2-10 will focus on competing response training. Competing 
response practice will be assigned for between-session homework. 
Monitoring CBIT integrity. CBIT sessions will be video recorded 
and a randomly selected 20% of sessions will be reviewed by the 
PI and rated using established CBIT compliance forms to ensure 
protocol adherence.
●TMS protocol: During TMS, a pulsed magnetic field is produced 
by a small coil positioned over a targeted area on the scalp, 
inducing an electric current in the brain that temporarily modulates 
cortical activity. Repetitive TMS (rTMS) paradigms use trains of 
pulses to induce cortical effects that outlast the duration of 
stimulation.55 The direction of the rTMS effect, either facilitation 
or suppression of cortical activity, depends on pulse frequency and 
sequence (i.e., intertrain interval). Research using neuroimaging 
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and electrophysiological recordings has demonstrated that single 
low frequency (1Hz) and continuous bursting frequency 
(continuous theta burst stimulation; cTBS) induce inhibitory 
effects.55–59 TBS and conventional rTMS have comparable effects 
on cortical excitability60,61 and similar safety profiles in pediatric 
samples.62,63 TBS has particular advantages for a pediatric 
population, specifically much shorter stimulation duration (i.e., 2-3 
min for TBS vs. 20-30 min for rTMS) and lower stimulation 
intensity.63 Parameters for the current study are presented below.
o
Motor threshold (MT) determination. Resting MT will be 
deﬁned as the minimum magnetic ﬂux needed to elicit a 
threshold EMG response (≥50 mV in peak-to-peak 
amplitude) in a resting target muscle (abductor pollicis 
brevis) in 5/10 trials using single-pulse TMS administered 
to the contralateral hand area of primary motor cortex. The 
MT procedure will occur during the first CBIT+TMS visit 
and this MT will be used to calculate stimulation intensity 
for all TMS sessions. Stimulation intensity may be adjusted 
to improve tolerability; all such adjustments will be 
reviewed by a study physician and documented.
o
rTMS coil positioning: Individualized using fMRI and 
electric field modeling. TMS effects strongly depend on the 
spatial distribution of the induced electric field in the 
brain.64 TMS targeting will be based on individual-level 
identification of the optimized coil location and orientation 
that induces the strongest electric field within SMA that 
show the highest parametric fMRI activation during the 
bilateral finger tapping task. This approach accounts for 
individual differences in physiology, which are prominent 
in developmental samples. We will create individual finite 
element method (FEM) models for each participant using 
the computer program SimNIBS (Danish Research Center 
for Magnetic Resonance, Copenhagen, Denmark and the 
Technical University of Denmark (Kgs Lyngby, Denmark) 
and participant anatomical MRIs, following procedures 
established by Co-I Dr. Opitz.65–67 Coil placement. The coil 
placement and orientation will be based on the individual 
models and continually monitored using a stereotaxic 
neuronavigation system (BrainSight 2.3.5, Rogue Research, 
Montreal, Quebec, Canada) running on an Intel-based 
Macintosh computer (Apple, Inc, Cupertino, CA). This 
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system permits targeting of individual cortical locations 
using individual structural and functional MRI.
●TMS administration. TMS parameters are as follows:
●
Pulse frequency: 1 Hz, cTBS, or sham (randomized 
between subjects) 
●
Pulse sequence: 
o
1 Hz: single train of 2000 pulses at 110% resting 
motor threshold (33 min duration) 
o
cTBS: bursts of 3 pulses at 30 Hz repeated every 
200ms (5 Hz burst frequency), single uninterrupted 
40 sec train, 600 total pulses at 90% resting motor 
threshold (40 sec duration)  
o
Sham: to enhance blinding, half of sham 
participants will be exposed to the 1 Hz sequence 
and half will be exposed to the cTBS sequence 
o
Number of sessions: 10 day sessions, delivered 
daily on weekdays   
o
Immediately after the stimulation ends, the 
participant will be transitioned to a private room for 
the CBIT session. The TMS Adverse Effects 
Questionnaire39 will be completed by the 
participant and TMS operator at the end of each 
study visit. 
●
rTMS sessions will be video recorded to later be coded for 
tic occurrences. 
●Blinding procedures will be implemented to control for 
expectancy effects related to TMS stimulation. Persons who will 
be blind to TMS status are: participants; parents (if applicable); 
study staff administering clinical assessments, coding TST videos, 
delivering CBIT therapy, and collecting the MRI data; and all 
study investigators except Drs. Fiecas and Chen. Unblinded 
personnel will be Dr. Fiecas, the study statistician and person 
responsible for randomization scheme oversight; Dr. Chen, TMS 
operator supervisor; and the TMS operator. Staff who administer 
clinical rating scales and code TST videos will not be present for a 
given participant’s CBIT+TMS visits to also ensure blinding to 
overall therapy progress. Staff will be trained and supervised on 
assessment scales by Dr. Jacob, who will audit YGTSS 
administrations for inter-rater reliability. Staff will be trained in 
TST coding by Dr. Conelea, who will code a set of video clips to 
monitor inter-rater reliability. For each of these measures (YGTSS 
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and TST), the supervisor will audit 100% of the first ⅓ of the 
initial visits, 50% of the second ⅓ of participants, and 20% of the 
third ⅓ of the participants for inter-rater reliability. Forms 
assessing blinding adequacy will be given to participants, parents, 
and blinded staff who conduct CBIT sessions and assessments 
visits at post-treatment.
●Emergent Unblinding Procedure: Unblinding of TMS status will 
occur in situations where staff deem this necessary for participant 
safety, to address a technical issue related to the TMS device, or 
another unforeseen situation in which TMS status is critical for 
study conduct. Unblinding will be limited to those individuals 
deemed most critical for addressing the inciting situation. 
Independent Evaluators (i.e., staff responsible for conducting pre-, 
post-, and follow-up assessments with participants) will not be 
intentionally unblinded to ensure that clinical functioning can be 
tracked by a staff member who is otherwise unfamiliar with the 
course of treatment.
●Remote options and COVID-19 related protocol 
considerations: The nature of the MRI and the TMS procedures 
requires that they be completed in-person. We will adhere to all 
COVID-19 related safety protocols and procedures for the facilities 
in which this equipment is located (NNL, CMRR), as well as our 
medical school approved laboratory Sunrise Plan. The consent/
assent and assessment procedures will be completed remotely via 
Zoom and REDCap if necessary due to COVID-19 social 
distancing precautions or optionally if preferred by participants 
(once social distancing is relaxed). Participants will complete 
CBIT sessions in a private research visit room in the Center for 
Neurobehavioral Development (CNBD) or the NNL. If needed for 
COVID-19 social distancing, the participant will interact with the 
CBIT therapist over Zoom to enable physical separation from the 
therapist. We will follow all University and facility protocols and 
recommendations for reducing COVID-19 risk in accordance with 
our CAN Lab approved Sunrise plans. 
5.3.
Study Duration: The total duration of the study for an individual 
participant will be up to 20 weeks (~4.5 months). The pre-and post treatment 
visits will take approximately 2.5-3.5 hours. Participants will have the option of 
splitting these into two separate visits within a week of each other, such that the 
MRI can be completed in a different visit than the rest of the assessment. The 1-
month and 3-month follow-up assessments will take approximately 1.5 hours. 
CBIT+TMS visits will be approximately 1.5 hours. Enrollment of participants is 
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anticipated to take 3 years. Completion of all study procedures and data analyses 
are anticipated to take an additional 2 years after the final participant completes 
the study procedures. 
5.4. Use of radiation: N/A 
5.5. Use of Center for Magnetic Resonance Research: All MRI data will be 
acquired at the CMRR. 
6.
Data and Specimen Banking 
6.1.
Storage and Access: 
●UMN: Questionnaire and video information will be stored on Box 
and will only be accessible to researchers. Research staff will 
access and analyze video records from AHC secured computers. 
MRI data will be stored and processed at CMRR. We will also 
store and process MRI and other data in the HIPPA compliant 
environment at MSI once that space is available.
●National Database for Clinical Trials (NDCT) related to Mental 
Illness: Per requirements of NIMH, the study funder, we will 
submit de-identiﬁed data to the NDCT.
6.2.
 Data: 
●UMN: All psychometric and diagnostic data collected via 
questionnaire will be de-identified and stored in Box and the AHC 
server. Digital video data will not be altered and will be held in 
Box and secure AHC servers. MRI data will be stripped of file 
information containing PHI.
●NDCT: We will upload raw de-identiﬁed data twice yearly and all 
other de-identiﬁed data at the time of publication or the end of the 
grant. We will ensure proper information is gathered to generate a 
global unique identiﬁer (GUID) for each participant. Data will be 
de-identiﬁed and include de-identiﬁed questionnaire information 
and quantitative output of video-based measures (i.e., tic frequency 
numbers from the TST, not the actual video). 
6.3.
Release/Sharing: 
●Identiﬁable videographic data or MRI data: Releasing identifiable 
videographic and/or MRI data would be done through a rigorous 
approval system: Data resulting from videos and MRIs acquired 
during the proposed project may be shared. Qualified researchers 
can request access to shared data through the PI. Researchers can 
view summary-level data, or can request access to query and 
download subject-level data. Researchers who would like to access 
shared data must complete a Data Use Certification (DUC) form 
and submit it for review by the study team. There are three criteria 
researchers must meet to be eligible to request access: (1) the 
researcher must have a research-related need to access the data, (2) 
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the researcher must be associated with an NIH-recognized research 
institution, defined as an institution registered in the NIH 
electronic research administration system (eRA Commons), and (3) 
the researcher’s institution must have an active Federalwide 
Assurance (FWA) and institutional IRB approval. Potential 
researchers must contract to destroy videographic and MRI data 
within 90 days of analysis, and provide a signed and witnessed 
Certificate of destruction. Researchers would be asked to cite the 
data source (University of Minnesota Psychiatry and applicable 
funding sources) in any published data resulting from the study.
7.
Sharing of Results with Participants 
7.1. Sharing Results: Participants will have the option to receive a written 
psychiatric diagnostic assessment report based only on clinically-validated 
questionnaires collected at the pre-assessment that can be used to inform 
care elsewhere. The report will be given directly to the parent or adult 
participant and will list any clinically significant diagnostic findings, such as 
positive diagnoses identified on the MINI. Minors will be informed of this. 
Participants will not be given individual feedback about other measures (i.e., 
TST, MRI) or clinical outcomes at post-treatment or follow-up; however, if 
participants/parents express interest in obtaining referrals for clinical care 
we will provide this assistance. Participants will be informed that overall 
study results will be posted on clinicaltrials.gov at the conclusion of the 
study. 
7.2. Sharing Genetic Results: N/A
7.2.3 Future analysis of genotypes: N/A 
8.
Study Population 
8.1. Inclusion Criteria:  
●Age 12-21 years at time of enrollment. 
●Current chronic motor and/or vocal tics, defined as tics for at least 
1 year without a tic-free period of more than 3 consecutive months. 
Tics must not be due to a medical condition or the direct 
physiological effects of a substance.  
●At least moderate tic severity, defined as a Yale Global Tic 
Severity Scale total score ≥14 (≥9 for those with motor or vocal 
tics only). 
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●Full scale IQ greater than 70. 
●English fluency to ensure comprehension of study measures and 
instructions.  
●Right-handed 
To increase external validity of findings, we will include participants 
taking psychotropic medications that have been stable for 6 weeks 
and expect to remain stable for the approximately 3-week 
intervention protocol (with the exception of those taking neuroleptic/
antipsychotic medications). Those who previously received tic-
specific therapy will be included if they meet the tic severity 
criterion. Youth receiving other forms of psychotherapy will be 
included provided these treatments are not focused on tics. All 
concurrent treatments will be monitored during the study period. 
8.2.
Exclusion Criteria:  
●Medical conditions contraindicated or associated with altered TMS 
risk profile, including history of intracranial pathology, epilepsy or 
seizure disorders, traumatic brain injury, brain tumor, stroke, 
implanted medical devices or metallic objects in the head, current 
pregnancy or girls of childbearing age not using effective 
contraception, or any other medical condition deemed serious or 
contraindicated by a study physician (Dr. Jacob or Dr. Lim).  
●Inability to undergo MRI. 
●Left handedness. 
●Active suicidality.  
●Previous diagnosis of psychosis or cognitive disability.  
●Substance abuse or dependence within the past year.  
●Concurrent psychotherapy focused on tics. 
●Neuroleptic/antipsychotic medications.  
●Taking a medication that has not reached stability criterion (same 
medication and dose for 6 weeks with no planned changes over the 
intervention period) 
8.3. Screening: A phonecall or secure video chat screening prior to study 
participation will be used to screen for inclusion/exclusion criteria. 
Exclusion criteria will be more thoroughly assessed during the pre-treatment 
assessment and by examining medical record documents. Medical history 
will be reviewed prior to rTMS administration using information gathered 
from participant/parent screening, which includes the Screening 
Questionnaire for rTMS Candidates questionnaire, and medical records 
obtained. If any potential exclusion criteria are identiﬁed where the 
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investigators judge more information is required for assessment, we will 
request relevant and available notes, lab studies, or talk to the participant’s 
physician directly. Participants identiﬁed to meet exclusion criteria 
following the pre-treatment assessment will be discontinued from 
participation and will not complete subsequent study procedures or visits 
(i.e., MRI, CBIT+TMS visits). 
9.
Vulnerable Populations 
9.1. Vulnerable Populations:  
Population / Group
Identify whether any of the 
following populations will be 
targeted, included (not necessarily 
targeted) or excluded from 
participation in the study. 
Children
Targeted Population
Pregnant women/fetuses/neonates
Excluded from Participation
Prisoners
Excluded from Participation
Adults lacking capacity to consent 
and/or adults with diminished 
capacity to consent, including, but 
not limited to, those with acute 
medical conditions, psychiatric 
disorders, neurologic disorders, 
developmental disorders, and 
behavioral disorders
Excluded from Participation 
Non-English speakers
Excluded from Participation
Those unable to read (illiterate)
Excluded from Participation
Employees of the researcher
Excluded from Participation
Students of the researcher
Excluded from Participation
Undervalued or disenfranchised 
social group
Included/Allowed to participate
Active members of the military 
(service members), DoD personnel 
(including civilian employees)
Included/Allowed to participate
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9.2. Additional Safeguards:  
●Children: The proposed study necessitates the inclusion of children 
because it focuses on a childhood-onset neurodevelopmental 
disorder. Tics begin in childhood and are most often studied and 
treated in children. The age period included in this study captures 
the period in which tics are typically at greatest severity, and it 
represents the typical age range used in existing studies on tic 
suppression and in TMS research focused on pediatric tic 
disorders. During adulthood, tics diminish for some impacted 
individuals, thereby making it less relevant to study tic treatments 
using adult-only samples. Currently, the first-line treatment for tics 
is CBIT, which all participants will receive. The risks associated 
with TMS are comparable to those posed by available medications 
for tics (https://n.neurology.org/content/92/19/896). Consent/assent 
procedures (described in 21 below) will ensure the parent and child 
Individual or group that is 
approached for participation in 
research during a stressful situation 
such as emergency room setting, 
childbirth (labor), etc.
Excluded from Participation
Individual or group that is 
disadvantaged in the distribution of 
social goods and services such as 
income, housing, or healthcare.
Included/Allowed to participate
Individual or group with a serious 
health condition for which there are 
no satisfactory standard treatments.
Included/Allowed to participate
Individual or group with a fear of 
negative consequences for not 
participating in the research (e.g. 
institutionalization, deportation, 
disclosure of stigmatizing behavior).
Excluded from Participation
Any other circumstance/dynamic 
that could increase vulnerability to 
coercion or exploitation that might 
influence consent to research or 
decision to continue in research.
Excluded from Participation
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are fully informed of study procedures, risks, and benefits, and that 
the child is in agreement with participation and understands he/she 
is able to decline participation or withdraw without penalty. 
Procedures for minimizing risk are described below.  
●Adult capacity to consent: Adult participants may be individuals 
with psychiatric or neurological conditions. We will assess 
capacity to consent by administering the MacCat-CR (MacArthur 
Competence Assessment Tool for Clinical Research); only those 
who pass the quiz (score at least 70%) will be deemed eligible to 
consent.  
●Individual or group with a serious health condition for which there 
are no satisfactory standard treatments: It is possible that some 
participants will have tics that have not responded to currently 
available standard treatments. As this is a clinical trial aimed at 
testing a possible new option for individuals with tics, we will not 
exclude those who have serious tics and otherwise meet study 
eligibility criteria. Participants will be informed of the 
experimental nature of the TMS and the possibility that they may 
be randomly assigned to sham TMS. 
●Other vulnerable categories: Our recruitment efforts will not 
specifically target individuals who are disenfranchised or 
disadvantaged or those in the military, but we will not exclude 
these individuals from participation. 
10.
Local Number of Participants 
10.1. Local Number of Participants to be Consented: We plan to enroll 60 youth 
(ages 12-21 years) with chronic tics. Chronic tics have a known male 
preponderance, so we anticipate recruiting three times as many male than 
female participants. 
11.
Local Recruitment Methods 
11.1. Recruitment Process:  
●
Flyers will be dispersed at the Department of Psychiatry and Behavioral 
Sciences, Center for NeuroBehavioral Development (CNBD), local 
mental health organizations, public physical and digital spaces (e.g. 
libraries, coffee shops, Minneapolis Reddit), community events, 
pediatric care facilities, for parents/adults to access and learn more about 
participation.  
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●
Local physicians and allied professions likely to encounter youth with 
tics (e.g., psychologists, counselors, pediatricians, neurologists) will be 
sent an informational letter describing the study. 
●
Departmental websites will host information regarding the study and 
inclusion and exclusion criteria for participation. Potential participants 
will have the option of sharing contact information with us via a link to 
the attached “REDCap Recruitment Contact Survey.” We will also post 
this information on the Research page of the Tourette Association of 
America. NAMI MN and other community groups we partner with will 
receive IRB approved language for online posting. 
●
The CAN Lab will utilize a social media Facebook page, Twitter 
account, TikTok account, Nextdoor account, and website to create an 
informative space about this research opportunity.  
●
The PI and study staff will conduct informational presentations about tic 
disorders for interested parties in the community (e.g., local mental 
health organizations, healthcare practice groups) in person or via 
webinars. For webinars, we will share information about the webinar 
and how to register publicly via CAN Lab social media and web pages. 
Registration will include the attached “Recruitment CAN Lab 
Permission to Contact” form. These presentations will be largely 
educational (e.g., what are tics, what the existing treatment guidelines 
are).  Brief information about study activities, inclusion/exclusion 
criteria, and study team contact information will be shared at the end of 
these presentations.   
●
Potential participants may also find information about this study through 
the Focus In NeuroDevelopment (FIND) network.  
●
This study will be listed at ResearchMatch.org. ResearchMatch is an 
electronic volunteer recruitment registry that allows people from 
anywhere in the country to self-register and express an interest in being 
prospectively considered for participation in research studies. This 
registry provides information about those volunteers to researchers who 
are looking for people to participate in studies, while protecting the 
privacy of the volunteers. 
●
We plan on utilizing MyChart to reach out to potential participants 
within the Fairview system. Those who may be eligible to participate in 
the study will be sent a MyChart message that provides a brief 
description of the study and its procedures as well as the contact 
information for our team so the individual can reach out to us if 
interested. A copy of the MyChart message that we plan to send to 
potentially eligible participants are attached in ETHOS. 
●
We will distribute IRB approved digital flyers and a link to the attached 
“REDCap Recruitment Contact Survey” via targeted/paid advertising on 
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digital platforms including Facebook, Instagram, Peach Jar (a 
communication website between schools and parents). 
●
We will work with clinicians at M Health Fairview clinics who will 
invite us to speak with their patients potentially interested in the study 
who have not opted out of research participation. Clinicians will 
introduce the research and give a warm hand-off to a member of the 
study team either in-person or virtually. Virtual platforms will include 
AmWell, Doxy, and Zoom. 
11.2. Identification of Potential Participants: Potential participants who self-
identify in response to recruitment materials/activities and contact the 
research team will be screened for eligibility. Potential participants 
identified through the FIND Network and ResearchMatch will be contacted 
by a member of the study team. 
11.3. Recruitment Materials: Recruitment materials include ﬂyers, online posting, 
contact information surveys, and letters sent to health care providers who 
are likely to work with youth who have tics. Copies of these materials are 
attached in ETHOS. Finally, social media accounts under the “CAN Lab” 
will be maintained for this study. A coordinating website “CAN Lab” will 
also be used to delineate participation information. The website and 
Facebook page will also provide study team contact information and a link 
to the “REDCap Recruitment Contact Survey.” The website and Facebook 
page will be compliant with HIPAA. No identifying information will be 
collected from these sources. Potential participants will be asked to directly 
contact the study team via phone or email or to complete the “REDCap 
Recruitment Contact Survey” for additional information and to learn more 
about study criteria. Registration for informational webinars will include the  
“Recruitment CAN Lab Permission to Contact” questions. The CAN Lab 
will use the University of Minnesota email: canlab@umn.edu for all email 
correspondence. 
11.4. Payment:  
●
Participants will receive up to $350 for completing study tasks. 
Participants will receive $30 for pre-treatment assessments, $50 per MRI 
scan (for a total of 2 scans), $10 per day for 10 days for treatment (per 
session), $30 for post-treatment assessment, $40 for 1 month follow-up, 
and $50 for 3 month follow-up. 
●
Compensation will be provided at the end of each visit or in a bulk sum 
at the participant’s request in the form of a GreenPhire ClinCard credit 
card. 
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12.
Withdrawal of Participants 
12.1. Withdrawal Circumstances: Anticipated circumstances under which 
participants will be withdrawn from the research without their consent 
include: 1) the participant does not/no longer meets inclusion/exclusion 
criteria; 2) study investigators decide that the participant has an emotional, 
physical, or behavioral reaction that poses a safety concern or interferes with 
data collection (e.g., poor compliance with instructions, too much anxiety to 
comfortably proceed with a task); 3) signiﬁcantly deteriorating clinical 
course (e.g., emergence of acute suicidality); 4) signiﬁcant adverse reaction 
to TMS, assessed using a TMS Symptom Rating Questionnaire daily; or 5) 
serious physical illness. Participants will be free to decide to withdraw at 
any time for any reason.  
12.2. Withdrawal Procedures: Study withdrawals will be documented. When safe 
and feasible, participants who are withdrawn or who decide to terminate 
participation prematurely (“drop out”) will be encouraged to return for a last 
assessment. This last assessment will consist of measures in the follow-up 
assessments (i.e., clinical measures only and not the MRI). We will make an 
attempt to provide participants with appropriate care referrals in the event of 
any withdrawals or drop-outs. 
12.3. Termination Procedures: Individual participants will be considered to have 
completed study procedures after the 3-month follow-up assessment (or 
earlier as a result of drop-out or investigator-initiated withdrawal). The 
entire study will be complete after analysis of all identiﬁable data is 
complete. After termination of the project, only de-identiﬁed data will be 
used for analysis. 
13.
Risks to Participants 
13.1. Foreseeable Risks:  
●General Potential Risk: The participant and their parent(s), in the 
case of a child participant, may feel coerced to participate. Every 
effort will be made to emphasize that participation in the study is 
voluntary. To address the potential risk of feeling coerced, standard 
procedures for obtaining informed consent will be followed. 
Specifically, all participants will be reminded that their 
participation is voluntary and that refusing to participate or 
withdrawing from the project at any time will not result in any 
negative consequences for the participant or his/her family. In 
addition, adult participants and child participants and their parents 
will be fully informed of study procedures and potential risks and 
benefits at the start of the study. It is possible that some children 
may feel coerced into participation. In an effort to guard against 
this potential for coercion, children will be reminded that there will 
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be no negative consequences for declining to participate or to 
allow use of data (i.e., no one will be angry with the child). If any 
participants are also receiving clinical care at UMN, any 
discussions about participation will be conducted with a study staff 
member who is not part of their clinical team. This includes initial 
assessment of interest in the study, consent process, managing 
concerns, or discussing a potential study drop. We will also 
provide families with contact information for the UMN Human 
Research Protection Program (HRPP) and Dr. Conelea and 
welcome them to contact either or both to discuss any concerns 
they may have.We will also engage the participant by creating a 
pleasant, positive atmosphere, including breaks as necessary to 
minimize boredom, frustration, and fatigue.  
●CBIT: CBIT has been tested in two large scale randomized trials, 
and there are no known risks associated with CBIT.10,68 
●Clinical assessment: Assessment instruments and clinician-
administered interviews are consistent with those typically used in 
research and clinical practices with this population. The youth and/
or their parent(s) may experience emotional distress in being asked 
to provide information of a more sensitive nature. To address 
potential emotional distress experienced by participants from 
completing the assessments, questions will be presented in a 
supportive manner and participants will be assured that they may 
refuse to answer/participate in part or all of the questions/
procedures. Participants will also be provided with multiple 
opportunities to take breaks. In addition, a clinical team consisting 
of licensed providers, Drs. Conelea, Jacob, and Lim, will be 
readily available. If participant suicidality or homicidality is 
reported during the course of the study, Dr. Conelea (or Drs. Jacob 
or Lim as back-up coverage) will follow standard clinical 
procedures to assess the severity and the suicidality and/or 
homicidality. As needed, participants/parents will be provided with 
appropriate referrals.  
●MRI: There is some inherent risk with MRI, especially in regard 
to metal implants. There is risk of discomfort associated with loud 
noises and the small space available in the scanner. Participants 
will undergo a thorough screen to determine individual eligibility 
for the MRI. Prior to receiving an MRI, participants will undergo a 
screening process to determine MRI eligibility. Additionally, all 
participants will be asked to change into scrubs per CMRR policy 
in order to ensure they have no metal on their person at the time of 
the scan. All participants and their parents, in the case of children, 
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will be fully informed of the potential risk. Ear protection will be 
provided to the participants for protection from the loud knocking 
sounds produced by the MRI machine. Only trained and qualified 
MRI technicians will be performing the MRI tests. In addition, 
although unlikely, if the investigators notice an incidental finding 
on an MRI the parent or adult participant will be notified and given 
a recommendation to consult with their primary care physician. 
Scans will not be reviewed for any abnormalities. Subjects with 
self-reported anxiety associated with MRI procedures will not be 
included in the study. 
●TMS, general: Noninvasive brain stimulation techniques (NIBS) 
have been used with thousands of children and adults. Three major 
review papers have specifically addressed the safety of TMS, 
rTMS, and transcranial direct current stimulation (tDCS) in 
pediatric populations.76,139,140 Collectively, these papers indicate that 
NIBS has been used in healthy children and the following pediatric 
clinical conditions: tic disorders/Tourette Syndrome, stroke, 
attention deficit hyperactivity disorder (ADHD), major depressive 
disorder, autism spectrum disorders (ASD), multiple sclerosis, 
epilepsy and seizure disorders, malnourishment, Rett Syndrome, 
Cockayne’s Syndrome, spasticity, schizophrenia/auditory 
hallucinations, language disorders, and dystonia. TMS is used as 
both a testing tool and a treatment. As a testing tool, the majority 
of children tolerate TMS well: in one study, 85% of the sample (n 
= 34 children) said they would do TMS again, and they ranked 
TMS as being more enjoyable than going on a long car ride, going 
to the dentist, or getting a shot at the doctor’s.141 No person 
experienced any change in their neurological examination, hearing, 
or any other tests that were performed, and all symptoms 
disappeared by the next day. Risks associated with rTMS are rare 
but should be recognized and prevented with appropriate 
precautions. Serious adverse risks include the induction of a 
seizure. Mild adverse effects include fainting, headache, dental 
pain, nausea, and other changes in memory, mood, and hearing. 
The overall occurrence of a mild adverse event is 5% in sham and 
real rTMS sessions combined.142 rTMS delivery may also interfere 
with implanted devices. rTMS is not appropriate for persons with 
medical devices such as deep brain stimulators, pacemakers and 
medication pumps. 
Participants will undergo thorough screening to determine 
individual eligibility for TMS. Very extensive exclusion criteria are 
applied for participation in this study to ensure that enrolled 
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participants are not at any excess risk for medical adverse events. 
The only absolute contraindication to TMS is the presence of 
metal hardware in close contact with the discharging coil. Certain 
medications may increase the risk of seizure with TMS. Potential 
participants will be assessed for use of such medications. 
Individuals will be excluded from participation in the event they 
are currently taking any agents in this group. In addition, medical 
records reviewed by a study physician (Drs. Jacob or Lim) and 
completion of the Screening Questionnaire for TMS Candidates, 
developed by the Safety of TMS Consensus Group69 will be 
administered and reviewed for TMS eligibility. An appropriately 
trained staff member will administer TMS and be present 
throughout TMS sessions to observe the participants. A standard 
questionnaire assessing side effects specific to TMS (TMS Adverse 
Effects Questionnaire39) will be completed at every TMS visit to 
identify and address any treatment-emergent adverse effects. The 
staff member delivering TMS will have updated first responder 
training, CPR training, and training in seizure management. The 
TMS administrator will immediately call 911 if serious adverse 
events occur. 
●
TMS, seizure risk and management: rTMS is FDA-approved 
as a noninvasive therapy for medication-refractory depression 
and obsessive compulsive disorder, where it is typically 
delivered at high frequency (10Hz). Its most significant potential 
risk is inadvertent seizure induction. Seizures have been 
associated with rTMS treatment in clinical research, particularly 
in the early trials (late 1980s - 1990s). Eight people (less than 
0.8% of the total) had seizures associated with rTMS treatment 
in clinical trials conducted before safety guidelines were 
established. These guidelines, which specified safe ranges for 
rTMS parameters, have more recently been affirmed and further 
detailed in light of much more clinical and research experience 
with the method.141 Seizures in animals and in adult humans have 
occurred only when the TMS magnet was used for impulses at 
sustained high-frequency (10Hz or greater), when the person had 
a pre-existing brain condition, or when the person was 
concurrently using a substance or medication. Based on the 
frequency of rTMS-related seizures reported in the literature, 
Rossi et al.38 determined that rTMS is associated with a less than 
1% risk of seizure induction for the general population and a 
1.4% risk in patients with epilepsy. There are three documented 
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cases of TMS-induced seizure in youth, all using high-frequency 
rTMS. In a 2011 case report,70 a 15 year old female with 
depression underwent high-frequency rTMS of 10Hz. The 
patient was taking a medication known to lower seizure 
threshold, sertraline 100mg. Follow-up of this patient over 4 
months indicated no subsequent seizures or other complications. 
In a 2013 case report,71 a 16 year old female with major 
depressive disorder underwent 10Hz rTMS. The patient was 
taking sertraline 150mg, olanzapine 75mg, and hydroxyzine 
25mg. The seizure occurred on the 12th day of rTMS. The patient 
recovered completely without sequelae. Additionally, the 
examination revealed a high level of blood alcohol concentration 
(0.20%) at the time of the seizure, leading to a clinical diagnosis 
of TMS-related seizure complicated by alcohol use. A case study 
from a laboratory at UMN reported a seizure in an adolescent on 
the 8th day of rTMS treatment for depression using 18Hz 
stimulation with an H-1 coil.72 No further seizures were reported 
through 6-month follow-up. Note that high-frequency, low-
frequency, and theta burst rTMS have been used in youth and 
adults with tics, ASD, and OCD and no seizures have been 
reported in these populations. Theta burst stimulation has 
demonstrated similar risk/safety profiles as other rTMS protocols 
in pediatric populations.63,73,74 
Management of potential seizures. As noted above, while seizure 
is very unlikely with the rTMS parameters and participant 
selection methods to be used, routine management of seizure will 
be carried out if needed. rTMS will be administered in a research 
area by trained personnel. TMS will be terminated immediately. 
The participant will be assisted in controlled reclining that 
prevents impact. Airway, breathing and circulation will be 
assessed. Unless tonic-clonic seizure activity occurs, the 
participant will be turned on one side to help clear the airway and 
avoid aspiration. Participants who convulse will be turned to one 
side as soon as movement ceases, and maintained in that position 
until recovery of awareness. Delayed recovery of normal 
consciousness beyond 30 seconds following a seizure will 
mandate a further medical and neurological evaluation. Note that 
initial measures for suspected seizures and syncope (see below) 
are identical. 
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●
TMS, uncomfortable sensations and pain: The most commonly 
reported side effects of TMS are headache (lasting up to a few 
hours) and pain or discomfort at the treatment site on the scalp. A 
large-scale study on the safety of rTMS in depression found that 
headaches or scalp discomfort were typically mild or moderate. 
Headaches and neck pain are believed to be due to muscle tension. 
rTMS will be terminated if it produces discomfort which is not 
tolerated by participants. If a bothersome headache persists for 
several hours (which we think is unlikely), participants may choose 
to use an OTC pain reliever such as acetaminophen or ibuprofen 
for pain. 
●
TMS, hearing: While temporary hearing loss is a theoretical risk 
of TMS, available data indicate TMS has no demonstrable effect 
on hearing. All participants will wear ear protection (34 NRR 
earplugs) during TMS. In order to inform and protect participants, 
we will take the following precautions: 1) Inform participants of 
the risk of permanent hearing loss, if an earplug should loosen, 
become detached, or fall out; 2) Inform participants that they 
should immediately report to the research staff any loosening or 
detachment of an earplug during TMS; 3) Immediately stop TMS 
to replace earplugs if the participants reports or if a staff member 
observes that an earplug has loosened or has fallen out; 4) Ask the 
participant if they are experiencing any hearing problems 
following every session of TMS or if the parent has noticed any 
hearing problems since the last TMS session; 5) Prompt referral for 
auditory assessment of all individuals who complain of hearing 
loss, tinnitus, or aural fullness following completion of TMS. 
●
TMS, syncope: Vasodepressor syncope (fainting) is a common 
reaction to anxiety and psycho-physical discomfort. It is thought to 
occur more often than epileptic seizures during TMS, as with many 
other medical procedures. Participants will be monitored for 
feeling any signs or symptoms of a pending syncopal event (i.e., 
feeling dizzy or lightheaded). TMS will immediately be stopped, 
and the subject will be assisted. See Management of potential 
seizures, above). 
●
Potential delay of non-experimental treatment. All participants 
will receive CBIT, a well-established treatment that is considered 
by the American Academy of Neurology to be the first-line 
intervention for tics.6 Because we exclude those with planned 
medication changes, participation in this study could cause a delay 
in effective pharmacological treatment with demonstrated efficacy. 
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●
Confidentiality. Personal information collected during study 
procedures could result in social and/or psychological risk if 
released inappropriately. However, this is an extremely unlikely 
event considering all of the protective measures and precautions 
taken to keep data secure (see below). Researchers will be 
carefully trained about the importance of confidentiality and 
required to undergo HIPAA training.  
●
Side Effects/Adverse Events. Adverse effects will be monitored 
very closely throughout the study, through structured 
assessments and clinical interactions. At all visits involving 
TMS, the TMS operator will conduct a general inquiry regarding 
any health complaints, recent illness or injury, and need for 
medical consultation since the previous visit. Reported 
complaints will be coded on a standardized Adverse Events 
tracking form. Although unlikely, based on the nature of this 
study, the rater and  study physician (Drs. Jacob and Lim) will 
rate whether the adverse event is related to the study or not. Dr. 
Conelea will then take relevant actions, which may include 
monitoring, adjunctive intervention within study protocol, or 
removal from the study. 
13.2. Reproduction Risks:  Currently, the effects of rTMS on hormonal cycles and 
the unborn fetus are unknown, therefore negative pregnancy test results and 
effective contraception will be required of childbearing age female 
participants.  
13.3. Risks to Others: N/A 
14.
Potential Benefits to Participants 
14.1. Potential Benefits: Several potential beneﬁts exist. All participants will 
receive a psychiatric diagnostic evaluation without charge that can 
potentially be used by future or current health providers. All participants 
will receive CBIT, the ﬁrst-line intervention recommended for tics by the 
American Academy of Neurology. Although not everyone who undergoes 
CBIT responds to the intervention, prior research shows that 50-60% of 
individuals experience an improvement in tic symptoms. Therefore it is 
likely that many participants will experience an improvement in tics from 
the CBIT alone (regardless of whether the experimental TMS augmentation 
has added beneﬁts). Participants and their families may also appreciate the 
opportunity to talk about their thoughts and feelings with trained personnel. 
If our participants do not experience improvement in tic symptoms at the 
end of the study, we will ensure that they will be provided useful treatment 
and referral information. Participants and their families may also ﬁnd beneﬁt 
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in participating in research that may help others in the future. The 
information obtained through this study will also be of general beneﬁt 
through adding to the body of knowledge concerning the treatment of 
chronic tics. 
15.
Statistical Considerations 
15.1. Data Analysis Plan:  
●Treatment of missing data.  
o
Strategies to minimize attrition: Every effort will be 
made to reduce barriers participants and their families 
encounter in attending study visits. All study visits will be 
scheduled in advance, and staff will work with adult 
participants and parents to identify potential barriers to 
attending study visits in an effort to produce solutions.We 
will also implement an Adjunctive Services and Attrition 
Prevention (ASAP) plan to minimize participant attrition 
and effectively manage clinical crises, which may occur in 
RCTs involving a clinical sample. Thus, by using ASAP 
guidelines, more participants should be able to continue in 
their assigned intervention, which will enhance subsequent 
intent-to-treat (ITT) analyses. Each participant will be 
allowed 1 ASAP session during CBIT+rTMS phase and, in 
the R33 phase only, 1 ASAP session during the follow-up 
phase. Participants who exceed the maximum number of 
sessions within any treatment phase will be prematurely 
terminated as defined below.  
o
Premature Termination. At any time, participants may 
deteriorate or develop clinical exigencies that lead study 
staff to recommend additional out-of-protocol treatments 
above and beyond that provided by ASAP guidelines (e.g., 
change in medications during the study). Such participants 
will be considered “premature terminators” (PMT) and 
classified as a protocol violation. In order to enhance the 
ITT analyses, "prematurely terminated" participants will 
continue to be treated within their assigned treatment arms 
insofar as possible, and assessments will continue 
according to protocol.  
o
Analysis population will be an intent-to-treat population 
including all enrolled participants who completed at least 1 
CBIT session.   
o
Treatment of Missing Data: All participants will remain 
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in the study unless consent is withdrawn or there are 
concerns about patient safety. While there is little that can 
be done to address missing data when participants drop out 
during the training process itself, we can compare baseline 
characteristics of those who drop out at this time versus 
those who do not and adjust models based on significant 
predictors of dropout. For those who drop out during the 
follow-up period or miss some assessments during follow-
up, we will use multiple imputation by chained equations 
(MICE) to allow for missing data without loss of those 
cases from the model under the assumption of Missing at 
Random (MAR). Sensitivity Analysis: If dropout status 
appears to be Missing Not At Random (MNAR), i.e., 
dropout is associated with an unobserved outcome, we will 
run sensitivity analyses using MICE to compare imputed 
and non-imputed models results to assess robustness of 
statistical inference. 
●Aim 1. Target engagement: Brain. 1) Primary measure of neural 
target engagement will be decreased activation in SMA. 
Hypothesis 1: Either or both active TMS groups will demonstrate 
within-subject decrease (effect size η2=0.18 in an ANOVA) in 
SMA activation post-treatment, as measured with an fMRI finger 
tapping task. While this is a large effect size in practice, we point 
out that Wu et al (2014) observed a much larger effect size of 
η2=0.41 in the decrease in SMA activity comparing active vs sham 
cTBS. 2) Secondary measure of neural target engagement will be 
change in fMRI resting state functional connectivity of at least one 
SMA-mediated circuit (SMA-DLS, SMA-M1). Hypothesis 2: 
Either or both active TMS groups will demonstrate within-subject 
change (effect size η2=0.18 in an ANOVA) in resting state fMRI 
connectivity (RSFC) of at least one SMA-mediated circuit (SMA-
DLS, SMA-M1) post-treatment. A region of interest (ROI) analysis 
will be performed to determine the time*treatment group 
differences in SMA activation elicited by an fMRI motor task 
(finger tapping). The SMA ROI will be identified by placing a seed 
(sphere with 5mm radius) that matches the coordinate used for 
individual TMS coil placement. Activation parameters in the SMA 
will be identified in a first-level analysis, using a general linear 
model (GLM) to model each subject’s SMA time course during the 
motor task. These activation parameters will be used in a 
subsequent linear mixed effects (LME) model. The predictors of 
the LME will include the baseline activation, group indicators for 
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the stimulation groups, and baseline x group interactions. Random 
effects will be used to model within-subject variation from the 
first-level analyses. Altogether, the LME will allow us to model 
how the within-subject change in activation from pre-treatment to 
post-treatment differs across active and sham conditions. In 
addition, we will also investigate the effects of each TMS regimen 
on the connectivity in the entire CSTC. To this end, we will extract 
the ROI-level time courses from each region in the CSTC, and we 
will use partial correlations to obtain an estimate of connectivity 
between each ROI pair within the CSTC while accounting for the 
data observed in the other ROIs. Given the collection of partial 
correlations for each study participant, we will use the SPU test, 
which uses the collection of partial correlations simultaneously, to 
assess for group differences across the sham and TMS regimens.75 
●Aim 2. Target engagement: Behavior. Hypothesis: Either or both 
active TMS groups will show within-subject improvement (small 
effect size of at least Cohen’s d = 0.3) in tic suppression ability as 
measured by the Tic Suppression Task (TST). TST “tic suppression 
ability” scores will serve as the primary outcome in an ANOVA 
model. An ANOVA will be used to establish if there exist 
differences in how the 1Hz, cTBS, and sham conditions affect 
change in tic suppression ability from pre- to post-treatment. 
Group indicators for these conditions will be the primary 
predictors for the model.  
●Aim 3. Assess dose-response relationship. Changes in brain (Aim 
1) and behavior (Aim 2) targets will be compared between active 
TMS groups (1Hz rTMS vs. cTBS) using ANOVA. In the case that 
both active TMS regimens are found superior to sham, we will 
compare the regimens on safety and feasibility. We will use 2-
sample t-tests to compare the two regimens using data from our 
safety and feasibility measures and prioritize the regimen with 
significantly better (p<.05) outcomes.  
15.2. Power Analysis: In Aim 1, hypothesis 1 our proposed sample size after 
accounting for expected attrition will give us 80% power to detect an effect 
size of at least η2=0.18 for differences in SMA activation between active 
TMS and sham. For Aim 2, our proposed sample size will give us 80% 
power to detect an effect size of at least d = 0.90 for a within-subject 
improvement in tic suppression ability. Our preliminary data showed effect 
sizes of this magnitude.  
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15.3. Data Integrity: 
●
Dr. Conelea and Dr. Fiecas, the study biostatistician, will directly train 
the study staff in issues of maintaining data integrity. Dr. Fiecas will 
oversee data quality control measures and design a customized 
randomization procedure and data management system for this project. 
This study will utilize the secure, web-based Research Electronic Data 
Capture (REDCap) system for data input. Data checking procedures will 
be implemented to ensure data integrity. Data file archival and back-up 
will be performed on a regular basis 
16.
Health Information and Privacy Compliance 
16.1.
Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information.   
☒ I am requesting that all research participants sign a HIPCO approved 
HIPAA Disclosure Authorization to participate in the research (either 
the standalone form or the combined consent and HIPAA 
Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of research 
participant authorization to participate in the research. 
Appropriate Use for Research:  
 
 
16.2.
Identify the source of Private Health Information you will be using for 
your research (Check all that apply)   
☐ I will use the Informatics Consulting Services (ICS) available through 
CTSI (also referred to as the University's Information Exchange (IE) 
or data shelter) to pull records for me 
☒ I will collect information directly from research participants. 
☐ I will use University services to access and retrieve records from the 
Bone Marrow Transplant (BMPT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) database. 
☐ I will pull records directly from EPIC. 
☐ I will retrieve record directly from axiUm / MiPACS 
☐ I will receive data from the Center for Medicare/Medicaid Services  
☐ I will receive a limited data set from another institution  
☒ Other.  Describe: Medical record documents deemed necessary to 
determine inclusion criteria are met will be collected. Adult 
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participants or parents will provide these documents themselves or 
complete a release of information for us to request the documents 
directly from their provider. 
16.3.
Explain how you will ensure that only records of patients who have agreed 
to have their information used for research will be reviewed: Participants 
will self-identify for the study. We will not look at any medical records to 
identify potential participants. 
16.4.
Approximate number of records required for review: N/A 
16.5.
Please describe how you will communicate with research participants 
during the course of this research.  Check all applicable boxes 
☐ This research involves record review only. There will be no 
communication with research participants. 
☐ Communication with research participants will take place in the course 
of treatment, through MyChart, or other similar forms of 
communication used with patients receiving treatment.  
☒ Communication with research participants will take place outside of 
treatment settings. If this box is selected, please describe the type of 
communication and how it will be received by participants.  
Participants will self-identify and provide us with contact 
information and preferred method of communication (phone, 
text, email) during the initial phone screen. All outgoing emails 
will be encrypted using the University’s encryption tool. Zoom 
video chat may be used for screening, assessment, and/or CBIT 
visits. We will use staff UMN Zoom accounts to host these calls. 
Video chats will be recorded on the AHC/HST devices listed 
below and uploaded immediately to Box. 
16.6.
Explain how the research team has legitimate access to patients/potential 
participants: 
16.7.
Location(s) of storage, sharing and analysis of research data, including any 
links to research data (check all that apply).   
☐ In the data shelter of the Information Exchange (IE)  
 
☐ Store 
☐ Analyze 
☐ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the 
HSCT (Hematopoietic Stem Cell Transplant) Database  
 
☐ Store 
☐ Analyze 
☐ Share 
☒ In REDCap (recap.ahc.umn.edu)  
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 ☒ Store 
☐ Analyze 
☒ Share 
☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In OnCore (oncore.umn.edu)  
 ☒ Store 
☐ Analyze 
☒ Share 
☒ In the University’s Box Secure Storage (box.umn.edu) 
 ☒ Store 
☒ Analyze 
☒ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server 
and IT Support Contact: 
 ☐ Store 
☐ Analyze 
☐ Share 
☒ In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices: 20170192, 20171538, 
20171356, 20150922, 20160281 
 ☐ Store 
☒ Analyze 
☐ Share 
☐ Other: 
Indicate if  data will be collected, downloaded, accessed, shared or stored 
using a server, desktop, laptop, external drive or mobile device (including a 
tablet computer such as an iPad or a smartform (iPhone or Android devices) 
that you have not already identified in the preceding questions 
☒I will use a server not previously listed to collect/download research data: 
MRI data will be stored and processed at CMRR on the following IP 
addresses: naxos2: 160.94.164.170, lnpi14: 128.101.115.231, lnpi15: 
128.101.115.161. We will also store and process MRI and other data in the 
HIPPA compliant environment at MSI once that space is available. 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) 
not previously listed  
☒I will use a mobile device such as an tablet or smartphone not previously 
listed: REDCap forms may be completed on a participant’s personal device 
or device #20171356. REDCap surveys are completed via the internet, so no 
data will be stored on devices. Digital video cameras will be used to record 
study assessment, CBIT sessions, and the TST (20180803, 20120967, 
20150922, 20171356, 20200509). Videos will be immediately uploaded to 
Box using an AHC-supported computer and deleted from the cameras. 
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Cameras will be stored in a locked cabinet in a locked room accessible only 
by study staff. If Zoom is used for these study tasks, we will instead record 
within Zoom and save videos directly to Box. 
16.8. Consultants. Vendors. Third Parties: We will store and analyze data on Box. 
MINI-7 administration will use the Nview digital platform and the Dept. of 
Psychiatry account, which is HIPPA-safe and HIPCO-approved data entry 
program. We will utilize analysis software (such as SPSS, DataVyu) running 
on the AHC-IS supported devices listed above. 
16.9. Links to identifiable data: Participant IDs will be used to label questionnaire, 
MRI, and video data. Consent and assent forms and any medical records 
obtained as part of eligibility determination will be stored in separate files 
from any data collected during the course of the study. We will have one file 
linking participant names and IDs that will be destroyed at the end of the 
study. The nature of the video analysis precludes de-identification of the 
videos. 
16.10.Sharing of Data with Research Team Members: Data will be shared among 
research team members via AHC-IS server, REDCap, or Box. 
16.11. Storage and Disposal of Paper Documents: Paper documents containing PHI 
collected in the course of this study will be retained by the study coordinator 
and kept in a locked cabinet in a locked research laboratory room in Diehl 
Hall suite 628. Paper documents will be digitized and stored on Box 
whenever possible. We will follow NIH and FDA guidelines for retention of 
records after the study concludes. 
17.
Confidentiality 
17.1. Data Security: All data collected during the course of this research will be 
kept confidential and be used solely for research purposes described in our 
proposal. Data will be stored in accordance with HIPAA guidelines and 
accessed only by researchers and staff affiliated with this study. Data will 
only be accessible to research staff directly involved with the study who 
have completed HIPAA, CITI, CTSI, and Department required training. 
Access to the data will be completed through AHC secured devices and/or 
cloud-based HIPAA compliant programs (Box, REDCap). All video coding 
procedures will be conducted within data servers identified above. All data 
will be marked using confidential identification codes to minimize the risk 
of the breach in confidentiality. A key linking participants’ identities and 
numerical subject codes will be stored in on Box. Questionnaire data will be 
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entered into REDCap and/or databases located on Box or the AHC 
supported server and be inaccessible to persons other than those on the study 
team. Consent forms will be stored in REDCap and backed up in a separate 
file location on Box from other study data. If any consent forms or study 
assessment measures are completed on paper (in the event of technical 
difficulties), forms will be scanned and stored in locked storage and 
digitized to Box. Only persons named on the IRB and involved in study 
coordination will have authorized access to consent forms and participant 
contact information. Videos of diagnostic interviews will only be reviewed 
by research staff for reliability purposes and erased at the conclusion of the 
study. During the CBIT+TMS visits, participants will be videotaped for the 
purposes of detecting tics during the TST and TMS and CBIT 
administration quality monitoring. These data will only be stored for 
research purposes. To the extent permitted by law, no participant 
information will be given to anyone without a signed release by the adult 
participant or child’s parents. No identifying information will be used in 
written or oral presentations of results. No data or other information 
collected as part of this study will be placed in participants’ medical, 
employment, or educational records. 
18.
Provisions to Monitor the Data to Ensure the Safety of Participants 
18.1. Data Integrity Monitoring:  
●
The PI will be responsible for data accuracy and quality assurance (e.g., 
data collection, entry, transmission, and analysis), trial management 
(e.g., enrollment, integrity of study procedures), and any interim 
analyses.
●
The PI will permit direct access to the study monitors and appropriate 
regulatory authorities to the study data and to the corresponding source 
data and documents to verify the accuracy of these data.
●
The NIMH CTOB Clinical Research Education, Support, and Training 
Program (CREST) will provide ongoing monitoring of regulatory issues 
(e.g., SAE reporting, IRB actions, disclosures of conﬂict of interest). 
Frequency of monitoring visits will occur after IRB approval, as soon as 
possible after the ﬁrst subject is enrolled, during the study data 
collection phase, and after the last participant has completed his/her 
participation in the study. This monitoring schedule may be revised 
based on considerations such as accrual rate, protocol deviations, 
magnitude of data corrections required, study stage (e.g. start-up or 
follow-up), or DSMB recommendation. Monitoring visits will be 
performed annually, at a minimum. The sponsor-investigator will permit 
direct access to the study monitors and appropriate regulatory authorities 
to the study data and to the corresponding source data and documents to 
verify the accuracy of these data.
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18.2. Data Safety Monitoring:   
●Data and Safety Monitoring Board: A Data and Safety 
Monitoring Board (DSMB) will be included in this project. The 
draft DSMB charter is attached and will be reviewed and signed by 
DSMB members at the first meeting. The members of the DSMB 
include one board-certified psychiatrist with pediatric TMS 
expertise, one psychologist with CBIT expertise, and one 
biostatistician. Members will not be otherwise involved in this 
project and will not be collaborators on any other of the 
investigators’ projects nor in their employ. Safety information will 
be collected with case report forms completed during study visits. 
They will meet prior to enrollment of the participant, after the first 
10 participants are enrolled, and annually thereafter to 1) monitor 
the safety, quality and conduct of this study and 2) decide whether 
adequate participant safeguards are in place. The DSMB will 
review: 1) study progress, including assessments of data quality 
and participant recruitment, accrual and retention; 2) outcome and 
adverse event data to determine whether there is any change to the 
anticipated benefit-to-risk ratio of study participation and whether 
the study should continue, be changed, or terminated; 3) external 
factors or relevant information (e.g., pertinent scientific literature 
reports or therapeutic developments, results of related studies) that 
may have an impact on the safety of study participants or the ethics 
of the research study; and 4) study procedures designed to protect 
the privacy of the research participants and the confidentiality of 
their research data. The study statistician will be responsible for 
generating a de-identified annual report of key events that will be 
reviewed as part of the safety monitoring of the protocol. The list 
of key events will specifically indicate: 1) seizures, 2) side effects 
to the study treatment, 2) hospitalization, and 3) premature drop-
out from treatment. Any serious adverse events will be updated on 
an expedited basis. Members of the DSMB may request a 
conference call of the group at any time. 
●
Reporting: All investigators will report unexpected serious adverse 
events (SAEs) or unanticipated problems involving risks to subjects to 
the UMN IRB and to the assigned NIMH Project Officer (PO). Reports 
will be made to the DSMB (detailed above). If DSMB notes serious and 
unexpected adverse events, or unanticipated problems involving risks to 
subjects or others which are related to the study, the PI and UMN IRB 
will be notified. This will be done via a letter from the DSMB Chair/
Administrator to Dr. Conelea for distribution to the institutional official, 
sponsor, and UMN IRB. Dr. Conelea will also submit a yearly progress 
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report to the UMN IRB summarizing the data and safety monitoring 
activities and outlining 1) whether participants’ safety, privacy and 
confidentiality has been consistently assured, 2) whether research 
instruments have been administered in a uniform manner and in a way 
that protects participants’ privacy, 3) progress towards recruitment goals, 
quality of data collection (e.g., appropriate completion of forms), and 
participant retention/attrition rates, and 4) a review of new scientific 
literature pertinent to the safety of participants or the ethics of research 
participation. Dr. Conelea will report to the UMN IRB and the assigned 
NIMH PO within the following time frame: 1) IRB/ISM/DSMB 
suspensions or terminations (within 3 business days), 2) deaths related to 
study participation (within 5 business days), 3) unexpected SAEs (within 
5 business days), 4) unanticipated problems involving risks to subjects 
or others (within 5 business days), 5) serious or continuing 
noncompliance (within 5 business days), 6) AEs deemed expected or 
unrelated to the study (with annual progress report), and 7) protocol 
deviations that do not affect the scientific soundness of the research 
plans or the rights, safety or welfare of the human subjects (with annual 
progress report).  
19.
Provisions to Protect the Privacy Interests of Participants 
19.1. Protecting Privacy: All consent procedures, assessments, and study activities 
will be conducted in private rooms by trained personnel. Participants will be 
repeatedly reminded that sharing of information and completion of study 
tasks are voluntary. Assessment of participant comfort will occur on an 
ongoing basis; research staff will ask the youth how they are feeling and if 
they are comfortable with starting/continuing a study activity. Parents and 
children will be given the opportunity to separately discuss concerns or 
responses to questions with research staff. Since we are working with 
minors, we will inform participants and their parent(s) that we are required 
to report if the subject is a danger to themselves or others or if they report 
child abuse/neglect. 
19.2. Access to Participants: It is necessary to access direct identiﬁers in order to 
maintain contact with the participant throughout the course of the study. 
Private information about the participant’s health status is necessary to 
achieve study aims (e.g., psychiatric diagnoses, tic severity). 
20.
Compensation for Research-Related Injury 
20.1. Compensation for Research-Related Injury: The following statement is 
included in the consent form: “In the event that this research activity results 
in an injury, treatment will be available, including first aid, emergency 
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treatment and follow-up care as needed. Care for such injuries will be billed 
in the ordinary manner to you or your insurance company. If you think that 
you have suffered a research related injury, let the study doctor know right 
away.” 
20.2. Contract Language: N/A 
21.
Consent Process 
Consent Process (when consent will be obtained): Child assent and informed consent 
from the parent (to allow their child to participate in this study) or adult consent only (for 
participants aged 18 years or older) will be administered at the start of the pre-treatment 
assessment visit and will be required for participation in study procedures. Specifically, 
the consent and youth assent documents will be read through with all potential 
participants, and focus will be placed on potential risks and benefits associated with study 
participation, any alternatives to participating in the research, that opportunities to receive 
treatment will not depend upon research participation, clinical care will not be affected by 
study participation, and that participation is voluntary. In addition, the investigators will 
try to foster an open exchange of information, encouraging potential participants and 
their families to discuss study particulars and ask questions prior to research involvement; 
to receive a copy of the consent form to discuss with family and friends, if desired; and to 
continue asking any questions that might arise during participation. Parents/adult 
participants will be informed that all assessment information will be kept confidential 
with the following three exceptions explicitly stated: participant or parent (1) suicidality, 
(2) homicidality, and (3) abuse. Finally, details on written consent and child assent forms 
will be presented in simple language approved by UMN IRB. Among individuals who 
provide informed consent, only those who fully meet the study entry criteria after the pre-
treatment assessment will be allowed to continue with the rest of the study. Participants 
who are active in the study when they turn 18 will be re-consented at the next visit/
session before additional study activities begin. 
  
Potential participants will meet with the designated team member for assent/consent and 
potential enrollment. Consenting to research activities will take place in a private room at 
the Study Site or electronic consent may be conducted remotely, by phone or videocall. 
Participants over 18 years of age will need to meet via videocall or in-person for the 
administration of the MacCat-CR. These participants will not complete this procedure via 
phone call per institutional policies. During this visit, the qualified Site Study personnel 
authorized by the Site Principal Investigator and the potential participant and their parent/
legal guardian will discuss the nature of the trial, the purpose of the research, the trial 
procedures, the possible risks and benefits of participation, confidentiality and the 
voluntary nature of participation in the trial (emphasizing the participant’s right to 
withdraw from the study at any time).   
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Following this discussion, potential participants and their parents/legal guardians will be 
offered the opportunity and encouraged to ask any study-related questions and enroll by 
providing written assent/consent on the IRB-approved form. For remote consent 
discussions, participants and/or their parent/legal guardian will navigate to the electronic 
consent/assent form shared through REDCap. The electronic consent/assent form has 
been designed so that the participant and their parent/legal guardian are unable to 
complete the consenting process without completing the consenting process with a 
member of the research team. Participants and/or their parent/legal guardian will first 
receive a “Read Only” version of the consent prior to the consent visit. Only after the 
research coordinator has completed the informed consent discussion and determined the 
parent/legal guardian and/or participant fully understand all procedures and are capable 
of informed consent will he/she sign the electronic consent form and deliver an “editable” 
version of the electronic consent form which the participants and/or their parent/legal 
guardian will be able to sign. For the electronic consent process to be considered 
complete, the consenting team member will access REDCap in real-time to confirm the 
parent/legal guardian and/or participant have signed the consent/assent form correctly.  
Participants will be allowed as much time as needed, with Site Study personnel or in 
private, to review consenting documents before making the decision to participate. 
Potential participants may invite a friend or family member to be present during the visit, 
to further discuss their decision to enroll and/or contact (e.g., phone call) a friend or 
family member that is not physically present for discussion before deciding to enroll.  At 
the potential participant’s request, Site Study personnel may be asked to ‘step-out’ of the 
room or end/mute the call during remote discussions, to provide privacy for such 
discussions. In addition, potential participants will be provided the option to defer their 
decision to allow them to review the consent form and other study information forms at 
their convenience, and later reconnect with the Site Study team remotely or return to the 
Study Site to enroll (i.e., complete the informed consent procedures).  No study activities 
will take place prior to completion of the consenting process.  
21.1. Waiver or Alteration of Consent Process (when consent will not be 
obtained): N/A 
21.2. Waiver of Written/Signed Documentation of Consent (when written/signed 
consent will not be obtained): N/A 
21.3. Non-English Speaking Participants: N/A 
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21.4. Participants Who Are Not Yet Adults (infants, children, teenagers under 18 
years of age):
●
Individuals under the age of 18 years will be considered to not have 
attained the legal age for consent to participate in research. 
Participants who are active in the study when they turn 18 will be re-
consented at the soonest possible time before additional study 
activities are completed.
●
Parental permission will be obtained from one parent, even if the other 
parent is alive, known, competent, reasonably available, and shares 
legal responsibility for the care and custody of the child.
●
Legal guardians will be allowed to provide permission if they provide 
documentation of their status as a legal guardian. 
●
Assent will be obtained from all of the children. 
●
The attached “Assent Form” will be used to document child assent 
prior to starting any study activities. 
21.5. Cognitively Impaired Adults, or adults with fluctuating or diminished 
capacity to consent: N/A 
21.6. Adults Unable to Consent: N/A 
22.
Setting 
22.1. Research Sites:  
●
Participants will self-identify by calling a research assistant located in the 
CAN Lab, part of the Department of Psychiatry and Behavioral Sciences 
(University of Minnesota Twin Cities campus). 
●
Assessment visits will occur within the UMN Center for Neurobehavioral 
Development (CNBD) or remotely via Zoom. CBIT+TMS visits will 
occur at the CNBD and Noninvasive Neuromodulation Laboratory (NNL). 
MRIs will be conducted at the Center for Magnetic Resonance Research 
(CMRR). 
●
If transportation acts as a barrier to participation, we will provide 
assistance with Uber, Lyft, or taxi. Participants or a legal guardian will be 
required to provide additional consent for staff to arrange transportation 
for research participants. 
22.2. International Research: N/A 
23.
Multi-Site Research 
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N/A 
24.
Coordinating Center Research 
        N/A 
25.
Resources Available 
25.1. Resources Available: 
●
Recruitment resources: Dr. Conelea is a psychologist on the faculty of 
the Child and Adolescent Division of the Department of Psychiatry and 
Behavioral Sciences and will have access to referral sources and 
healthcare providers in the community who treat young people with tic 
disorders. The research team has access to the FIND Network to recruit 
from over 500 potential families with and without children with 
neurodevelopmental diagnoses. Additional recruitment efforts will be 
posted through the departmental and laboratory websites and social 
media. It is expedited that the research team will be able to recruit 60 
participants through the delineated recruitment plan.
●
Facilities: Private space for conducting participant visits is available at 
the CNBD. MRI acquisition will be available through the CMRR. We 
will have access to the TMS equipment at the Noninvasive 
Neuromodulation Laboratory. 
●
Training: Research staff will be directly trained in study procedures by 
Dr. Conelea, and she will continually assess their protocol knowledge 
and skill performance on an on-going basis. Additional supervision to 
research staff as needed will be provided by co-investigators with the 
relevant expertise. Dr. Conelea is supported by a Project Director, Dr. 
Sunday Francis, who will also support supervision and training of 
clinical research coordinators. All staff with access to research 
participants will have completed HIPAA and CITI training, and the 
University of Minnesota IRB's Assessing Capacity to Consent training 
(e.g., children). These standards will be upheld throughout the study 
period. 
●
Medical or psychological resources for participants in event of an 
anticipated or unanticipated consequence of research:  The study 
investigator team includes a licensed psychologist (Dr. Conelea),  
psychiatrists (Dr. Lim and Dr. Jacob), and a pediatrician (Dr. Jacob). All 
are on the faculty in the Department of Psychiatry and Behavioral 
Sciences. As such, they will have access to referral sources within and 
outside of the department. 
●
Time devoted to the research: The PI, Co-Investigators, Project Director, 
and study staff will dedicate time to this project in accordance with 
funding provided via an NIMH grant. The research team will hold 
regular meetings to discuss study procedures and progress. 
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