Repetitive Transcranial Magnetic Stimulation for Adolescent Depression: Efficacy, Predictive Biomarkers, and Mechanisms
Phase: NA
Conditions: Treatment Resistant Depression
Sponsor: University of Minnesota

Protocol 
 
University of Minnesota
Clinical Protocol: 
Medical Device Investigational Plan 
Repetitive Transcranial Magnetic Stimulation 
for Adolescent Depression: Efficacy, Predictive 
Biomarkers, and Mechanisms 
Regulatory Sponsor: 
 
Kathryn R. Cullen, M.D 
 
 
 
 
 
Department of Psychiatry 
 
 
 
 
 
University of Minnesota 
Funding Sponsor: 
University of Minnesota Department of 
Neuroscience MnDrive 
Study Product: 
Brainsway deep TMS Machine 
Protocol Number: 
rTMS 
IDE Number: 
G150132 
Version: 
Version 1 - June 19, 2015 
 
Version 2 – July 15, 2015 
 
Version 3 – August 5, 2015 
 
Version 4 – October 15, 2015 
 
Version 5 – November 12, 2015 
 
Version 6 - March 10, 2016 
 
Version 7 – April 15, 2016 
 
Version 8 – November 30, 2016 
 
 
 
 
 
Version 9 - May 22, 2017 
 
 
 
 
 
Version 10- June 19, 2017 
 
 
 
 
 
Version 11- August 31, 2017 
 
 
 
 
 
Version 12 – December 18, 2017 
 
 
 
 
 
Version 12.1 – January 26, 2018 
 
 
 
 
 
Version 13 – February 07, 2018 
 
 
 
 
 
Version 14 – March 28, 2018  
 
 
 
 
 
Version 15 – September 20, 2018 
 
 
 
 
 
Version 16 – November 05, 2018 
 
 
 
 
 
Version 17 – February 08, 2019 
 
 
 
 
 
Version 18 – February 09, 2020 
Version 19 – June 11, 2020 
Version 20 – September 16, 2020  
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Version 21 – December 22, 2020 
Version 22 – February 17, 2021 
CONFIDENTIAL 
This document is confidential and the property of the University of 
Minnesota. No part of it may be transmitted, reproduced, published, 
or used by other persons without prior written authorization from 
the study sponsor. 
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1. Table of contents 
1. Table of Contents 
 
 
 
 
 
 
2 
List of Abbreviations 
 
 
 
 
 
 
3 
2. Report of prior investigations  
 
 
 
 
4 
3. Investigational plan 
 
 
 
 
 
 
6 
4. Risk analysis 
 
 
 
 
 
 
 
23 
5. Description of the device 
 
 
 
 
 
31 
6. Monitoring procedures  
 
 
 
 
 
32 
7. Manufacturing information 
 
 
 
 
 
33 
8. Investigator information 
 
 
 
 
 
34 
9. IRB Information  
 
 
 
 
 
 
36 
10. Sales information 
 
 
 
 
 
 
37 
11. Environmental impact statement 
 
 
 
 
38 
12. Labeling  
 
 
 
 
 
 
 
39 
13. Informed consent materials  
 
 
 
 
40 
14. References 
 
 
 
 
 
 
 
41 
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List of Abbreviations 
3T 
 
3 Tesla 
ADHD  
Attention-Deficit/Hyperactivity Disorder 
AE 
 
Adverse Event 
ANT 
 
Attention Network Task 
ANOVA 
Analysis of Variance 
ARC 
 
Ambulatory Research Center 
 
ATR 
 
Antidepressant Treatment Record 
BDI-II  
Beck Depression Inventory 
CVLT-II 
California Verbal Learning Test 
CDRS-R 
Children’s Depression Rating Scale - Revised 
CFR 
 
Code of Federal Regulations 
CGI 
 
Clinical Global Impressions Scale 
CMRR  
Center for Magnetic Resonance Research 
CRF 
 
Case Report Form 
CSSRS 
Columbia Suicide Severity Rating Scale 
CSSRS-SLV Columbia Suicide Severity Rating Scale – Since Last Visit 
DCCS  
Dimensional Change Card Sort Task 
D-KEFS 
Delis-Kaplan Executive Function System 
DLPFC 
Dorsolateral Prefrontal Cortex 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – 5th 
Revision 
DSMB  
Data and Safety Monitoring Board 
DSMP  
Data and Safety Monitoring Plan 
ECT 
 
Electroconvulsive Therapy 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
HCP 
 
Human Connectome Project 
HIPAA  
Health Insurance Portability and Accountability Act of 1996 
ICH 
 
International Conference on Harmonisation 
IDAS  
Inventory of Depression and Anxiety Symptoms 
IDS 
 
Investigational Drug Services 
IRB 
 
Institutional Review Board 
K-SADS 
Kiddie Schedule of Affective Disorders and Schizophrenia 
MADRS 
Montgomery-Asberg Depression Scale 
MDD  
Major Depressive Disorder 
MEPa  
Motor Evoked Potential Amplitude 
MEP 
 
Motor Evoked Potential 
MRI 
 
Magnetic Resonance Imaging 
MT 
 
Motor Threshold 
PHI 
 
Protected Health Information 
PHQ-9 
Patient Health Questionnaire 
RSFC  
Resting State Functional Connectivity 
rTMS  
Repetitive Transcranial Magnetic Stimulation 
SAE 
 
Serious Adverse Event 
SHAPS 
Snaith-Hamilton Pleasure Scale 
STAI  
State-Trait Anxiety Inventory 
TASS  
Transcranial Magnetic Stimulation Adult Safety Screening Form 
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TEPS  
Temporal Experience of Pleasure Scale 
TRD 
 
Treatment-Resistant Depression 
UTox  
Urine Toxicology Screen 
WASI  
Weschler Abbreviated Scale of Intelligence 
YMRS  
Young Mania Rating Scale 
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2. Report of prior investigations 
Depression is a leading cause of disability and global disease burden.1 About 
25% of all cases first emerge during adolescence,2 and an adolescent onset 
predicts poorer psychosocial functioning and higher levels of suicidality.3–5 
The brain undergoes important refinement during adolescence.6–9 Due to 
developmental differences, the neural mechanisms underlying disease and 
treatment response could differ from adults, highlighting the need to study 
adolescents separately. Unfortunately, about 20% of adolescents with 
depression do not respond to currently-available treatments.10–12 adolescents 
with treatment-resistant depression (TRD) likely have neural abnormalities 
that are distinct from other patients and that are not alleviated with standard 
treatments. Novel treatments addressing these early dysfunctions in neural 
circuitry could restore healthy neurodevelopment during adolescence thereby 
preventing long-term morbidity and addressing a significant financial burden 
for society.  
Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment 
for TRD in adults. rTMS applies a pulsatile magnetic field to the scalp which 
painlessly induces electrical currents to the brain.13 Typically rTMS is applied 
to the dorsolateral prefrontal cortex (DLPFC), a brain region that is 
hypoactive in depression.14 Whereas standard rTMS stimulates superficial 
(1cm depth) cortical areas, recent advances in rTMS coil technology support 
stimulation of deeper (5 cm depth)13 limbic structures that are also relevant 
to depression.15 Deep rTMS is FDA-approved for adults with TRD.16 
Unfortunately, although rTMS is generally safe in children and adolescents,17 
research in adolescent depression TRD is far behind. Only two small, open-
labeled rTMS studies in adolescent TRD have been conducted, both using 
standard rTMS, which have suggested 30%18 and 70%19 response rates. No 
randomized, controlled trials (RCTs) of rTMS have yet been conducted 
adolescent TRD, and no studies have examined deep rTMS in adolescent 
TRD. To address these gaps, the current study will conduct an open label trial 
testing deep rTMS in adolescents with TRD.  
Additional gaps in neuromodulation research include the need to understand 
mechanisms underlying clinical response to rTMS and to identify neural 
biomarkers capable of predicting a positive clinical response.20 Translational 
approaches are especially critical in adolescent research; given ongoing 
neurodevelopment, neural abnormalities and their malleability to treatment 
may be different in adolescents than adults. Severe depression is associated 
with impaired neuroplasticity.21 Repetitive stimulation of synapses promotes 
growth of dendritic spines 22 and enhances neuronal excitability; these 
changes promote brain plasticity and recovery offunction.15,23 The motor 
threshold (MT; the stimulus intensity required to achieve a reliable motor 
evoked potential [MEP]) and the MEP amplitude (MEPa) are measures of 
cortical excitability.24 Recent developmental research using rTMS has shown 
that depressed youth have greater MTs than healthy youth, and that among 
depressed youth, MT decreases with age.25 This emphasizes the opportunity 
to explore whether rTMS might reverse neuroplasticity/excitability 
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abnormalities in depressed youth, and the importance of studying 
adolescents separately from adults. Neuroimaging is another promising way 
to test the effects of rTMS on brain plasticity. Research has found that rTMS 
leads to increased regional cerebral blood flow in the DLPFC, anterior 
cingulate cortex, and limbic structures (e.g. amygdala).26–28 Functional 
neuroimaging can measure resting state functional connectivity (RSFC); 
impaired RSFC within default mode and fronto-limbic networks have been 
found in depression.29–32 rTMS can manipulate RSFC and potentially could 
restore abnormalities in depression.33 Previous work examining RSFC before 
and after rTMS in adults with depression has shown that rTMS normalized 
abnormalities in the default mode network.34 No imaging studies have been 
conducted examining how rTMS affects neural networks in adolescents with 
TRD. To advance current understanding of how rTMS impacts neuroplasticity, 
whether these changes are a key ingredient for the efficacy of rTMS, and 
whether these markers can predict treatment response, the current study will 
measure RSFC within neural networks, MT and MEPa before and after deep 
rTMS treatment in adolescents with TRD. 
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3. Investigational plan 
3.1 
Name of investigational device: 
Brainsway Deep Transcranial Magnetic Stimulation (TMS) Machine 
3.2 
Intended use of the investigational device: 
The Brainsway TMS machine will be used to provide repeated TMS 
(rTMS) as a novel treatment for adolescent treatment-resistant 
depression. 
3.3  
Objectives of the clinical investigation: 
3.3.1  Primary objective. 
To measure the feasibility, tolerability, safety and efficacy of a 30 
session course of rTMS in adolescents with Treatment Resistant 
Depression (TRD).  
 
 
3.3.2 Secondary objective(s). 
a. To establish the optimal dose (energy of stimulation, measured by 
percentage of motor threshold [MT]) that balances safety and 
efficacy for adolescents with depression.  
b. To examine whether changes in neuroplasticity promote successful 
rTMS treatment in adolescents with TRD.  
c. To identify potential biomarkers for predicting a positive treatment 
response to deep rTMS that will be pursued in future research.  
3.4 
Title of clinical protocol: 
Repetitive Transcranial Magnetic Stimulation for Adolescent 
Depression: Efficacy, Predictive Biomarkers, and Mechanisms 
3.5 
Study design: 
3.5.1 General study design. 
1.
This study will be an open-label 6-week (30 session) trial of active 
repetitive transcranial magnetic stimulation (rTMS) using a fixed 
frequency (10 Hz) and target stimulation intensity of 120% of MT. 
Some may receive a lower intensity as tolerated. If 2 participants 
experience a major safety event at 120% of MT, we will decrease the 
stimulation intensity to 100% of MT and complete the remainder of the 
subjects at that energy level. 
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3.5.2 Study design schematic. 
 
 
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Intake & Cogni-ve Ba0ery
MRI
rTMS Week 1
Post-Tx Assessment
MRI
Month 1 Follow Up
End
Month 2 Follow Up
Month 3 Follow Up
Month 4 Follow Up
Month 5 Follow Up
Month 6 Follow Up
rTMS Week 3
rTMS Week 2
rTMS Week 4
rTMS Week 5
rTMS Week 6

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3.6 
Subject selection: 
3.6.1 General characteristics of the proposed subject 
population(s). 
Male and female adolescents aged 12-18 years old with a diagnosis 
of Major Depressive Disorder and who are currently in a depressive 
episode that has lasted at least 4 weeks who are resistant to 
antidepressant treatment as clinically defined by the study 
physician  using the Antidepressant Treatment Record (ATR). 
3.6.2 Anticipated number of research subjects. 
The goal is to run a total of 30 participants through the protocol. In 
order to ensure that we enroll a sufficient number of adolescents 
with depression that will meet criteria for the study, we estimate 
that up to 60 participants will need to be consented into the study 
for initial psychiatric screening. 
3.6.3 Inclusion/Exclusion criteria. 
Inclusion Criteria
Determinant
Aged 12-18 years old 
Phone screen, medical 
records (if available)
Diagnosis of Major Depressive Disorder
K-SADS, medical 
records (if available)
Experiencing a current MDD episode with a 
duration of ≥ 4 weeks 
KSADS, medical records 
(if available)
A Children’s Depression Rating Scale-
Revised (CDRS-R) score of >40
CDRS-R
Resistance to treatment, defined by failure 
to respond adequately to at least one 
antidepressant treatment*
Antidepressant 
Treatment Record 
(ATR), patient/parent 
interview, discussion 
with treating physician 
(when possible), 
medical record (if 
il bl )
Female participants who are sexually active 
during the course of the study must use a 
form of birth control for the duration of the 
study 
Phone screen, medical 
records (if available), 
Pregnancy test
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Exclusion Criteria
Determinant
Any subject with a clinically defined 
neurological disorder or insult including, 
but not limited to, a condition likely to 
increase the risk of seizure; such as, space 
occupying brain lesion; any history of 
seizure; history of cerebrovascular 
accident; transient ischemic attack within 
two years; cerebral aneurysm; dementia; 
brain surgery; history of stroke 
Phone screen, self-
report, medical records 
(if available), CMRR 
safety screening form, 
TASS
Any subject with an increased risk of 
seizure for any reason, including prior 
diagnosis of increased intracranial pressure 
or history of significant head trauma with 
loss of consciousness for ≥ 5 minutes
Phone screen, self-
report, medical records 
(if available), CMRR 
safety screening form, 
TASS
Failure of the Transcranial Magnetic 
Stimulation Adult Safety Screening (TASS) 
questionnaire as indicated by a positive 
response without clinician explanation and 
approval
TASS
Subjects with cardiac pacemakers, 
implanted medication pumps, intracardiac 
lines, or acute unstable cardiac diseases
Phone screen, CMRR 
safety screening form, 
TASS
Subjects with conductive, ferromagnetic, 
or other magnetic-sensitive metals 
implanted in the head within 30 cm of the 
treatment coil excluding the mouth that 
cannot safely be removed should be 
excluded. Examples include cochlear 
implants, implanted electrodes/stimulators, 
aneurysm clips or coils, stents, bullet 
fragments, jewelry and hair barrettes
Phone screen, CMRR 
safety screening form, 
TASS
Subjects with active or inactive implants 
(including device leads), including deep 
brain stimulators, cochlear implants, and 
vagus nerve stimulators
Phone screen, CMRR 
safety screening form, 
TASS
Inability to locate and quantify a motor 
threshold as defined in the protocol
Initial rTMS visit
History of treatment with ECT or TMS 
therapy for any disorders
Phone Screen, ATR, 
medical records (if 
available)
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Participation in any investigational drug 
trial within 4 weeks of the baseline visit
Phone Screen, ATR
Pregnancy
Urine pregnancy test  
(MRI appointment)
IQ < 80
WASI
Clinically significant laboratory abnormality 
or medical condition, that in the opinion of 
the investigator would hinder the subject in 
completing the procedures required by the 
study
Phone screen, medical 
records (if available)
 Currently actively suicidal with intent and 
plan.
Phone screen, K-SADS, 
medical records (if 
available), BDI-II, C-
SSRS, PHQ-9
Unstable psychotherapy (therapy must be 
for at least 3 months prior to entry into the 
study, with no anticipation of change in the 
frequency or treatment focus of the 
therapeutic sessions over the duration of 
the study)
Phone screen
A diagnosis of current substance use 
disorder (within the past 12 months), 
Schizophrenia, Bipolar Disorder, or Autism
Phone screen, K-SADS, 
medical records (if 
available)
Refusal to cooperate with study procedures
Consent appointment
Recent change (i.e., new medication or a 
dose increase) in dose of antidepressant 
medication (within 6 weeks prior to initial 
evaluation). This includes all 
antidepressants and any adjunctive 
psychotropic medications that are being 
used to address problems related to mood 
or anxiety (e.g. antipsychotic medications, 
mood stabilizers). **
Phone screen, ATR, 
medical records (if 
available), self-report, 
K-SADS
Current treatment with Bupropion at a 
dose greater than 150mg per day.
Phone screen, medical 
records (if available)
Current treatment with a stimulant 
medication as an adjunct medication for 
depression.***
Phone screen, medical 
records (if available)
Current treatment with a stimulant 
medication.***
Phone screen, medical 
records (if available), K-
SADS
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* Although we will use the ATR to record information regarding the 
duration and dose of each past or current medication trial, we will 
not use the ATR to define inclusion criteria. Rather, inclusion criteria 
will be defined as a failed trial to an antidepressant based on the 
impressions of the patient, parent/guardian and (when possible) 
treating clinician.  
** If there has been a recent discontinuation or decrease in 
antidepressant dosage of a medication we will require varying 
lapses of time before study entry depending on medication type as 
follows: Antidepressant medications = 4 weeks, mood stabilizers 
(e.g. Lithium, Valproate) = 2 weeks, Antipsychotic medications = 2 
weeks, Stimulant medications = 1 week 
***If participants are being treated with stimulant medications for 
ADHD or as an adjunct strategy for their depression, we will require 
them to discontinue the stimulant prior to starting the study 
treatment and wait 1 week before they begin the study as listed 
above. 
3.7  
Study procedures: 
3.7.1 Recruitment.  
 
 
1. We will send letters and study brochures to local clinicians who 
treat adolescent depression.  
2. We will screen electronic medical records of adolescents with a 
diagnosis of depression who are seen in the clinics and hospital 
services of the University of Minnesota, Medical Center and 
Masonic Children’s Hospital. When potential cases are identified 
through screening, we will contact the treatment team to 
discuss whether the patient might be suitable for consideration 
for the study, and if so, we will ask the treatment team to 
request permission from the family to have the research team 
contact the family to explain the study. The outpatient 
Psychiatry Clinic in the Department of Psychiatry at the 
University of Minnesota provides new patients the opportunity to 
indicate whether they are interested in being contacted to hear 
about research studies or whether they prefer to not be 
contacted. Access to this contact information is managed by the 
Department of Psychiatry Research Recruitment Specialist. The 
Research Recruitment Specialist describes research 
opportunities to patients and provides the contact information of 
interested patients to departmental researchers conducting 
studies for which they might be eligible. We will receive this 
contact information to recruit participants for this study. We will 
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only contact patients who have indicated an interest in hearing 
about research.We will post flyers and advertisements in local 
community outlets about our study. 
3. Research staff will utilize social media accounts such as 
(Facebook, Twitter, Instagram, independent website, etc.) to 
create an informative space about research opportunities and 
information about depression, self-harm and mental health for 
adolescents and young adults. Social media accounts for this 
research lab (RAD Lab) will be used for this study as well as 
accounts for the University of Minnesota Department of 
Psychiatry managed by the Research Recruitment Specialist 
working on behalf of research staff for recruitment. A 
coordinating website radlab.umn.edu will be used to describe 
participation information, including inclusion and exclusion 
criteria and amount of time to complete study. This information 
will also be listed on the UMN Department of Psychiatry website 
(“z.umn.edu/findastudy”). The website and media pages will 
provide study team contact information and IRB approval 
number. Media sites will be compliant with HIPAA: no identifying 
information will be collected and potential participants will be 
advised to contact the research team directly via phone or email 
for additional information about this study. The lab will include 
the following disclosure: “Disclaimer: The information on this 
site is not intended or implied to be a substitute for professional 
medical advice, diagnosis or treatment. All content, including 
text, graphics, images and information, contained on or 
available through this website, is for general information 
purposes only. Please contact your physician to form a plan that 
addresses you or your child's specific needs” wherever space is 
allotted. 
4. Research staff, in coordination with the Research Recruitment 
Specialist, will create community engagement events for the 
purpose of education and awareness around adolescent 
depression, self-harm, mental health and the accompanied 
cultural stigma of seeking support. These events would focus on 
the needs of the community, awareness education, providing 
resources of support and mentioning this and other current 
research studies. All materials related to specific study 
recruitment would be submitted for approval.  
       
             
3.7.2 Screening, consent and diagnostic procedures. 
(a) The parent/guardian of each participant will first complete an  
initial, brief telephone interview with a research team member. 
The study will be briefly explained to the parent/guardian, and 
will ask a set of questions about the child’s medical history. This 
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will serve to select participants likely to meet inclusionary 
criteria and to screen out participants who meet exclusionary 
criteria. Families that are interested in pursuing the study and 
who pass the screen will be scheduled for a diagnostic 
interview.  
(b) The consent process will take place in the Ambulatory Research  
Center at the University of Minnesota. Consent and assent may 
also be obtained remotely using telecommunication (e.g., 
phone, Zoom). One of the members of the research staff will 
review the study procedures, risks and benefits as described in 
the consent form with the parent/guardian and in the assent 
form with the adolescent. The families will be given time to read 
the materials and ask any questions they have about the study. 
The research staff member will pose a set of questions to the 
parent/guardian and the adolescent to ensure that they fully 
understand the procedures, risks, and voluntary nature of the 
study. We will attempt to obtain consent from both parents 
except where it is not possible (e.g. death of a parent, parent 
does not have custody) or it is prohibitive to do so (e.g. parent 
lives in another state, parent is unavailable during reasonable 
business hours). 
For remote consent procedures, we will either use REDCap, 
email (using encrypted email by including [encrypt] in the 
subject line), or mail the ICF to the participant or parent/
guardian. We will take special precautions to protect 
confidentiality (e.g. verify with the participant that the mailing 
address or email is correct and it is acceptable to send the 
consent in this way). The person consenting the participant or 
parent/guardian will have the same consent discussion remotely 
[e.g., over phone, zoom] that they would have had in-person 
(including asking questions to gauge comprehension and 
answering the participant’s or parent/guardian’s questions). The 
rights and welfare of the participants will be protected by 
emphasizing that the quality of their medical care will not be 
affected by their decision to participate in this study. If the 
participant or parent/guardian consents, they will complete and 
sign the ICF (in all appropriate sections) using REDCap email 
(using encrypted email by including [encrypt] in the subject 
line) a scanned PDF, fax, or mail the signed and dated ICF to the 
research team. A pre-paid, self-addressed envelope will be 
provided to the participant or parent/guardian if they choose to 
mail the signed ICF. Once the ICF (signed & dated by the 
participant or LAR) is received by the research team, the study 
team member who explained the study will sign the appropriate 
signature line with the current date. They will then send a copy 
of the fully executed ICF back to the participant. They will 
document the consent process in a separate note to file/
progress note. Study procedures will not begin until all aspects 
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of the remote consent process are complete. A copy of the 
ICF will not be included in the participant’s Electronic Health 
Record. 
(c) Directly after the consent process, families that have agreed to  
 
participate in the study will then participate in a comprehensive 
diagnostic assessment.  
 
Clinician-administered measures: Separate diagnostic interviews 
with parent/guardian and adolescent will be conducted using the 
Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-
PL). A member of the research staff will complete the 
Antidepressant Treatment Record (ATR), Clinical Global Impressions 
Scale (CGI), and the Children’s Depression Rating Scale Revised 
(CDRS-R) with parent/guardian. A different member of the research 
team will complete the Children’s Depression Rating Scale Revised 
(CDRS-R), Montgomery-Asberg Depression Scale (MADRS), 
Columbia Suicide Severity Rating Scale (C-SSRS), the Young Mania 
Rating Scale (YMRS), and the Edinburgh Handedness Scale with 
participant. These will be collected data using REDCap, a HIPAA-
compliant data collection platforms.  
 
Self-report clinical measures: Participants will also be asked to 
completed a number of self-report measures including the Beck 
Depression Inventory (BDI-II), Inventory of Depression and Anxiety 
Symptoms (IDAS), Temporal Experience of Pleasure Scale (TEPS), 
Snaith-Hamilton Pleasure Scale (SHAPS), State-Trait Anxiety 
Inventory (STAI) and the Tanner Pubertal Staging Questionnaire. 
 
Neurocognitive measures: We will have the participant complete 
the Weschler Abbreviated Scale of Intelligence (WASI), two 
subtest version to obtain an accurate estimate of intelligence 
quotient (IQ) as well as a cognitive battery including the 
Attention Network Task (ANT), Dimensional Change Card Sort 
Task (DCCS), California Verbal Learning Test (CVLT-II), and the 
Delis-Kaplan Executive Function System (D-KEFS) Trail Making 
Test.  
 
 
(d) After the diagnostic assessment is complete, a consensus  
 
meeting takes place among the research team to integrate the 
combined information from parent/guardian and adolescent 
KSADS interviews, rating scales and medical records (if 
available), to confirm the DSM-5 psychiatric diagnoses. If 
participants meet the above inclusion criteria and do not have 
any of the exclusion criteria, they will be invited to participate in 
the remaining portions of the study. 
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3.7.3 Pre- and Post rTMS Treatment Measurements of  
 
 
Neuroplasticity 
MRI Procedures.  
Prior to the MRI and beginning of TMS treatments, parents will be 
asked to complete safety screening forms to verify that their child 
is safe to undergo those procedures. The research team will utilize 
the CMRR Center’s screening tools and adhere to the screening SOP 
during enrollment of all research participants in this protocol. The 
CMRR Center’s screening tools and SOP are IRB approved under the 
CMRR Center Grant (HSC# 1406M51205) and information 
regarding screening procedures is publically available on the CMRR 
website (CMRR Policies / Procedures).If at any time it is discovered 
that a participant meets exclusion criteria, they will not be allowed 
to participate further in the study. 
 
Scanning will take place at the Center for Magnetic Resonance 
Research (CMRR) on a 3T Siemens Prisma scanner at baseline 
(after the clinical assessment, before the first treatment) and after 
the last rTMS treatment. Participants will complete MRI safety 
forms and provide a urine sample to rule out substance use (all 
participants) and pregnancy (females only).  
 
A high-resolution T1 image will be collected (voxel size=1mm 
isotropic; TR=2530ms; TE=3.65ms, T1=1100ms, flip angle=7°, 5 
minutes).  
 
Functional data will be acquired using the Human Connectome 
Project (HCP)38 multiband echo planar imaging sequence (whole 
brain T2*-weighted functional volumes, 72 contiguous slices; 
TR=720ms; TE=34.2ms; flip angle=55o, FOV=212mm; voxel 
size=2mm isotropic; matrix=106x106; multiband factor=8; 12 
minutes) during rest with eyes open while viewing a fixation cross.  
Participants will be asked to complete a task fMRI in which they are 
presented with a series of visual stimuli, (human faces of varying 
emotion expressions with positive, negative or neutral words 
printed over the faces). During the task, participants will be asked 
to decide whether the words printed over the faces are positive or 
negative regardless of the emotion of the face shown. Each subject 
will complete four distinct blocks of the task.  
3.7.4  Study treatment procedures. 
All study visits regarding TMS will take place in the Park Plaza 
Building, 5775 Wayzata Boulevard, St. Louis Park. The Brainsway 
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rTMS machine was FDA approved in 2008 as a treatment for 
depression in adults. It has not been FDA approved for use with 
children and adolescents at this time. 
3.7.4.1. Allocation to treatment:  
All participants will receive active rTMS. The target stimulation 
intensity for all subjects will be 120% of MT, but some may receive 
a lower intensity as tolerated. There is no longer a sham phase to 
this protocol. If 2 participants experience a major safety event at 
120% of MT, we will decrease the stimulation intensity to 100% of 
MT and complete the remainder of the subjects at that energy 
level. 
3.7.4.2. Initial Visit:  
Side Effects Baseline Assessment. In the first treatment visit 
research staff will complete the Side Effects Form before treatment, 
in order to obtain a baseline assessment of pre-TMS treatment 
symptoms.  
Motor Mapping and Treatment Tolerance. In the first visit, the study 
physician will fit the cap, determine the ideal location for 
stimulation, and measure motor threshold (MT) (the lowest energy 
intensity where a muscle twitch can be observed, or a 
depolarization measured by EMG, in the right abductor pollicus 
brevis, when the device is placed over the M1 region of the left 
motor cortex).  Beginning at 80% to 100% of MT, we will gradually 
titrate up the intensity to 120% depending on participant tolerance,  
increasing no faster than 10% of MT daily (as applicable). This is 
done until the participant is able to tolerate 120% of MT for the 
duration of their 30 treatment sessions. If the participant has not 
been able to titrate up to 120% of MT after 2 weeks, they will 
complete the study treatment visits at the most tolerable % of MT, 
as clinically determined by on-site treating Psychiatrist. The 30 
treatment sessions will begin at this first visit and include all 
subsequent titration visits even if participant is not able to tolerate 
120% of MT.  
3.7.4.3. Study Treatment:  
Adolescents will receive 6 weeks of active rTMS, targeting mainly 
the left DLPFC for 20 minutes/day, 5 days/week administered by a 
trained technician. Active treatment will be 55 trains of 10 Hz, train 
duration 3.6 seconds, stimulation intensity and titration as 
described above, inter-train interval 20 seconds, 1980 pulses/
session.  
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Participants will be asked to complete the Patient Health 
Questionnaire (PHQ-9) and have their vitals taken daily before each 
rTMS session.  
A member of the research staff will meet weekly with patients and 
parent/guardians to complete the Children’s Depression Rate Scale 
Revised (CDRS-R). Participants will meet with study staff who will 
adminsiter the Young Mania Rating Scale (YMRS), Clinical Global 
Impressions Scale (CGI), Montgomery-Asberg Depression Rating 
Scale (MADRS), and Columbia Suicide Severity Rating Scale – Since 
Last Visit (C-SSRS SLV) . The research staff will also monitor 
treatment tolerance using the Side Effects Form for Children and 
Adolescents. Adolescents will also complete the self-report Beck 
Depression Inventory (BDI-II), State-Trait Anxiety Inventory 
(STAI), the Temporal Experience of Pleasure Scale (TEPS), and the 
Snaith-Hamilton Pleasure Scale (SHAPS) weekly. At week 6, the 
participants will be asked to repeat the ANT, DCCS, California 
Verbal Learning Test (CVLT-II), and the Delis-Kaplan Executive 
Function System (D-KEFS) Trail Making Test. The TMS operator will 
measure MT and MEPa weekly. In addition, the MT and MEPa will be 
repeated as deemed clinically necessary by research staff based on 
patient symptoms and side effects. 
After the completion of treatment, all participants will undergo a 
final assessment during which they and their parents will be asked 
to meet with evaluators again to complete the CDRS-R. Participants 
will also be asked to complete the BDI-II, MADRS, CGI, C-SSRS, 
STAI, TEPS, SHAPS, and IDAS.  
All measures with the exception of the DKEFS, Ant, DCCS and 
CVLT-II will be collected via REDCap, a HIPAA-compliant data 
collection platform. 
3.7.4.4  Breaking the blind:   
 
None of the participants in this study will be blinded to their study 
conditions. 
3.7.4.5 Treatment adherence/Study compliance:  
Participants will not need to be monitored for non-compliance of 
device procedures as their treatments will be administered by a 
trained technician. However, if a participant neglects to attend 
treatment sessions, they will be excluded from the study. 
3.7.5 
Follow-up procedures. 
3.7.5.1 Procedures to assess efficacy: 
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During the course of treatment, a member of research staff will 
meet with study participants on a weekly basis to measure MT 
and MEPa and to complete the Children’s Depression Rating 
Scale – Revised (CDRS-R) with the participant. The participant 
will also complete the Beck Depression Inventory-II (BDI-II) on 
a weekly basis. These depression scales will be compared 
throughout the course of the study to look for improvement.  
After treatment has been completed, participants will be re-
assessed to determine their level of depressive symptoms post-
treatment. Participants whose CDRS-R scores have decreased 
by at least 50% will be considered treatment responders.  
All participants will be asked to complete 6 monthly follow-up 
appointments by in-person or video conferencing interview to 
assess the length of response to treatment and monitor the 
effects of treatment long term. 
Remote Conduct of Study Procedures 
(a)Study staff will collect data using HIPAA-compliant data 
collection platforms (e.g., REDCap, Zoom) as necessary during 
the period of heightened public health concern due to 
COVID-19. 
(b)The above practices are in accordance with the Office of the Vice 
President for Research’s documents Human Research Checklist: 
Preparing for Impact of COVID-19 and Frequently Asked 
Questions: COVID-19 and Human Research released by the 
UMN Human Research Protection Program at the University of 
Minnesota, Twin Cities on March 10, 2020 and March 11, 2020 
(respectively). 
3.7.5.2 Procedures to assess safety: 
During the course of treatment, a member of the research staff 
will meet with study participants on a weekly basis to monitor 
treatment tolerance using the Side Effects Form for Children and 
Adolescents. During the course of treatment, MT will be 
monitored to make sure it doesn’t decrease by more than 10% 
from week to week. MT will also be assessed and adjusted 
based on clinical presentation of the participant (i.e. if 
participant experiences side effects potentially related to MT 
needing to change before the scheduled weekly adjustment). A 
cognitive battery will be used at baseline and week 6 to assure 
there are not any significant changes in cognitive function due 
to treatment. We will also administer the Young Mania Rating 
Scale (YMRS) on a weekly basis to assure that participants are 
not experiencing treatment-induced mania. The Clinical Global 
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Impressions scale (CGI) will be given on a weekly basis. If the 
participant scores a 6 or 7 on the CGI, it will prompt a 
conversation between the PI, the treating TMS physician, the 
participant and the parent/guardian about whether or not they 
should continue in the study. The conversation and decision will 
be documented. 
Suicide risk will be monitored at each visit using the Columbia 
Suicide Severity Rating Scale (C-SSRS). If the participant is 
deemed to be acutely suicidal, he or she will be referred for 
appropriate emergency treatment and will exit the study.   
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3.7.6  Schedule of activities (Study Table). 
Int
ak
e
M
RI 
1
rT
M
S 
W
ee
k 
1
rT
M
S 
W
ee
k 
2
rT
M
S 
W
ee
k 
3
rT
M
S 
W
ee
k 
4
rT
M
S 
W
ee
k 
5
rT
M
S 
W
ee
k 
6
M
RI 
2
Fin
al 
Ass
ess
me
nt
Fo
llo
w-
up 
1
Fo
llo
w-
up 
2
Fo
llo
w-
up 
3
Fo
llo
w-
up 
4
Fol
lo
w-
up 
5
Fo
llo
w-
up 
6
Consent
X
KSAD-S
X
CDRS-R
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BDI-II
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C-SSRS (LV or 
SLV)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TEPS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SHAPS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IDAS
X
X
X
X
X
X
X
X
Side Effects Form
X
X
X
X
X
X
Safety Screen
X
X
X
UTox
X
X
Pregnancy Test
X
X
MRI
X
X
rTMS
X
X
X
X
X
X
MT
X
X
X
X
X
X
MEPa
X
X
X
X
X
X
YMRS
X
X
X
X
X
X
X
ANT
X
X
D-KEFS Trail 
M ki
X
X
CVLT-II
X
X
WASI
X
ATR
X
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Int
ak
e
M
RI 
1
rT
M
S 
W
ee
k 
1
rT
M
S 
W
ee
k 
2
rT
M
S 
W
ee
k 
3
rT
M
S 
W
ee
k 
4
rT
MS 
We
ek 
5
rT
MS 
We
ek 
6
M
RI 
2
Fin
al 
Ass
ess
me
nt
Fol
lo
w-
up 
1
Fol
lo
w-
up 
2
Fol
lo
w-
up 
3
Fol
lo
w-
up 
4
Fol
lo
w-
up 
5
Fol
lo
w-
up 
6
Edinburgh
X
Tanner
X
PHQ-9
X
X
X
X
X
X
STAI
X
X
X
X
X
X
X
  X
MADRS
X
X
X
X
X
X
X
X
CGI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
DCCS
X
X
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3.8 
Study outcome evaluations: 
3.8.1 Study endpoints. 
 
 
 
 
Primary outcome measure: CDRS-R. 
Secondary outcome measures: 
BDI-II, C-SSRS, TEPS, SHAPS, IDAS, MADRS, CGI, STAI 
Endpoint for all participants is after the completion of the 6-month 
follow-up appointment.  
3.8.2 Sample size determination. 
The purpose of this study is to obtain pilot data upon which to base 
a subsequent pivotal study of rTMS for adolescents with TRD. We 
have chosen a total sample size of 30. 
 
 
3.8.3 Outcome data and data analysis. 
3.8.3.1 
rTMS intensity safety analysis 
The design of this study will allow us to collect data on which levels 
of stimulation intensity are safe to use with adolescent participants.   
3.8.3.2 
rTMS effectiveness data analysis 
Repeated measures ANOVAs will examine the effects of rTMS at 
varying levels of stimulation intensities (80%, 100% and 120% of 
MT) on weekly CDRS-R scores and on measures of neuroplasticity 
change (pre- vs. post-treatment RSFC, MET, and MEPa scores). 
Separate analyses of the pre- vs post-treatment CDRS-R scores will 
include group, neuroplasticity change measures, and interaction 
terms to identify whether change in neuroplasticity moderates 
reduction in depression symptoms. Parallel analyses will use logic 
regression with binary responder vs. non-responder outcomes. To 
identify potentially predictive biomarkers of responsiveness to 
rTMS, logistic regression of responder vs. non-responder on 
measures of baseline measures of neuroplasticity will be used. 
3.8.3.3 
Neuroimaging data analysis 
We will optimize components from the HCP minimum processing 
pipeline to fit our imaging protocols and will include gradient non-
linearity distortion corrections, distortion correction caused by 
magnetic field inhomogeneity, co-registration of functional and 
anatomical images, non-linear registration to MNI template brain, 
intensity bias corrections, highpass filtering, re-sampling of the 
data onto the cortical mesh (surface analyses), and denoising of 
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the data using ICA-fix.40 Network Analysis. We will quantify RSFC 
within fronto-limbic and default mode networks as described in our 
prior work. 
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4. Risk analysis 
4.1 Anticipated risks: 
4.1.1  Screening Visit  
Our clinical assessment of all adolescents and parents of children 
enrolled in the study involves asking questions about feelings, past 
experiences, and family history. Some of these topics may cause 
the subjects and/or their parents discomfort or distress. 
Participants are encouraged to share only what they feel 
comfortable with and will not be induced to discuss anything that 
makes them too uncomfortable. 
4.1.2. Repetitive Deep Transcranial Magnetic Stimulation 
(rTMS)  
 
The device to be used in this study is a Brainsway Repetitive Deep 
Transcranial Magnetic Stimulation (rTMS) machine. rTMS is 
considered to be a safe brain stimulation technique that rarely 
results in adverse events. However, there is a risk that rTMS could 
induce a seizure in the participant. Because of standards set for 
rTMS, the risk of seizure has been very well contained. Our 
treatment parameters are well within these safety guidelines. We 
will ask subjects if they have any medical conditions and if they are 
taking any medications. Important medical information such as 
pro-epileptic medications and no history of seizure will be collected 
to screen out those at risk for a rTMS-induced seizure. Safe 
practices will be further ensured by establishing the location for 
testing and treatment within the University of Minnesota’s 
Ambulatory Research Center (ARC) which is located one floor above 
the Emergency Room of the University of Minnesota Medical Center 
(UMMC) Riverside hospital or at the MINCEP Epilepsy Clinic in St. 
Louis Park. Research team members that will be administering 
rTMS will be trained in CPR and in seizure first aid. In the event 
that a participant has a seizure in the ARC, research team members 
will provide initial support and call 888, which will prompt hospital 
staff to come to assist the participant.  In the event that a research 
participant has a seizure at the MINCEP Clinic, the staff if equipped 
to provide treatment. 
 
One of the risks associated with rTMS is treatment-induced mania. 
A member of the research staff will perform the Young Mania Rating 
Scale (YMRS) with the participant each week to determine if the 
participant is experiencing symptoms of mania. 
 
Other mild adverse effects include fainting, headache, dental pain, 
and other changes in memory, mood, and hearing. The overall 
occurrence of mild adverse events is 5% in sham and real rTMS 
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combined. If headaches or dental pain occur, the participant will be 
given Acetaminophen. 
In extreme situations, for subjects reporting pain or discomfort that 
is severe or intolerable, topical application of lidocaine at the 
treatment site has been found to be useful and may be used, at the 
discretion of the site PI, for this study. Additionally, study personnel 
may decrease the “intensity” of the treatment strength to 80% of 
MT as necessary.  It is common that the scalp discomfort abates 
following the first 2-3 treatments.  Titration to maximum treatment 
power will occur as tolerated by each subject. Although if titration 
to the assigned intensity has not occurred after 2 weeks, the 
participant will be excluded from the study. Any report of scalp 
burning sensation by a subject will result in discontinuation of 
treatment for the day.  Treatment would be offered the following 
day or as tolerated within the study timeframe  
rTMS may interfere with implanted devices. rTMS is not appropriate 
for persons with medical devices such as deep brain stimulators, 
pace-makers, and medication pumps. Participants will be screened 
for previous surgeries that might include metal, indwelling medical 
devices, etc. Participants with devices, etc. will not be allowed to 
participate. 
It can be very loud while receiving rTMS. This can be uncomfortable 
and may affect the participant's hearing. Participants will be asked 
to wear ear plugs which will significantly reduce the amount of 
noise. 
4.1.3. MRI scanning  
The device to be used in the study is a 3 Tesla Seimens Prisma MRI 
machine.  
The magnet in the scanner may cause electronic devices like 
watches to malfunction, and some metal objects can be pulled into 
the scanner. Participants will be screened prior to the scan to make 
sure they have nothing in their body which could be magnetic or 
affected by the magnetic field of the scanner. Participants will be 
asked to change into scrubs to ensure they have no metal on their 
person. 
It may be uncomfortable lying still in the scanner for the amount of 
time required. The participant may experience some stiffness and 
soreness in the muscles from being still. To make participants as 
comfortable as possible, we will provide soft pads to help support 
the next, back, and legs. 
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The scanner itself makes a lot of noise while it is running. This can 
be uncomfortable and may affect the participant's hearing. 
Participants will be asked to wear ear plugs which will significantly 
reduce the amount of noise. Participants will also be wearing 
headphones in addition to the earplugs to allow them to hear the 
investigators and listen to music. 
Some people may become uncomfortable in the scanner because 
they are not comfortable being in enclosed spaces. We will screen 
for claustrophobia before we bring the participant to the scan 
center. They will have the option of using a mock scanner prior to 
going into the scanner to assess their level of comfort. They will not 
be required to participate in the scan or continue the scan if they 
are uncomfortable. 
There is a chance we may discover that the participant is pregnant. 
We may also obtain a false positive with the urine toxicology screen 
or pregnancy test. If we discover a participant is pregnant, we will 
let them know. We will also inform them of the risk of obtaining a 
false positive and encourage them to follow up with their primary 
care physician. Although there are no known risks associated with 
scanning pregnant women, we will not scan someone who is 
pregnant. We will not inform the participant’s parent of the results 
unless we feel the pregnancy would cause serious problems for the 
participant. 
There is a chance we might find something abnormal when we look 
at the images of the participant's brain. We will send all images to a 
trained radiologist after the scan so they can be assessed for 
abnormalities. These images will not have any identifying 
information about the patient. If the radiologist recommendation is 
to further investigate the unusual results of the pictures, the 
investigator will contact the participant. 
4.1.4. Text Message Risks 
  
Participants will be able to opt in to communicating with study staff 
via text message to arrange their appointments and receive study 
instructions. There are risks associated with communication via text 
message. Risks of sending or receiving text messages include, but 
are not limited to:   
• 
Others can intercept messages   
• 
Text messages may be viewed by University of Minnesota 
staff depending on the nature and timing of said messages, and 
may be monitored by the University to ensure appropriate use.   
If messages are sent or received on an employer-owned device, the 
employer may have the right to save and read the messages. The 
cell-phone provider may also have the right to save and read text 
messages.   
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 4.2 
Adverse event recording/reporting  
4.2.1 Adverse event definitions. 
Adverse effect. Any untoward medical occurrence in a clinical study 
of an investigational device; regardless of the causal relationship of 
the problem with the device or, if applicable, other study treatment 
or diagnostic product(s). 
Associated with the investigational device or, if applicable, other 
study treatment or diagnostic product(s).  There is a reasonable 
possibility that the adverse effect may have been caused by the 
investigational device or, if applicable, the other study treatment or 
diagnostic product(s). 
Disability.  A substantial disruption of a person’s ability to conduct 
normal life functions. 
Life-threatening adverse effect.  Any adverse effect that places the 
subject, in the view of the investigator-sponsor, at immediate risk 
of death from the effect as it occurred (i.e., does not include an 
adverse effect that, had it actually occurred in a more severe form, 
might have caused death). 
Serious adverse effect. Any adverse effect that results in any of the 
following outcomes: death, a life-threatening adverse effect, 
inpatient hospitalization or prolongation of existing hospitalization, 
a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. 
•
Hospitalization shall include any initial admission (even if less 
than 24 hours) to a healthcare facility as a result of a 
precipitating clinical adverse effect; to include transfer within 
the hospital to an intensive care unit.  Hospitalization or 
prolongation of hospitalization in the absence of a precipitating, 
clinical adverse effect (e.g., for a preexisting condition not 
associated with a new adverse effect or with a worsening of the 
preexisting condition; admission for a protocol-specified 
procedure) is not, in itself, a serious adverse effect.   
Unexpected adverse effect.  Any adverse effect, the frequency, 
specificity or severity of which is not consistent with the risk 
information described in the clinical study protocol(s) or elsewhere 
in the current IDE application, as amended. 
Unanticipated adverse device effect.  Any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, 
or associated with, a device, if that effect, problem, or death was 
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not previously identified in nature, severity, or degree of incidence 
in the investigational plan or IDE application (including a 
supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, 
safety, or welfare of subjects. 
 
 
4.2.2  Eliciting adverse effect information.  
Clinical study subjects will be routinely questioned about adverse 
effects at study visits. 
4.2.3  Recording and assessment of adverse effects. 
All observed or volunteered adverse effects (serious or non-serious) 
and abnormal test findings, regardless of treatment group, if 
applicable, or suspected causal relationship to the investigational 
device or, if applicable, other study treatment or diagnostic 
product(s) will be recorded in the subjects’ case histories.  For all 
adverse effects, sufficient information will be pursued and/or 
obtained so as to permit 1) an adequate determination of the 
outcome of the effect (i.e., whether the effect should be classified 
as a serious adverse effect) and; 2) an assessment of the casual 
relationship between the adverse effect and the investigational 
device or, if applicable, the other study treatment or diagnostic 
product(s).    
Adverse effects or abnormal test findings felt to be associated with 
the investigational device or, if applicable, other study treatment or 
diagnostic product(s) will be followed until the effect (or its 
sequelae) or the abnormal test finding resolves or stabilizes at a 
level acceptable to the investigator-sponsor. 
4.2.3.1  Abnormal test findings:   
An abnormal test finding will be classified as an adverse effect if 
one or more of the following criteria are met: 
•
The test finding is accompanied by clinical symptoms. 
•
The test finding necessitates additional diagnostic 
evaluation(s) or medical/surgical intervention; including 
significant additional concomitant drug or other therapy.  
(Note: simply repeating a test finding, in the absence of any 
of the other listed criteria, does not constitute an adverse 
effect.) 
•
The test finding leads to a change in study dosing or 
exposure or discontinuation of subject participation in the 
clinical study. 
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•
The test finding is considered an adverse effect by the 
investigator-sponsor.  
4.2.3.2  Causality and severity assessment: 
The investigator-sponsor will promptly review documented 
adverse effects and abnormal test findings to determine 1) if the 
abnormal test finding should be classified as an adverse effect; 
2) if there is a reasonable possibility that the adverse effect was 
caused by the investigational device or, if applicable, other study 
treatment or diagnostic product(s); and 3) if the adverse effect 
meets the criteria for a serious adverse effect. 
If the investigator-sponsor’s final determination of causality is 
“unknown and of questionable relationship to the investigational 
device or, if applicable, other study treatment or diagnostic 
product(s)”, the adverse effect will be classified as associated 
with the use of the investigational device or study treatment or 
diagnostic drug product(s) for reporting purposes.  If the 
investigator-sponsor’s final determination of causality is 
“unknown but not related to the investigational device or, if 
applicable, other study treatment or diagnostic product(s)”, this 
determination and the rationale for the determination will be 
documented in the respective subject’s case history.  
4.2.4 Reporting of adverse effects to the FDA.  
The investigator-sponsor will submit a completed Form FDA 3500 A 
to the FDA’s Center for Devices and Radiological Health for any 
observed or volunteered adverse effect that is determined to be an 
unanticipated adverse device effect.  A copy of this completed form 
will be provided to all participating sub-investigators.   
The completed Form FDA 3500 Awill be submitted to the FDA as 
soon as possible and, in no event, later than 10 working days after 
the investigator-sponsor first receives notice of the adverse effect. 
If the results of the sponsor-investigator’s follow-up evaluation 
show that an adverse effect that was initially determined to not 
constitute an unanticipated adverse device effect does, in fact, 
meet the requirements for reporting; the investigator-sponsor will 
submit a completed Form FDA 3500 A as soon as possible, but in 
no event later than 10 working days, after the determination was 
made. 
For each submitted Form FDA 3500 A, the sponsor-investigator will 
identify all previously submitted reports that that addressed a 
similar adverse effect experience and will provide an analysis of the 
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significance of newly reported adverse effect in light of the 
previous, similar report(s). 
Subsequent to the initial submission of a completed Form FDA 3500 
A, the investigator-sponsor will submit additional information 
concerning the reported adverse effect as requested by the FDA. 
4.2.5 Reporting of adverse effects to the responsible IRB.  
In accordance with applicable policies of the University of Minnesota 
Institutional Review Board (IRB), the investigator-sponsor will 
report, to the IRB, any observed or volunteered adverse effect that 
is determined to meet all of the following criteria: 1) associated 
with the investigational device or, if applicable, other study 
treatment or diagnostic product(s); 2) a serious adverse effect; and 
3) an unexpected adverse effect.  Adverse event reports will be 
submitted to the IRB in accordance with the respective IRB 
procedures.  
Applicable adverse effects will be reported to the IRB as soon as 
possible and, in no event, later than 10 calendar days following the 
investigator-sponsor’s receipt of the respective information.  
Adverse effects which are 1) associated with the investigational 
drug or, if applicable, other study treatment or diagnostic 
product(s); 2) fatal or life-threatening; and 3) unexpected will be 
reported to the IRB within 24 hours of the investigator-sponsor’s 
receipt of the respective information.  
Follow-up information to reported adverse effects will be submitted 
to the IRB as soon as the relevant information is available.  If the 
results of the sponsor-investigator’s follow-up investigation show 
that an adverse effect that was initially determined to not require 
reporting to the IRB does, in fact, meet the requirements for 
reporting; the investigator-sponsor will report the adverse effect to 
the IRB as soon as possible, but in no event later than 10 calendar 
days, after the determination was made. 
4.3 
Withdrawal of subjects due to adverse effects: 
Subjects who experience severe adverse events including a seizure, 
treatment-induced mania, or other unanticipated problem where the 
study physician feels it would be unsafe for the patient to continue, 
will be immediately withdrawn from the study. In the case of other 
serious adverse events, the study physician and the patient/family 
will decide whether it would be safe and prudent to have the subject 
continue in the study based on the situation. Subjects who 
experience mild to moderate adverse events will be allowed to 
discontinue if they choose. 
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Subjects withdrawn from study participation due to an adverse effect 
will not be replaced as we have included more people than necessary 
in our original sample size for situations such as subject withdrawal 
or bad MRI data. 
4.4 
Stopping Rules 
In certain cases, participants will be withdrawn from the study for 
their safety. These cases include: 
•
A seizure,  
•
Treatment induced mania as indicated by a YMRS score 
of ≥14,  
•
A suicide attempt or acutely suicidal with plan of intent. 
•
The MT decreases by more than 10% from one week to 
the next, or decreases to where it is 70% or lower than 
the baseline MT. 
•
Excessive motor activation develops (movements in 
upper or lower extremities) for more than 3 treatments 
at the assigned % of motor threshold for that 
participant.  
•
The participant cannot tolerate treatment at the 
assigned % of motor threshold for that participant. 
•
The participant’s depression has significantly worsened 
(received a 6 or 7 on the CGI), and either the P.I., the 
study physician, the participant, the parent felt that it 
would be in the patient’s best interest to stop the study. 
•
TMS technologist is unable to locate and quantify a 
motor threshold. 
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5. Description of the device 
We will be using a Brainsway Deep Transcranial Magnetic Stimulation 
device for this study. This device utilizes an H-coil within a helmet to 
deliver stimulation to participants. 
The department of Psychiatry has already purchased a BrainSway rTMS 
machine, which has been installed in the MINCEP Epilepsy Clinic in St. 
Louis Park. Periodically, the machine may be moved to the Ambulatory 
Research Center (ARC) during periods of transition at the MINCEP Clinic. 
Therefore the equipment and personnel will be ready for the project. 
The BrainSway company has provided assurance that we will be able to 
use the machine at no cost for the study participants 
No changes to the investigational device during the course of the study 
are anticipated. 
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6. Monitoring procedures 
Independent monitoring of the clinical study for clinical protocol and IDE 
application compliance will be conducted periodically (i.e., at a minimum 
of annually) by qualified staff of the University of Minnesota’s Clinical 
and Translational Science Institute (CTSI) monitoring staff. 
   
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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7. Manufacturing information 
Brainsway, manufacturer of the Brainsway Deep TMS System, is certified by 
and operates according to the ISO Quality Management standards: ISO 
1348: 2008 +AC: 2012  
This ensures that Brainsway applies and maintains its Quality Management 
System according to strict guidelines. All departments within Brainsway, 
including Manufacturing, Processing, Packing, Storage and Installation are 
monitored in accordance with the ISO 1348: 2008 and all GMP Guidelines 
Brainsway also has a Quality Assurance department which checks the various 
processes in place within standard work processes.  
All information is stored and allows Brainsway to perform traceability of any 
given product.  
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8. Investigator information 
The proposed research team has the combined expertise necessary to 
conduct the proposed innovative study testing deep rTMS in adolescents with 
TRD and measuring its associated brain mechanisms. Our team has a strong 
track record of collaborating that has led to important advances in identifying 
neurobiological indices of adolescent depression. All investigators involved in 
the proposed study are committed to (a) conducting the investigation in 
accordance with the investigational plan and FDA regulations; (b) supervising 
all testing of the device; and (c) ensuring that the requirements for obtaining 
informed consent are met. 
Dr. Kathryn Cullen, the P.I., is a child and adolescent psychiatrist in the 
Department of Psychiatry who has been practicing and conducting research 
with depressed adolescents over the past eight years. She is P.I. on two NIH-
sponsored grants using MRI technology to evaluate adolescent depression 
and self-injury. She is in the process of conducting a number of treatment 
trials, including a parallel study testing ketamine as a novel treatment for 
adolescents with TRD.  
Dr. Bonnie Klimes-Dougan is a faculty member in the Psychology Department 
who has been conducting clinical evaluations and research on adolescent 
depression for the past 20 years and has been collaborating with Dr. Cullen 
on adolescent depression studies for eight years. She supervises a practicum 
for Ph.D. psychology students who will conduct clinical assessments of the 
adolescent participants and their parents under her supervision. She will also 
assist in providing “blind”, unbiased post-treatment clinical assessment to 
determine treatment responsiveness.  
Dr. Kelvin Lim is a psychiatrist and neuroimaging expert whose work has 
recently moved into using neuromodulation techniques to understand and 
treat mental illness. Dr. Lim served as a research mentor to Dr. Cullen for her 
NIH career development award, and they continue to work closely on several 
different projects.  
Dr. Suma Jacob, M.D. is an associate professor of Child and Adolescent 
Psychiatry at the University of Minnesota who has significant experience in 
clinical trials in child and adolescent psychiatric disorders. Dr. Jacob has 
undergone TMS training through BrainSway. 
Dr. Bryon Mueller is an MRI physicist land an expert in applying the proposed 
advanced technology to examine brain networks, and is an invaluable 
member of the team. He will develop and implement the proposed 
neuroimaging protocol and supervise the processing and imaging data 
analyses.  
Dr. Lynn Eberly is an expert statistician from the Division of Biostatistics, 
School of Public Health. She serves as Dr. Cullen’s statistics mentor on her 
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NIH K23 award and on her CTSI K to R award, and is a co-principal 
investigator with Dr. Cullen on a translational trial testing the impact of a 
novel medication on brain circuitry in adolescents with self-injury. Dr. Eberly’s 
expertise in longitudinal statistical analysis incorporating clinical and imaging 
measures is necessary for the project’s successful completion.  
. 
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9. IRB Information 
Significant public scrutiny and media coverage have occurred over the past 
year regarding psychiatric investigational drug trials performed at the 
University of Minnesota, including the institutional review of such studies. As 
such, the University of Minnesota has decided to transfer review of all clinical 
trials taking place within the Department of Psychiatry to Quorum Review 
IRB. 
Quorum Review IRB 
1501 Fourth Avenue, Suite 800 
Seattle, WA 98101 
Phone: (877) 472-9883 
 
  (206) 448-4082 
Fax:    (206) 448-4193 
For more information about the individuals who comprise the IRB review 
panels, please see the attached document. 
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10. Sales information 
The device is not being sold or leased for purposes of the Study. The Device 
is Brainsway property, which is currently stationed at Research Institution’s 
premises via a separate unrelated agreement. Pending signature of a CTA, 
Brainsway agrees for the device to be used for purposes of this Study.  
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11. Environmental impact statement 
An environmental impact assessment or claim for categorical exclusion is no 
longer required per 21 CFR 25.34(g). 
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12. Labeling 
Please refer to the FDA-approved Instructions for Use (IFU) for the system, 
attached hereto as Exhibit A.  Caution: Use of the system in a manner not 
consistent with the IFU constitutes investigational use and may entail 
significantly increased risk.  
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13. Informed consent materials 
Please see attached Consent, Assent, and HIPAA forms. 
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14. References 
Berlim MT, Van Den Eynde F, Tovar-Perdomo S, Chachamovich E, Zangen A, & Turecki 
G. Augmenting antidepressants with deep transcranial magnetic stimulation (DTMS) 
in treatment resistant depression. The World Journal of Biological Psychiatry 2014: 
Early online 1-9 
Bloch Y, Grisaru N, Hard EV, Beitler G, Faivel N, Ratzoni G, et al. Repetitive 
transcranial magnetic stimulation in the treatment of depression in adolescents: an 
open-label study. J ECT 2008;24(2):153e9 
Carpenter LL, Janicak PG, Aaronson ST, Boyadis T, Brock DG, Cook IA, Dunner DL, 
Lanocha K, Solvason HB, & Demitrack MA. Transcranial magnetic stimulation (TMS) 
for major depression: A multisite, naturalistic, observational study of acute 
treatment outcomes in clinical practice. Depression and Anxiety 2012 29:587-596. 
Chiramberro M, Lindberg N, Isometsa E, Kahkonen S, Appelberg B. Repetitive 
transcranial magnetic stimulation induced seizures in an adolescent patient with 
major depression: A case report. Brain Stimulation 2013 (6):830-833 
Dunner DL, Aaronson ST, Sackheim HA, Janicak PG, Carpenter LL, Boyadjis T, Brock 
DG, Bonneh-Barkay D, Cook IA, Lanocha K, Solvason HB, Demitrack MA. A multisite, 
naturalistic, observational study of transcranial magnetic stimulation for patients with 
pharmacoresistant major depressive disorder: Durability of benefit over a 1-year-
follow-up period. J Clin Psychiatry 2014 75(12):1394-1401 
Garvey MA & Gilbert DL. Transcranial magnetic stimulation in children. European 
Journal of Paediatric Neurology 2004 (8):7-19 
Gilbert DL, Garvey MA, Bansal AS, Lipps T, Zhang J, & Wassermann EM. Should 
transcranial magnetic stimulation research in children be considered minimal risk? 
Clinical Neurophysiology 2004 (115):1730-1739 
Krishnan C, Santos L, Peterson MD, Ehinger M. Safety of non-invasive brain 
stimulation in children and adolescents. Brain Stimulation 2015 (8):76-87 
Lefaucheur JP, Abdre-obadia N, Antal A, Ayache SS, Baeken C, Benniger DH, Cantello 
RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, 
Hummel FC, Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Olivero 
A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, 
Siebner HR, Slotema CW, Stagg CJ, Vall-Sole J, Ziemann U, Paulus W &Garcia-Larrea 
L. Evidence-based guidelines on the therapeutic use of repetitive transcranial 
magnetic stimulation (rTMS). Clinical Neurophysiology 2014 (125):2150-2206 
Levkovitz Y, Isserles M, Padberg F, Lisanby SH, Bystritsky A, Xia G, Tendler A, 
Daskalakis ZJ, Winston JL, Dannon P, Hafez HM, Reti IM, Marales OG, Schlaepfer TE, 
Hollander E, Berman JA, Husain MM, Sofer U, Stein A, Adler S, Deutsch L, Deutsch F, 
Roth Y, George MS, Zangen A. Efficacy and safety of deep transcranial magnetic 
stimulation for major depression: a prospective multicenter randomized controlled 
trial. World Psychiatry 2015 14(1):64-73 
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Rapinesi C, Bersani FS, Kotzalidis GD, Imperatori C, Del Casale A, Di Pietre S, Ferri 
VR, Serata D, Raccah RN, Zangen A, Angeletti G & Girardi P. Maintenance deep 
transcranial magnetic stimulation sessions are associated with reduced depressive 
relapses in patients with unipolar or bipolar depression. Frontiers in Neurology 2015 
6(16): 1-5 
Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, Di Lazzaro V, 
Ferreri F, Fitzgerald PB, George MS, Hallett M, Lefaucheur JP, Langguth B, Matsumoto 
H, Miniussi C, Nitsche MA, Pascual-Leone A, Paulus W, Rossi S, Rothwell JC, Siebner 
HR, Ugawa Y, Walsh V, & Ziemann U. Non-invasive electrical and magnetic 
stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles 
and procuedures for routine clinical and research application. An updated report from 
IFCN committee. Clinical Neurophysiology 2015 (126):1071-1107 
Wall CA, Croarkin PE, Sim LA, Husain MM, Janicak PG, Kozel FA, Emslie GJ, Dowd SM, 
Sampson SM. Adjunctive use of repetitive transcranial magnetic stimulation in 
depressed adolescents: a prospective, open pilot study. J Clin Psychiatry. 2011 
Sep;72(9):1263-9. 
Wall CA, Croarkin PE, Maroney-Smith MJ, Haugen LM, Baruth JM, Frye MA, Sampson 
SM, Port JD. Magnetic Resonance Imaging-Guided, Open-Label, High-Frequency 
Repetitive Transcranial Magnetic Stimulation for Adolescents with Major Depressive 
Disorder. J Child Adolesc Psychopharmacol. 2016 Feb 5. [Epub ahead of print] 
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