Glutamatergic and GABAergic Biomarkers in rTMS for Adolescent Depression
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Mayo Clinic

 
 
Glutamatergic and GABAergic Biomarkers in 
rTMS for Adolescent Depression 
 
NCT03363919 
 
26JUL2021 

Adolescent Biomarker Guided rTMS 
Mayo Clinic IRB # 17-004958  
 Version 6 Date:  26 July 2021 
 
 
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Glutamatergic and GABAergic Biomarkers in rTMS for Adolescent Depression 
 
 
Principal Investigator: 
 
Paul Croarkin DO, MS 
Department of Psychiatry and Psychology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 
 
 
croarkin.paul@mayo.edu 
 
 
 
Co-Investigator(s) 
 
 
Department of Psychiatry and Psychology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 
 
 
 
Department of Psychiatry and Psychology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 
 
 
 
 
Center for Magnetic Resonance Research 
University of Minnesota – Minneapolis 
2021 6th ST SE 
Minneapolis, MN  55455 
 
 
 
 
(Biostatistician) 
Associate Professor 
Department of Clinical Sciences 
Division of Biostatistics 
 

Adolescent Biomarker Guided rTMS 
Mayo Clinic IRB # 17-004958  
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2 
 
UT Southwestern Medical Center 
Dallas, TX  75390-8828 
 
     
 
   
 
 
 
Department of Psychiatry and Psychology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 
 
 
 
Department of Psychiatry and Psychology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 
 
 
 
Department of Psychiatry and Psychology 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 
 
 
Funding Sponsor: 
 
National Institute of Mental Health  
(1R01 MH113700) 
 
Neuronetics, Inc. 
(Grant-in-kind for equipment support) 
 
 
Study Product: 
NeuroStar TMS Therapy® System in 
XPLOR research configuration 
Protocol Number:   
May Clinic IRB# 17-004958  
IDE Number: 
 
 G170212 
 

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 Protocol Date  6 June 2018 Version (3.0)  
 
Version 
No. 
Date 
Major Changes 
1 
16Sept2017 
Initial 
2 
26Sept2017 
DSMB recommended changes 
3 
6June2018 
Add MRI/MRS portion and other recommendations from NIMH 
monitor report 
4 
10May2019 
Complete Baseline assessments at Screening Visit to ease subject 
burden/ use of i2b2 as a recruitment tool/ IRB approved phone 
script, email and contact letter used for recruitment 
5 
20Jan2020 
Blurred Vision: FDA requested protocol changes/added side effect 
“blurred vision” to consent form/changes in AE documentation  
6 
26 July 2021 
The FDA recommended additional screening and monitoring for 
extrapyramidal twitching/trembling prior to starting the study 
procedures and throughout the study. The Abnormal Involuntary 
Movement Scale (AIMS) will be collected at the screening visit 
and at weekly assessments during Phase I and II investigational 
treatments and at the 6 month posttreatment visit.  
 
 
 
 
 
 

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Table of Contents 
STUDY SUMMARY .................................................................................................................................  
1 
INTRODUCTION ............................................................................................................................  
1.1 
BACKGROUND .......................................................................................................................................... 1.2
 
INVESTIGATIONAL DEVICE ............................................................................................................................ 
1.3 
PRECLINICAL DATA .................................................................................................................................. 1.4
 
CLINICAL DATA TO DATE......................................................................................................................... 1.5
 
STUDY RATIONALE AND RISK ANALYSIS (RISKS TO BENEFITS RATIO) ......................................................... 
1.5.1 
Study Rationale .............................................................................................................. 1.5.2
 
Anticipated Risks ..................................................................................................................  
1.5.3 
Potential Benefits ..................................................................................................................  
1.6 
ANTICIPATED DURATION OF THE CLINICAL INVESTIGATION ......................................................................... 
2 
STUDY OBJECTIVES .................................................................................................................... 3
 
STUDY DESIGN ..............................................................................................................................  
3.1 
GENERAL DESIGN..................................................................................................................................... 3.2
 
PRIMARY STUDY ENDPOINTS ........................................................................................................................ 
3.3 
SECONDARY STUDY ENDPOINTS…………………………………………………………………………. 
3.4 
PRIMARY SAFETY ENDPOINTS ....................................................................................................................... 
4 
PARTICIPANT SELECTION, ENROLLMENT AND WITHDRAWAL .........................................  
4.1 
INCLUSION CRITERIA ................................................................................................................................ 4.2
 
EXCLUSION CRITERIA ................................................................................................................................... 
4.3 
PARTICIPANT RECRUITMENT, ENROLLMENT AND SCREENING ...................................................................... 
4.4 
EARLY WITHDRAWAL OF PARTICIPANTS ....................................................................................................... 
4.4.1 
When and How to Withdraw Participant………………………………………………………………….. 
4.4.2 
Data Collection and Follow-up for Withdrawn Participant…………………………………………… 
5 
STUDY DEVICE .............................................................................................................................  
5.1
 
DESCRIPTION……………………………………………………………………………………………..5.
2 
METHOD FOR ASSIGNING PARTICIPANTS TO TREATMENT GROUPS ............................................................... 
5.3 
PREPARATION AND ADMINISTRATION/IMPLANTATION OF INVESTIGATIONAL DEVICE……………….5.4
 
PACKAGING AND LABELING ..................................................................................................................... 5.5
 
MASKING/BLINDING OF STUDY ..................................................................................................................... 
5.6 
RECEIVING, STORAGE, DISTRIBUTION AND RETURN…………………………………………………….. 
6 
STUDY PROCEDURES ...................................................................................................................  
6.1 
VISIT 
1…………………………………………………………………………………………………6.2
 
VISIT 2………………………………………………………………………………………………… 
    6.3          Daily Visits…………………………………………………………………………………………… 
7 
STATISTICAL PLAN ......................................................................................................................  
7.1 
SAMPLE SIZE DETERMINATION ..................................................................................................................... 
7.2 
STATISTICAL METHODS................................................................................................................................. 
8 
SAFETY AND ADVERSE EVENTS ........................................................................................... ….. 
8.1 
DEFINITIONS ............................................................................................................................................. 8.2
 
RECORDING OF ADVERSE EVENTS............................................................................................................ 8.3
 
SPONSOR-INVESTIGATOR 
REPORTING 
OF 
UNANTICIPATED 
ADVERSE 
DEVICE 
EFFECTS 
AND 
UNANTICIPATED PROBLEMS ........................................................................................................................................ 
8.3.1 
Sponsor-Investigator Reporting, Notifying Mayo IRB ........................................................ 8.3.2
 
Sponsor-Investigator Reporting: Notifying the FDA .................................................................  
         8.3.3      Deviations From Investigational Plan……………………………………………………………..  

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8.4 
UNBLINDING PROCEDURES (BREAKING THE BLIND) (AS NECESSARY IF THE STUDY IS BLINDED) .................. 
8.5 
STOPPING RULES ...................................................................................................................................... 8.6
 
MEDICAL MONITORING…………………………………………………………………………………. 
8.6.1 
Independent Data and Safety Monitoring Board ............................................. ………………… 
9 
DATA HANDLING AND RECORD KEEPING ...............................................................................  
9.1 
CONFIDENTIALITY .................................................................................................................................... 9.2
 
SOURCE DOCUMENTS .................................................................................................................................... 
9.3 
CASE REPORT FORMS .................................................................................................................................... 
9.4 
DATA MANAGEMENT ............................................................................................................................. 
    9.5         DATA SECURITY AND CONFIDENTIALITY……………………………………………………..…    
9.6          Records Retention……………………………………………………………………………………….. 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .............................................................  
10.1 
STUDY MONITORING PLAN ....................................................................................................................... 61 
10.2 
AUDITING AND INSPECTING ........................................................................................................................... 
11 
ETHICAL CONSIDERATIONS ................................................................................................... 12
 
STUDY FINANCES .........................................................................................................................  
12.1 
FUNDING SOURCE .................................................................................................................................. 12.2
 
PARTICIPANT STIPENDS OR PAYMENTS ......................................................................................................... 
13 
PUBLICATION PLAN ................................................................................................................. 14
 
REFERENCES ............................................................................................................................. 15
 
ATTACHMENTS (APPENDIX A) ...................................................................................................  
16     ATTACHMENTS (APPENDIX B)……………………………………………………………………..  
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ATHF 
Antidepressant Treatment History Form. 
BDI-II 
Beck Depression Inventory-II 
CDRS-R 
Children’s Depression Rating Scale, Revised 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression-Severity Scale 
CRF 
Case Report Form 
CSP 
Cortical Silent Period 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTQ 
Childhood Trauma Questionnaire  
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GABA 
Gamma aminobutyric acid 
HIPAA 
Health Insurance Portability and Accountability Act 
Hz 
Hertz 
ICF 
Intracortical facilitation 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
cTBS 
Continuous Theta Burst Stimulation 
iTBS 
Intermittent Theta Burst Stimulation 
LDLPFC 
Left Dorsolateral Prefrontal Cortex 
LICI 
Long Interval Intracortical Inhibition 
MDD 
Major Depressive Disorder 
MEP 
Motor Evoked Potential  
MINI 
Mini International Neuropsychiatric Interview 
ms 
Millisecond 
MRI 
Magnetic Resonance Imaging 
MRS 
Magnetic Resonance Spectroscopy 
MT 
Motor Threshold 
NIH 
National Institute of Health 
NIMH 
National Institute of Mental Health 
PDS 
Pubertal Development Scale and Tanner Staging 
PI 
Principal Investigator 
QIDS-A17-SR 
Quick Inventory of Depressive Symptoms  
 
Adolescent Self-Report 
RDLPFC 
Right Dorsolateral Prefrontal Cortex 
rTMS 
Repetitive Transcranial Magnetic Stimulation 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SHAPS 
Snaith-Hamilton Pleasure Scale 
SIT-R3 
Slosson Intelligence Test – Revised 
SICI 
Short Interval Intracortical Inhibition 
SOP 
Standard Operating Procedure 
TASS 
Transcranial Magnetic Stimulation Adult Safety Screen 

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T 
Tesla 
TBS 
Theta Burst Stimulation 
TEAE 
Treatment Emergent Adverse Event 
TEEQ-A and TEEQ-P 
Treatment 
Expectations 
and 
Experience 
Questionnaires 
Adolescent and Parent Versions 
TMS 
Transcranial Magnetic Stimulation 
TORDIA 
Treatment of Resistant Depression in Adolescents  
UADE 
Unanticipated Adverse Device Effect 
UPIRTSO 
Unanticipated Problems Involving Risk to Participants or 
Others 
YMRS 
Young Mania Rating Scale 

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Study Summary 
 
Title 
Glutamatergic and GABAergic Biomarkers in rTMS for Adolescent 
Depression 
Running Title 
Adolescent Biomarker Guided rTMS 
IRB Protocol 
Number 
17-004958 
Phase 
Pivotal  
Methodology 
Phase I is a double-blind, randomized, biomarker-stratified trial of 1 Hz 
vs. 10 Hz rTMS.  Phase II is for participants who do not respond to 
Phase I treatment and is a biomarker guided, double-blind trial of 
continuous vs intermittent theta burst stimulation (TBS). Please note 
that transcranial magnetic stimulation (TMS) biomarkers will be 
collected in this protocol during the course of the proposed 
interventions. Participants in Phase I will also be offered   3 and 7 Tesla 
Magnetic Resonance Imaging (MRI) and Magnetic Resonance 
Spectroscopy (MRS) scans at the University of Minnesota Center for 
Magnetic Resonance Research. 
Overall Study 
Duration 
5 years 
Participant Time 
Commitment 
Phase I – 6 months (1 week screening, 6 weeks of active treatment, 6 
month follow up visit) 
 
Phase II- 6 months (1 week screening, 2 weeks of active treatment, 6 
month follow up visit) 
Objectives 
To perform an effectiveness and target validation trial of 1 Hz vs. 10 Hz 
rTMS with a randomized, biomarker-stratified design. The target 
engagement and stratification biomarker is intracortical facilitation 
(ICF) a measure of glutamatergic tone in the brain.  Cortical GABA, 
glutamate, and glutamine measured with 7 Tesla MRS will be collected 
in healthy controls at baseline and depressed participants at baseline and 
after 6 weeks of TMS treatment in phase I.  
Number of 
Participants 
Phase I- 120 participants  
Phase II- 50 participants (maximum) 
MRI – 100 Depressed Subjects (Must be Eligible for Phase I) 
             30 Healthy Controls 
Diagnosis and Main 
Inclusion Criteria 
Depressed adolescent (ages 12-18) participants with moderate to severe 
major depressive disorder (MDD) defined by a score of 40 or greater on 
the Children’s Depression Rating Scale, Revised (CDRS-R) and an 
interview with the Mini International Neuropsychiatric Interview 
(MINI). 
Study Device 
NeuroStar® TMS Therapy System in XPLOR research configuration 

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Duration of 
Exposure 
Phase I - 6 weeks (30 sessions) and 3 week taper (3 sessions for one 
week, then 2 sessions for the next week, then 1 session for the last week 
of the taper).  Based on randomization participants will either receive 
sessions of 1 Hz rTMS at 120 % motor threshold (MT) with 2400 
continuous pulses or 10 Hz rTMS at 120 % MT with 4 seconds on and 
36 seconds off for 2400 pulses.  Both 1 Hz and 10 Hz rTMS sessions 
will be delivered to the left dorsolateral prefrontal cortex (LDLPFC). 
 
Phase II- 2 weeks (10 sessions) of continuous theta burst (cTBS) or 
intermittent theta burst (iTBS) based on biomarker (ICF) status. Note 
that TBS sessions involve the delivery of 3 pulses of 50 Hz stimulation 
given every 200 milliseconds (ms) or 5 Hz.  Participants assigned to 
cTBS will receive 10 daily sessions (5 sessions per week for two weeks) 
with 120 second trains of uninterrupted TBS for 1800 pulses at 80% 
MT. Participants assigned to iTBS will receive 10 daily sessions (5 
sessions per week for two weeks) with 2 second trains every 10 seconds 
for a total of 570 seconds for 1800 pulses.  Both cTBS and iTBS 
sessions will be delivered to the LDLPFC. 
  
NeuroStar TMS is not an implant. Stimulation is delivered during the 
daily sessions in the neurostimulation suite.   
Reference therapy 
Not Applicable 
Statistical 
Methodology 
For the primary aim, a linear mixed model analysis of repeated 
measures will be used to evaluate the repetitive transcranial magnetic 
stimulation (rTMS) by biomarker status interaction effect on depression 
severity (CDRS-R score) over 6 weeks of rTMS. 
 
For the secondary aim, a within-participant linear mixed model analysis 
of repeated measures will be used to examine the change in ICF over 6 
weeks of rTMS. 
 
For the exploratory aims, a within-subjects linear mixed model analysis 
of repeated measures will be used to examine the change in cortical 
MRS measures of GABA, glutamate, and glutamine over 6 weeks of 
rTMS 
treatment 
in 
depressed 
adolescents. 
A 
multiple  
mediation/moderation path analytic model will be used to estimate the 
direct effect as well as the total and specific indirect effects of rTMS 
treatment on depression severity (at the 6-week endpoint) through each 
potential baseline moderator (anhedonia and adversity).   
 

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1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the procedures described in this protocol, applicable United States government 
regulations and Mayo Clinic policies and procedures.  
1.1 
Background 
Adolescent depression is a substantial global public health problem which contributes to 
academic failure, occupational impairment, deficits in social function, substance use disorders, 
teen pregnancy, and completed suicides.1-3 Existing treatment approaches such as psychotherapy, 
pharmacotherapy, or combinations often have suboptimal results and uncertain safety profiles.3-6 
For example, ongoing controversies regarding the effectiveness and safety of selective serotonin 
reuptake inhibitors underscore the concern that current treatment modalities do not target 
relevant, pathophysiology in a neurodevelopmentally informed manner.5  This is a lost 
opportunity as intervention early in life could prevent years of disability and suffering on an 
individual level and a substantial societal economic burden.  Unfortunately, interventions for 
adolescent depressive disorders are often simply adapted from existing adult treatments and 
studied in heterogenous groups of adolescents7. Dimensional and experimental medicine 
approaches offer the opportunity to optimize existing treatment options and catalyze innovation 
for adolescent depression.8,9 For example, anhedonia and historical adversity are key elements of 
the negative valence systems domain and markers of treatment resistance.10-12  A refined 
understanding of anhedonia and adversity would provide the opportunity to develop targeted 
treatment approaches. 
 
Imbalances in GABAergic and glutamatergic tone play a key role in depression,13,14 
pathophysiologic stress responses,15 and emotional numbing or anhedonia found in behavioral 
manifestations of the negative valence system.16 These GABAergic and glutamatergic 
imbalances have differential causes, effects, and behavioral manifestations in adolescents as 
compared to adults.17-19 For example, recent preclinical work has demonstrated that repeated 
stress in adolescent rats inhibits GABAergic projections to the amygdala thereby impairing 
regulatory neurocircuitry.20  In adult rats, chronic stress facilitates glutamatergic excitatory 
neurotransmission with ensuing effects on the lateral nucleus of the amygdala, hippocampus, and 
frontal cortex.21-23 Developmental differences in frontolimibic GABAergic and glutamatergic 
tone may underlie variances in adolescent depressive symptom presentations and treatment 
responsivity.20,24,25  A deeper understanding of frontolimbic GABAergic and glutamatergic tone 
in adolescent depression would assist with precision medicine approaches and intervention 
development.  Certain types of transcranial magnetic stimulation (TMS) provide noninvasive 
measures of cortical GABAergic and glutamategeric tone.26-28 There are different types of TMS.  
Repetitive TMS (rTMS) delivers multiple pulses per session over many days or weeks for 
therapeutic purposes.  The effects of rTMS can also be studied as a probe of brain function.  
Theta burst stimulation (TBS) is a form of rTMS that is thought to have more rapid effects on 
synaptic plasticity and clinical symptoms than standard rTMS.  Single and paired-pulse TMS 
paradigms are used to study the physiology of the brain.  Neurophysiological measures collected 
with transcranial magnetic stimulation (TMS) such as intracortical facilitation (ICF), short-
interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), and the 

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cortical silent period (CSP) are noninvasive measures of cortical GABAergic and glutamatergic 
tone.28-31  
 
Neurostimulation technologies such as rTMS have great potential as enduring, brain-based 
interventions for depression in adolescents.32,33  Treatment with rTMS addresses pathologic 
imbalances in cortical GABAergic inhibitory and excitatory glutamatergic frontolimbic 
neurocircuitry.34-36  At present, adults with broad presentations of depression are typically treated 
empirically with high frequency (10 Hz) rTMS applied to the LDLPFC as this dosing approach 
has been widely studied.37,38  However, prior literature suggests that low frequency (1 Hz) rTMS 
applied to the right dorsolateral prefrontal cortex (RDLPFC) may be equally effective with 
superior tolerability.39-42 Left-sided, 1 Hz rTMS applied to the LDLPFC may have similar 
antidepressant and neurophysiologic effects as RDLFPC 1 Hz rTMS.  For example, early studies 
with positron emission tomography43 and near infrared spectroscopy44 suggest that prefrontal 1 
Hz rTMS has a global, bilateral effect on brain activity. Questions of laterality in therapeutic 1 
Hz rTMS have been inadequately studied and prior research often utilized right-sided 1 Hz based 
on dogma more than science.45-47  Other work posits that patients with depression may have 
variable responses to these two dosing strategies (1 Hz vs. 10 Hz) necessitating a more 
sophisticated neurobiological understanding and precision medicine approaches.34,48  Although 
rTMS has demonstrated promise for adolescent depression, the mechanisms of 1 Hz vs. 10 Hz 
rTMS dosing have not been adequately studied in adolescent depression, creating a substantial 
knowledge gap.33  Research in this area is critical as the neurobiologic effects of 1 Hz and 10 Hz 
rTMS in adolescent depression likely diverge from adult depression. 49-51 The study of 1 Hz 
rTMS in adolescents is particularly critical as it would have advantages in terms of safety and 
tolerability 
for 
widespread 
dissemination. 
A 
basic, 
neurodevelopmentally 
informed 
understanding of standard rTMS dosing approaches (1 Hz and 10 Hz) is an ethical and scientific 
prerequisite for future large, pivotal studies of patterned dosing such as TBS for adolescent 
depression.51,52   
Currently our group is leading a multicenter randomized, sham-controlled trial of rTMS for 
adolescent depression (A Randomized, Sham-Controlled Trial Evaluation of the Safety and 
Effectiveness of NeuroStar Transcranial Magnetic Stimulation (TMS) Therapy in Depressed 
Adolescents).  Phase I of the study is a 6 week (30 treatment sessions), randomized, sham-
controlled study of 10 Hz rTMS delivered to the left dorsolateral prefrontal cortex (LDLPC).  
The rTMS is targeted and dosed with the abductor pollicis brevis, “5-cm rule.”  Phase II is a 6 
week open-label treatment course of 10 Hz rTMS for participants who did not respond to 
treatment in Phase I.  Phase III is a follow-up phase for subjects that had clinical benefit in Phase 
I or II.  The target enrollment for this study is 100 participants.  Presently, 99 participants have 
enrolled and it is anticipated that enrollment will close in late 2017 or early 2018.  Hence, the 
proposed dose finding and target validation study would not be expected to run concurrently with 
the existing industry trial.  While the current industry supported effort will provide important 
systematic data and practical experience, the study design has inherent limitations. As a result, 
findings will not substantially advance the mechanistic understanding of rTMS in the context of 
neurodevelopment.2,5 First, the industry supported study design replicates a longstanding flaw of 
interventional work in children and adolescents (spanning psychotherapy, pharmacology, and 
novel therapeutics) in which adult protocols and dosing schedules are simply applied to children 
or adolescents.6-8  Second, the current industry supported clinical trial will not inform target 
engagement efforts nor advance understanding of the neurobiological underpinnings of 

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adolescent depression and responsivity to 10 Hz rTMS. Third, there is a paucity of data on low 
frequency (1 Hz) rTMS in adolescents and in general.9-11  Systematic data demonstrating benefit 
of 1 Hz rTMS in adolescent depression or subpopulations would have utility as this dosing might 
be more tolerable, safe, and optimal for widespread delivery. 
 
Hence for the present protocol we have designed an effectiveness and target validation trial of 1 
Hz vs. 10 Hz rTMS. While the inclusion of a sham arm would be ideal, there are substantial 
pragmatic and financial barriers to completing such a study as a single site while concurrently 
addressing other critical National Institute of Mental Health (NIMH) priorities. Studies of 1 Hz 
rTMS and mechanistic studies of rTMS in adolescents would address a substantial knowledge 
gap and could provide further innovations. Unfortunately, there is a low probability that this will 
be studied systematically outside of a federally funded grant and even less likely that the 
neurobiologic mechanisms associated with 1 Hz and 10 Hz rTMS in adolescent depression will 
be adequately studied.   
 
Developmentally informed, targeted interventions with rTMS for adolescent depression could 
reap important gains on an individual and population level as cortical, GABAergic and 
glutamatergic tone continues to change throughout development setting the stage for important 
future functions.17,53  Prior rTMS research focused on depression often has a fatal flaw as 
heterogenous groups of patients have been studied with insufficient clinical characterization.33,52  
Anhedonia54 and adversity55,56 in depressed adolescents are important dimensional traits to 
quantify in terms of GABAergic tone, glutamatergic tone, and treatment responsivity to 1 Hz and 
10 Hz rTMS.  Examining a cohort of depressed adolescents and healthy controls with TMS 
neurophysiology would deepen our understanding of the role of GABA and glutamate in the 
negative valence systems domain.56,57  
 
Prior work demonstrates that anhedonia is a marker of treatment resistance, poor outcomes, and 
suicidality.  For example, recent multivariate analyses from the landmark Treatment of Resistant 
Depression in Adolescents (TORDIA) study identified a dimensional measure of anhedonia as 
the primary predictor of increased time to remission and decreased depression-free days in a 
large (n=334) cohort of adolescents with treatment resistant depression.11 Notably patients with 
historical sexual or physical abuse also had decreased response rates in the TORDIA study.10  In 
other recent work, anhedonia severity in depressed adolescents was associated with illness 
severity, suicidality, duration of illness, and number of depressive episodes.12  Although 
incompletely understood, anhedonia and historical adversity appear to have associations with 
accentuated disruptions in GABAergic58 and glutamatergic59,60 tone in frontolimbic circuitry.   
Recent work demonstrated that adolescents with anhedonia have decreased GABA levels in the 
anterior cingulate cortex16 while glutamatergic tone in the basal ganglia was associated with 
clinical measures of anhedonia.61  Preclinical work also implicates imbalances of GABAergic 
and glutamatergic tone in treatment resistance.23,62 These collective findings suggest that 
depressed adolescents with anhedonia or historical adversity are a population in great need of 
effective, brain-based interventions.  Dimensional studies of anhedonia and adversity will assist 
in the development of targeted, neurobiologically informed treatments.8,9  
 
 
MRS Biomarkers of GABAergic and Glutamatergic Tones in rTMS Studies  

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Prior work demonstrated that the glutamine to glutamate ratio (Gln/Glu) is a sensitive measure of 
cortical glutamate-glutamine cycle dysfunction in severe psychiatric disorders. In our prior MRS 
study, 6 weeks of 10 Hz rTMS modulated cortical glutamatergic tone in depressed adolescents.  
Baseline, posttreatment, and 6 month follow up MRS 3 T scans examined glutamate 
concentrations in 8 cm voxels from the left dorsolateral prefrontal and anterior cingulate cortices  
(Figure1).  Spectroscopic data were collected with an optimized, intermediate echo time, point 
resolved spectroscopy (PRESS) sequence and 2-dimensional J-resolved averaged PRESS 
sequence. After 6 weeks of rTMS, mean Gln/Glu ratios increased from baseline and at 6 month 
follow-up in both voxels with both sequences.  Mixed model repeated measures analysis 
revealed a significant negative relationship between depression severity as assessed with the 
CDRS-R and the Gln/Glu ratio in the dorsolateral prefrontal cortex (b̂  = –0.00127; 95% CI, –
0.00207 to –0.00048; raw P=.003; false discovery rate P=.01).  Hence, throughout treatment and 
follow-up period, decreases in depressive symptom severity had an indirect relationship to 
increases in the Gln/Glu ratio.  This initial work presents many unanswered questions.  
Resolving GABA, glutamate, and glutamine at 3 T in a single acquisition is challenging to 
impossible. Special techniques can be used to quantify each of the neurochemicals separately, 
but that results in three different acquisitions which dramatically increases acquisition time.  Our 
current methodologies do not adequately resolve cortical GABA concentrations and may yield 
imprecise measures of glutamine concentrations as Cramer-Rao lower bounds (CRLB) criteria 
are suboptimal.  Current work with 7 T MRS demonstrates promise in resolving and quantifying 
GABA, glutamate, and glutamine in a single acquisition. To our knowledge, 7 T MRS has not 
been used to study adolescent depression previously.63,64 
 
Ultra-High Field MRS for Biomarker Development in Adolescent Depression  
 
Recent work in adult humans with 7 T MRS and stimulated echo acquisition mode (STEAM) 
sequence has enhanced the detection and resolution of glutamate, glutamine and GABA 
(Figure2). In young adults (18 to 22 years of age), glutamate and glutamine could be quantified 
separately in the early visual cortex with very low CRLB of 2.0% ± 0 and 2.7 ± 0.3%, 
respectively which is not possible at 3 T.  Additionally, GABA was quantified with CRLB of 
13.5 ± 4.6%.  The spectra were acquired in 5 minutes from 2 x 2 x 2 cm3 volume of interest 
placed in the early visual cortex with STEAM sequence (TR = 5 s, TE = 8 ms, number of 
averages = 64). Additionally, quantified glutamate, glutamine and GABA concentrations from 
spectra acquired at TE of 8 ms removes a possible confound of changing T2.  Good quality data 
can be obtained in the frontal lobe using a prototype coil.63,64  
1.2 
Investigational Device 
 
The NeuroStar™ XPLOR® TMS Therapy System will be used to deliver all of the proposed 
investigational rTMS sessions (1 Hz, 10 Hz, cTBS, and iTBS).  The NeuroStar™ XPLOR® TMS 
Therapy System is a clinical research option for the NeuroStar™ TMS Therapy System that 
provides features necessary to conduct randomized trials and other TMS research.  The 
NeuroStar™ TMS Therapy System is a computerized electromechanical instrument that 
produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce 
electrical currents in localized regions of the cerebral cortex for use in the treatment of MDD in 
adults who have failed to receive benefit from antidepressant medications.  The XPLOR® 

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research configuration consists of three coils: a known-active coil identical to the NeuroStar™ 
TMS System treatment coil and two identical, “blinded” coils.  One of the blinded coils provides 
active treatment identical to the known-active NeuroStar™ TMS system treatment coil; the sham 
coil provides acoustically indistinguishable (from active) pulses and a gentle percussive 
sensation that simulates scalp sensations produced during active treatment. Please note that the 
sham and blinded coils will not be used in this protocol. 
 
The proposed study also involves the investigational use of the Magstim Model 200 magnetic 
nerve stimulator to collect cortical neurophysiological biomarkers with single and paired-pulse 
TMS.  Please reference previous I111173-Study Determination.  Previous US FDA risk 
determinations have communicated that single and paired-pulse TMS biomarker studies do not 
fall into the scope of Investigational Device Exemption (IDE) regulation and do not require an 
IDE application. Data collected with the Magstim Model 200 magnetic nerve stimulator is for 
basic physiological research of major depressive disorder.  We do not intend to collect data on 
the safety and effectiveness of the Magstim Model 200 magnetic nerve stimulator.  
The Magstim Model 200 will be used to collect the proposed TMS biomarkers: motor threshold 
(MT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), long interval   
intracortical inhibition (LICI), and cortical silent period (CSP).  The Magstim Model 200 is a 
magnetic nerve stimulator FDA approved for the stimulation of peripheral nerves for diagnostic 
purposes. As with other magnetic stimulators it is made up of two distinct components:  
 
a. A high current pulse generator producing currents of approximately 5,000 amps.  
b. A stimulating coil producing magnetic pulses with field strengths of approximately 1 
tesla and a pulse duration of 1 ms. 
 
Magnetic stimulation is achieved by discharging the Magstim Model 200 coil near 
neuromuscular tissues. Current flows from the instrument through the coil in one of two 
directions (depending on which side of the coil is facing the scalp). If side A is visible and side B 
is facing the site of stimulation, coil current flows in a counterclockwise direction and within the 
tissues current flows in a clockwise direction. If side B is visible and side A is facing the site of 
stimulation, coil current flows in a clockwise direction and within the tissues current flows in the 
counterclockwise direction. In the coil, current flows from positive to negative. Within tissues, 
current flow signifies the movement of ions. 
 
The Mayo Clinic Neurostimulation Laboratory is equipped with two single-pulse magnetic 
stimulators (Magstim 200) and a bi-stim module for the delivery of paired magnetic stimuli at 
interstimulus intervals as short as 1 ms. A bank of 4 custom-modified electrically isolated 
bioelectric amplifiers is used to record the motor evoked potential (MEP) for motor threshold 
determination. These bio-amplifiers are battery powered for AC isolation and customized to 
reduce artifact induced by magnetic pulses. Features include low distortion and noise. They have 
especially rapid rate recovery after saturating signals. The amplified signals are digitized with 
Dell Dimension P200V (200 MHz) personal computers using analogic LS-DAS-12 A/Ds (250 
kHz). Computing facilities in the lab include a personal computer for the acquisition of 
electrophysiological data. 
 

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Figure 1. Feasibility of 10 Hz 
rTMS for Adolescent Depression. 
1.3 
Preclinical Data 
 
Please see prior IDE applications G060269, G110091, G120121, present IDE application, prior 
Study Determination (I111173), and all associated references.   
 
1.4 
Clinical Data to Date 
 
Please see prior IDE applications G060269, G110091, G120121, present application, prior Study 
Determination (I111173), and all associated references. 
  
Preliminary Studies: Our prior research with TMS measures of ICF53,65 and investigation studies 
of 10 Hz rTMS66-70 form the basis of this application.  Collectively, this body of work suggests 
that ICF has utility as a biomarker in depressed adolescents53,65, rTMS may modulate cortical 
measures of glutamatergic tone,70 and that investigational, therapeutic rTMS protocols have 
feasibility for adolescents with moderate to severe depressive symptoms.64,69  Our prior work 
informed a multicenter, industry sponsored clinical trials of rTMS.  To our knowledge, clinical 
trial efforts have only examined standard adult dosing of 10 Hz rTMS in adolescents with no 
consideration or examination of developmental differences, mechanistic effects, and biomarkers.  
To our knowledge, no prior studies of adolescent depression have examined rTMS dose 
comparisons (1 Hz vs. 10 Hz) or explanatory biomarkers in the context of variable dosing.33,52  
Developmentally informed studies of 1 Hz and 10 Hz rTMS for adolescent depression are 
essential as adolescents may have differential treatment and neurophysiological responses. An 
enhanced understanding of the neurophysiology of rTMS in adolescents would inform future 
work with intermittent theta burst stimulation and could catalyze the development of new 
experimental dosing strategies for rTMS in adolescent depression.          
 
Our lab has now treated more than 30 depressed 
adolescents in the course of three distinct studies of 10 
Hz rTMS, at 120% motor threshold, applied to the left 
dorsolateral prefrontal cortex for 30 sessions over 6 
weeks.66,69  Initial results are encouraging in terms of 
feasibility and patient retention.  Primary clinical 
outcome measures with the clinician rated CDRS-R and 
secondary self-report measures with the 17 item Quick 
Inventory of Depressive Symptomatology Adolescent 
Version 
Self-Report 
(QIDS-A17-SR) 
demonstrated 
significant improvements throughout the 6 week 
treatments, posttreatment, and at a 6 month follow up 
visit (Figure 1). The durability of clinical effect at 6 
months is noteworthy and seldom seen in interventional studies of adolescent depression.  
However, these initial efforts have simply examined adult dosing schedules of 10 Hz rTMS and 
are not informed by target engagement strategies.  
 

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1.5 
Study Rationale and Risk Analysis (Risks to Benefits Ratio) 
1.5.1 Study Rationale 
 
Repetitive transcranial magnetic stimulation (rTMS) is a promising brain-based treatment for 
adolescent depression, but target engagement dosing strategies are not adequately understood.33 
A leading theory suggests that rTMS addresses pathological imbalances in cortical gamma-
aminobutyric acid (GABA) and glutamatergic tone.  There is a substantial knowledge gap 
regarding precision medicine approaches for dosing rTMS and the mechanisms associated with 1 
Hz and 10 Hz rTMS in adolescent depression.  Disruptions in excitatory and inhibitory 
neurotransmission are also implicated in negative valence and depression.  Anhedonia and early 
adversity are associated with poor outcomes in adolescent psychiatric disorders and may be 
linked to accentuated imbalances of cortical glutamatergic and GABAergic tone10,12,15,16,71.  
Clarifying the mechanisms of rTMS for adolescent depression could catalyze intervention 
discovery for treatment resistant populations.47,52 
 
To solve these problems we propose a novel dose finding and target validation study of rTMS for 
adolescent depression with a biomarker-stratified, randomized design. 72 Intracortical facilitation 
(ICF), 63 a transcranial magnetic stimulation (TMS) measure of cortical glutamatergic tone is the 
target engagement biomarker for the proposed trial.  A cohort of adolescents (ages 12-18) with 
clinically significant depression defined as 40 or greater on the CDRS-R will be stratified 
according to baseline ICF (high defined as > 1.5 or low defined ≤ 1.5)26,28,65 and then randomized 
to 6 weeks of either left prefrontal 1 Hz or 10 Hz rTMS.   The research team will collect weekly 
ICF and CDRS-R measures during treatment. We will assess baseline anhedonia with a 
composite measure from relevant CDRS-R and Beck Depression Inventory-II (BDI-II) items. 
We will assess lifetime adversity with the Childhood Trauma Questionnaire (CTQ).  Depressed 
adolescent participants who do not respond to 1 Hz or 10 Hz rTMS will be offered the 
opportunity to participant in an exploratory, 2 week trial of iTBS or cTBS (novel dosing 
strategies of TMS therapy). An ideal study would include a sham arm.  As noted there are 
substantial financial and pragmatic barriers to this in the proposed study.  Further, the proposed 
study is focused on developing a mechanistic understanding of different doses of rTMS and the 
effectiveness of 1 Hz rTMS compared to 10 Hz as this has not been adequately addressed in 
previous work.  
 
Aim 1 examines the relative efficacy of 6 weeks low frequency (1 Hz) or high frequency (10 
Hz) left prefrontal rTMS according to a baseline ICF (ICF-15 % MEP amp) measure of 
glutamatergic tone in depressed adolescents.  We will employ a biomarker stratified design.  
Depressed adolescents will be stratified by baseline ICF low (≤ 1.5) or ICF high (>1.5) 
groups prior to randomization.  
• We expect that 6 weeks of 1 Hz rTMS will have greater efficacy (assessed by improvement in 
CDRS-R) in depressed adolescents with high baseline ICF compared to adolescents with low 
baseline ICF. 
• We expect that 6 weeks of 10 Hz rTMS will have greater efficacy (assessed by improvement in 
CDRS-R) in depressed adolescents with low baseline ICF compared to adolescents with high 
baseline ICF. 

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• 6 weeks of 1 Hz rTMS will have greater efficacy (assessed by improvement in CDRS-R) than 
6 weeks of 10 Hz rTMS in depressed adolescents with high baseline ICF. 
• 6 weeks of 10 Hz rTMS will have greater efficacy (assessed by improvement in CDRS-R) than 
6 weeks of 1 Hz rTMS in adolescents with low baseline ICF. 
 
Aim 2 examines changes in weekly ICF and CDRS-R across 6 weeks of either 1 Hz or 10 Hz 
rTMS. 
• We anticipate that ICF measures will decrease in depressed adolescents receiving 6 weeks of 1 
Hz rTMS. 
• We anticipate that ICF measures will increase in depressed adolescents receiving 6 weeks of 
10 Hz rTMS. 
• Depressive symptom improvement will have a direct relationship with ICF decrease in 
depressed adolescents receiving 6 weeks of 1 Hz rTMS and an indirect relationship with ICF 
increase in depressed adolescents receiving 10 Hz rTMS. 
 
Exploratory Aim 3  
 
Aim 3a: To compare 7 T MRS cortical measures of GABAergic tone and glutamatergic 
neurochemistry in depressed adolescents and healthy control adolescents. 
 
Aim3b: To examine potential changes in cortical GABAergic and glutamatergic neurochemistry 
after a six week course of either 1 Hz or 10 Hz rTMS in depressed adolescents. 
 
Hypothesis:  
 
1. Depressed adolescents will have decreased cortical levels of GABA as assessed with 7 T MRS 
compared to healthy control adolescents. 
 
2. Depressed adolescents will have increased cortical levels of Glutamate as assessed with 7 T 
MRS compared to healthy control adolescents. 
 
3. Bilateral cortical 7 T MRS measures of GABA will increase after 6 weeks of 1 Hz rTMS in 
depressed adolescents. 
 
4. Bilateral cortical 7 T MRS measures of Gln/Glu will decrease after 6 weeks of 1 Hz rTMS in 
depressed adolescents. 
 
5. Bilateral cortical 7 T MRS measures of GABA will decrease after 6 weeks of 10 Hz rTMS in 
depressed adolescents. 
 
6. Bilateral cortical 7 T MRS measures of Gln/Glu will increase after 6 weeks of 10 Hz rTMS in 
depressed adolescents. 
Exploratory Aim 4 examines clinical moderators of treatment (anhedonia and adversity) in this 
sample of adolescents undergoing treatment with 1 Hz and 10 Hz rTMS.  
 
Hypothesis: 

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6 weeks of low frequency (1 Hz) rTMS vs. high frequency (10 Hz) rTMS will have greater 
efficacy (as assessed by CDRS-R) in depressed adolescents with anhedonia and adversity 
compared to depressed adolescents without anhedonia and adversity 
 
The proposed project will examine an rTMS dosing, target engagement strategy for adolescent 
depression and refine understanding of GABAergic and glutamatergic contributions to negative 
valence.  Findings will inform the clinical dissemination of rTMS for adolescent depression and 
provide insights to further treatment innovation for disorders of the negative valence systems 
domain early in life.9,52 
 
To our knowledge the NeuroStar® TMS Therapy System in XPLOR research configuration has 
been used most often in prior investigational studies of adolescent depression.33,69 Our group has 
existing and ongoing collaborations with Neuronetics as documented in referenced IDE 
applications: G060269, G110091, G120121.  The present, proposed IDE application would 
deliver investigational, therapeutic TMS therapy (1 Hz, 10 Hz, cTBS, and iTBS) with the 
NeuroStar® TMS Therapy System in XPLOR research configuration. 
 
Although the interventional component of the study (randomized biomarker stratified trial of 1 
Hz or 10 Hz rTMS and extension trial of cTBS or iTBS) is considered more than minimal risk to 
adolescents, TMS treatments offer a potential direct benefit for the individual participants.33,47  
Notably all depressed, adolescent participants will received an active form of TMS.  There is no 
placebo or sham condition.  In addition, the schedule of mood assessments and daily assessments 
during the interventional portion of the study for any adverse events has been developed for the 
purpose of monitoring the participants’ well-being. 
 
All families and participants for this study will be provided with a consent/assent form 
describing this study and providing sufficient information for Participants to make an informed 
decision about their participation in this study.  This consent/assent form will be submitted with 
the protocol for review and approval by the Mayo Clinic IRB. The formal consent/assent of a 
participant, using the approved IRB consent/assent form, must be obtained before that participant 
undergoes any study procedure.  This form must be signed and dated by the participant the 
participant’s legally-authorized representative, and the individual obtaining informed 
consent/assent. 
 
1.5.2 Anticipated Risks and Protections 
 
TMS and TBS Safety Concerns in Humans 
 
This study will utilize different types of TMS.  Single and paired-pulse TMS is used to collect 
neurophysiologic data.  Therapeutic rTMS (1 Hz, 10 Hz, cTBS, and iTBS) applies multiple 
magnetic pulses to the brain over many (30-40 in this protocol) sessions for treatment 
purposes.32,73 
 
Potential risk of seizure: There is a small risk of seizure associated with the use of TMS. This is 
regarded as the most serious adverse event ever reported in TMS studies to date. Seizures have 

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been reported to result from single-pulse TMS but have occurred most frequently with repetitive 
rTMS.74,75  The risk for seizure with iTBS may be higher than standard rTMS (1 Hz or 10 Hz).74   
Participants who have a past history of neurological disorders such as strokes or epilepsy have 
the greatest risk. This incidence is still low (0.6% or less) which is comparable to the reported 
incidence of seizures with antidepressant medications..74,75 The role of TMS in some case reports 
of seizures is equivocal76,77 but the possibility of TMS inducing seizures in participants without 
prior neurological pathology cannot be entirely discounted. There have been 17 case reports of 
seizures during TMS in healthy participants, depressed participants, or participants with other 
disorders not thought to confer a seizure risk (such as pain).72 It is also noteworthy, that in a 
recent, multicenter trial of rTMS involving 301 adult patients receiving rTMS at 120% motor 
threshold, 3,000 pulses per session, five days a week for 4-6 weeks (this is rTMS delivered at the 
upper limits of recommended safety guidelines) there were no seizures nor elevated rates of 
serious adverse events.38  Reported seizures associated with rTMS have also been self-limited 
and beyond careful monitoring and neurological assessment have not required acute treatment.  It 
is also important to note that there is no evidence that a single seizure, or even a series of induced 
seizures, makes a subsequent seizure more likely in an otherwise healthy individual. However, it 
is also true that there are potential psychosocial consequences of a seizure, including the 
potential psychosocial impact.  There are 3 case reports of seizures in adolescents with 
depression undergoing rTMS treatments. In two of these instances the adolescents were taking 
psychotropic medications.78,79  In one instance the adolescent used alcohol the night before rTMS 
treatment.79 One case report described a seizure in an adolescent undergoing deep TMS.80 In our 
experience thus far and to our knowledge there have been no seizures in depressed adolescents 
receiving NeuroStar rTMS treatments. 
 
With regard to the potential for seizures, all patients will be carefully screened for current or 
historical factors that may increase the risk of seizures (see Exclusion criteria). The Transcranial 
Magnetic Stimulation Adult Safety Screen (TASS) will be used to specifically query for any 
potential seizure risks. Neurologic disease which may increase the risk for seizures is part of the 
exclusion criteria.74,75 Patients undergoing TMS in the proposed study will not be taking 
medications which could potentially lower their seizure threshold. All TMS sessions will be 
supervised by a board-certified child and adolescent psychiatrist and all personnel involved will 
be provided with training in the identification of potential prodromal signs or symptoms of a 
seizure, particularly the identification of more subtle behavioral events which may herald the 
occurrence of a frontal lobe seizure, such as changes in level of consciousness or inattention.  All 
TMS sessions will be conducted in the neurostimulation suite with access to medical facilities 
and equipment in the event a seizure should occur.  Seizure monitoring will be by visual 
observation. Investigators have the capability to manage a seizure if it were to occur. The Mayo 
Clinic Neurostimulation Lab has direct access (within minutes) to emergency medicine services. 
 
In the event of a seizure, the supervising physician will initiate appropriate clinical care as 
defined within the clinical rTMS practice.  In the management of seizures, attention must be 
taken to minimize the risk of aspiration, and when possible guiding the patient into the left lateral 
decubitus position is desirable.  Because seizures in the context of TMS are brief (typically <60 
seconds) and without serious physical sequelae, efforts will be focused on preventing 
complications of the seizure rather than initiating any specific medication that is not required 
unless a seizure is prolonged.  If a prolonged seizure (>60 seconds) is identified, appropriate 

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response measures will be initiated which may include notifying a hospital-based pediatric rapid 
response team and/or escorting participant to the emergency medicine department upon 
stabilization (located directly across from TMS building).  The patient may be provided 
lorazepam (or equivalent benzodiazepine available in the resuscitation cart) to abort the seizure.  
To date, status epilepticus has never been described following rTMS.47,74,75 
 
 
If a seizure occurs during the study, TMS treatment as part of the study will be discontinued.  
Ongoing monitoring of mood and neurocognitive symptoms per the study protocol will be 
offered.  Any seizure will be reported to the Mayo Clinic IRB, Data and Safety Monitoring 
Board (DSMB), Neuronetics, and the FDA as required per agreements, regulations, and policies. 
 
Neuropsychological function after TMS: Several studies have examined the short-term effects 
of rTMS administration across a range of stimulation parameters, and found little or no evidence 
to suggest a change in cognitive function as a result of rTMS administration.66,74,75 Although 
there is no evidence to suggest an untoward effect on cognitive function as a result of rTMS 
administration the study team will collect neurocognitive data at baseline, posttreatment (Phase I 
and Phase II), and at a 6 month follow-up visit.  A Mayo Clinic Consultant, Pediatric 
Neuropsychologist, 
 
 PhD will oversee the implementation, training, 
administration, quality assurance, and data analyses of neurocognitive testing (NIH Toolbox) 
 
Potential risk of alteration of auditory threshold: During TMS, the coil produces an audible, 
high energy click. Existing evidence suggests that TMS can result in transient changes in 
auditory threshold if no precautions are taken (such as wearing earplugs during TMS).  Ear plugs 
are required for all participants and study personnel during any TMS procedure.  These are worn 
routinely during TMS protocols to mitigate this risk.38,74  Participants will undergo audiometry 
testing at baseline and upon completion of 6 week rTMS (1 Hz or 10 Hz) and once again (if 
applicable) after the two week trial (of either cTBS or iTBS). 
 
Potential for unintended behavioral change: (e.g., worsening of depression or induction of 
mania): Crying has been reported in some patients receiving left prefrontal rTMS. There is no 
evidence to suggest that a frank worsening of depression may be seen in patients with major 
depression receiving rTMS. On the other hand, mania has been observed in bipolar disorder 
patients who have received rTMS.38,74,75  Dr. Croarkin and the study team will be available 24 
hours a day to address any concerns participants or families have regarding changes in behavior.  
Adverse events are monitored at every treatment visit.  Dr. Croarkin or a board-certified child 
and adolescent psychiatrist will remain in the neurostimulation suite (in a room adjacent to the 
rTMS treatment room) during all rTMS treatment sessions.   
 
Suspected treatment-induced mania will be evaluated using the Young Mania Rating Scale 
(YMRS).  A YMRS score of ≥ 20 will prompt administration of the M.I.N.I.(age 18) or M.I.N.I. 
KID to determine whether or not the Participant meets the Diagnostic and Statistical Manual of 
Mental Disorders, Fifth Edition (DSM-5) criteria for mania.  A YMRS score of 20 or greater will 
be considered an adverse event (AE) and will be monitored using the YMRS; the emergence of 
DSM-5 verified mania will be treated as a serious adverse event (SAE) and will also be 
monitored using the YMRS.   
 

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Please note that Dr. Croarkin works with a team of Board Certified Child and Adolescent 
Psychiatrists with expertise in adolescent depression, suicidality, severe psychiatric disorders in 
childhood, rTMS protocols, and clinical research. These psychiatrists are co-investigators and 
colleagues.  One of these physicians (in the event Dr. Croarkin is away) or Dr. Croarkin is 
present in the treatment suite during rTMS delivery and available 24 hours a day in the event of 
emergencies.  While our group has never had a participant with emergent mania in an rTMS 
protocol, we have experience and comfort in addressing psychiatric emergencies in general.  We 
have standard operating procedures that the team of psychiatrists are comfortable with and have 
experience implementing.  For example, this team collectively has had experience in 
hospitalizing research participants. The overriding guiding principal for our research team is that 
participant safety is our central priority.  Any decisions regarding clinical monitoring, referral for 
higher levels of treatment, and ongoing study participation are informed by what will optimize 
each participant’s safety and clinical status.   Beyond this, the Mayo Clinic Division of Child and 
Adolescent Psychiatry (11 board certified child and adolescent psychiatrists) always has an 
individual on call for psychiatric emergencies. While these colleagues are not co-investigators, 
they receive training on a regular basis regarding ongoing adolescent research efforts.  All 
members of the Child and Adolescent Psychiatry Division have proficiency and comfort in 
dealing with psychiatric emergencies. They contact the PI (Dr. Croarkin) or the covering 
research child and adolescent psychiatrist with any emergency involving a research participant.  
Research participants are ultimately offered standard of care interventions based on clinical 
presentation and need regardless of stage of participation (to include emergent evaluation in 
outpatient clinic, emergency medicine visits, or psychiatric hospitalization in Mayo Clinic, 
Generose 1-West, an 18 bed inpatient unit which is located directly below our neurostimulation 
treatment suite). 
 
Potential risk of movement of metallic objects in the patient’s body: Because of the brief, but 
intense local magnetic field induced by the TMS coil, any metallic object in the vicinity of the 
coil, namely within the head region, may slightly move as a result. Patients with metallic objects 
in or near their head are excluded from the study. Patients will be specifically instructed to 
remove any magnetically sensitive jewelry or other objects near their head.  Patients with 
metallic objects in or near their head are excluded from the study. Patients will be specifically 
instructed to remove any magnetically sensitive jewelry or other objects near their head.38,74,75 
 
Potential for development of headache or local pain at the site of stimulation: TMS 
administration may result in the development of a transient headache during or after the TMS 
session, and the development of pain localized near the site of the stimulation coil. These effects 
are thought to be due to the direct activation of muscles and nerves near the stimulating coil. This 
is more common with rTMS and TBS than with single or paired-pulse TMS. TMS sessions or 
measurements will be discontinued immediately in the event of any significant scalp discomfort 
or pain.  Participants will be counseled on the use of ibuprofen to relieve pain or discomfort as 
necessary.38,74,75 
 
Unimproved depression or Clinical Deterioration: Continued depression or worsening of 
depressive symptomatology is always a risk of depression, even for those treated with 
medication and/or psychotherapy.  Clinical deterioration due to the underlying psychiatric 
conditions is also a risk. The PI (Dr. Croarkin) is a board-certified child and adolescent 

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psychiatrist, and the research team at Mayo Clinic has prior research experience with child and 
adolescent depressed populations.  The research team includes 3 other board certified child and 
adolescent psychiatrists with experience delivering investigational rTMS to adolescents, 
extensive experience with suicidal adolescents, and clinical research experience. Should 
worsening of depression occur, Dr. Croarkin (or a child and adolescent psychiatrist research 
team member) will follow standard policies and procedures developed by the Mayo Clinic Child 
and Adolescent Psychiatry Division in the Department of Psychiatry and Psychology. The study 
psychiatrist will implement strategies to ensure each partcipant’s safety and optimal clinical 
outcome (e.g., comprehensive assessment of depressive symptomatology including possible 
lethality, immediate notification to the adolescent participant’s legal guardian, and referral to 
community treatment providers). Implementation of strategies to mitigate worsening of 
depression will be tailored to the specific needs of the individual. 
 
During the consent process, participants and families will be educated about the possibility of 
significant changes in mood, suicidal thinking, and/or behaviors during the treatment.  These 
changes could include emergence of mania, worsening of depression, and/or suicidal thinking 
and behaviors. Both the participants and parent(s) will be told to initiate contact with their study 
doctor, if the participant experiences any significant mood or behavior changes including 
suicidal ideation.  Principal Investigator contact information is included in the consent/assent 
document.  Furthermore, during the treatment phases of the study, participants will have frequent 
contact with the study team (5 visits per week) and assessments weekly where changes of 
psychological symptoms will be queried.  Ongoing monitoring for worsening of depression and 
emergence of suicidal ideation and/or behaviors will be evaluated using the CDRS-R, C-SSRS, 
and clinical global impression-severity scale (CGI-S). 
 
Suicidal behavior: Patients with current suicidal ideation or past suicide attempts are eligible for 
the study (unless outpatient treatment is not clinically indicated), as ongoing suicidal ideation 
and behaviors are frequently seen in depressed youth. Therefore, ongoing suicidal ideation or 
worsening of suicidal ideation and behavior is a risk. The PI (Dr. Croarkin) is a board-certified 
child and adolescent psychiatrist with extensive experience treating adolescents with suicidal 
behavior.  The research team includes three other board certified child and adolescent 
psychiatrists.  Dr. Croarkin or the research child and adolescent psychiatrist will follow standard 
policies and procedures developed by the Mayo Clinic Child and Adolescent Division and 
implement strategies (e.g., comprehensive assessment of depressive symptomatology, 
assessment of suicidal ideation [inclusive of intent, means, and plan], immediate notification of 
the adolescent participants’ legal guardian, referral for admission to Generose, 1-West, the Mayo 
Clinic Child and Adolescent Inpatient Psychiatry unit [in cases of immediate lethality]). 
Implementation of strategies to mitigate suicidal behavior will be tailored to the specific 
presenting needs of the individual. 
 
Please note that Dr. Croarkin works with a team of Board Certified Child and Adolescent 
Psychiatrists with expertise in adolescent depression, suicidality, severe psychiatric disorders in 
childhood, rTMS protocols, and clinical research. These psychiatrists are co-investigators and 
colleagues.  One of these physicians (in the event Dr. Croarkin is away) or Dr. Croarkin is 
present in the treatment suite during rTMS delivery and available 24 hours a day in the event of 
emergencies.  We have standard operating procedures that the team of psychiatrists are 

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comfortable with and have experience implementing.  For example, this team collectively has 
had experience in hospitalizing suicidal research participants. The overriding guiding principal 
for our research team is that participant safety is our central priority.  Any decisions regarding 
clinical monitoring, referral for higher levels of treatment, and ongoing study participation are 
informed by what will optimize each participant’s safety and clinical status.   Beyond this, the 
Mayo Clinic Division of Child and Adolescent Psychiatry (11 board certified child and 
adolescent psychiatrists) always has an individual on call for psychiatric emergencies. While 
these colleagues are not co-investigators, they receive training on a regular basis regarding 
ongoing adolescent research efforts.  All members of the Child and Adolescent Psychiatry 
Division have proficiency and comfort in dealing with psychiatric emergencies. They contact the 
PI (Dr. Croarkin) or the covering research child and adolescent psychiatrist with any emergency 
involving a research participant.  Research participants are ultimately offered standard of care 
interventions based on clinical presentation and need regardless of stage of participation (to 
include emergent evaluation in outpatient clinic, emergency medicine visits, or psychiatric 
hospitalization in Mayo Clinic, Generose 1-West, an 18 bed inpatient unit which is located 
directly below our neurostimulation treatment suite).   
 
MRI/MRS Safety Concerns in Humans 
 
Potential Risks 
 
The effects of magnetic fields in an MRI scanner have been extensively studied, and there are no 
known significant risks with an MRI exam. Some subjects may be bothered by feelings of 
confinement (claustrophobia), and by the noise made by the magnet during the procedure. 
Subjects will wear earplugs while in the magnet. Subjects with pacemakers, implanted 
defibrillators or other implanted electronic or metallic devices may not participate. Subjects with 
braces may not participate in the MRI/MRS scan portion of the study.  
 
Clinical Assessments and Neurocognitive Testing with NIH Toolbox 
 
The psychiatric assessment, interview, and rating scales in this study are time consuming and 
may bring up upsetting issues. If child abuse is detected, the research team is obligated to follow 
mandatory, federal, state, and institutional reporting laws.  On occasion participants clinically 
deteriorate during a research assessment.  Dr. Croarkin or a board-certified child and adolescent 
psychiatrist from the research team will be available 24 hours a day for these situations.  A Mayo 
Clinic Consultant, Pediatric Neuropsychologist, 
, PhD will oversee the 
implementation, training, administration, quality assurance, and data analyses of neurocognitive 
testing (NIH Toolbox) 
 
Confidentiality 
 
The potential for a breach in confidentiality always exists, specifically with the written research 
data and study databases. However, information that is obtained will be stored in locked file 
drawers in locked offices; data will have identifying information sheered from it to prevent loss 
of confidentiality, all computers and databases will be password protected with passwords 
available to limited study personnel, and all staff must sign confidentiality certificates.   

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Loss of confidentiality is a potential risk because participants will be asked to disclose their 
recent medications history, information pertaining to demographics, family history, and 
psychiatric history.  Since code numbers will be given to each participant and data will be stored 
by code number, the risk of loss of confidentiality will be minimal. Only personnel working on 
this project at Mayo Clinic and the University of Minnesota Center for Magnetic Resonance 
Research will have access to the data.  Only data that are pertinent to the study will be collected 
so that seriousness of loss of confidentiality will be minimized.  The alternative to participating 
in this project is to decline.  Participants will be at no risk if they decline to participate. 
 
1.5.3  Potential Benefits 
 
Although the interventional component of the study (randomized biomarker stratified trial of 1 
Hz or 10 Hz rTMS and extension trial of cTBS or iTBS for nonresponders) is considered more 
than minimal risk to adolescents, TMS treatments offer a potential direct benefit for the 
individual participant.33 81,82 Notably all depressed, adolescent participants will received an 
active form of TMS.  There is no placebo or sham condition.  In addition, the schedule of mood 
assessments and daily assessments during the interventional portion of the study for any adverse 
events has been developed to optimize monitoring the participant’s well-being. 
 
Standard TMS dosing (1 Hz and 10 Hz) has been applied more broadly than TBS to children and 
adolescents in the course of investigational, therapeutic studies.83  The intent for the proposed 
intermittent theta-burst stimulation (iTBS) and continuous theta-burst (cTBS) exploratory 
extension trial (Phase II of the proposed study) is to maximize the infrastructure of the proposal 
for both research participants and our field.  Theta burst stimulation (TBS) is an alternative 
dosing approach in which 3-pulse 50 Hz bursts are delivered at 5 Hz.  With iTBS, 2 second trains 
are delivered to the LDLPFC every 10 seconds for 1800 pulses putatively inducing plasticity 
changes that resemble long-term potentiation. Continuous theta-burst stimulation (cTBS) 
delivers 2 second trains of 5 Hz stimulation continuously for 1800 pulses In general it has been 
speculated that iTBS sessions increase cortical excitability and that cTBS sessions decrease 
cortical excitability.83-85  
 
In the course of a NIMH career development award focused on neurostimulation the PI/sponsor 
has taken every opportunity to interact with national and international clinical communities that 
focus on the delivery of TMS therapies.  This has included volunteering for the Clinical TMS 
Society Board of Directors, attending International Brain Stimulation conferences, and visiting 
multiple national and international TMS clinics and laboratories.  From these experiences it is 
clear that TBS protocols are increasingly delivered in clinical settings to adults and adolescents 
despite a relatively underdeveloped understanding of the in vivo neurophysiological effects in 
humans. This is particularly concerning in the context of developing children. Systematic study 
and data collection (efficacy measures, safety, adverse events, and neurophysiological data) 
focused on TBS is critical in this context. Based on prior experience of the PI, research 
participants (and their parents) who do not receive benefit from the proposed, primary, 
experimental therapeutic protocol (Phase I: 6 weeks of either 1 Hz or 10 Hz rTMS) would 
appreciate the availability of an additional treatment protocol with an experienced center in 
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opportunity to maximize resources and collect novel pilot data for future grant submissions 
(Exploratory Clinical Trials of Novel Interventions for Mental Disorders R61/R33).8  
 
1.6 Anticipated Duration of the Clinical Investigation 
 
It is anticipated that the proposed study will be five years in duration.  For individual 
participants, Phase I (biomarker stratified, randomized trial of 1 Hz vs. 10 Hz rTMS) is 10 weeks 
in duration.  Phase II (trial of cTBS vs iTBS based on ICF biomarker status) is 3 weeks in 
duration. 
 
2 Study Objectives 
 
The proposed study is a dose finding, effectiveness, and target validation study of rTMS for 
adolescent depression with a biomarker stratified design. 72 Intracortical facilitation (ICF), 65 a 
transcranial magnetic stimulation (TMS) measure of cortical glutamatergic tone is the target 
engagement biomarker for the proposed trial.  In phase I, a cohort of adolescents (ages 12-18) 
with clinically significant depression defined as 40 or greater on the Children’s Depression 
Rating Scale-Revised (CDRS-R) will be stratified according to baseline ICF (high defined as > 
1.5 or low defined ≤ 1.5) and then randomized to 6 weeks of either left prefrontal 1 Hz or 10 Hz 
rTMS.   The research team will collect weekly ICF and CDRS-R measures during treatment. We 
will assess baseline anhedonia with a composite measure from relevant CDRS-R and Beck 
Depression Inventory-II (BDI-II) items. We will assess lifetime adversity with the Childhood 
Trauma Questionnaire (CTQ).  
 
Participants in Phase I will be offered the opportunity to have 3 and 7 T MRI and MRS looking 
for biomarkers at baseline and after 6 weeks of treatment.  A subgroup of depressed adolescent 
participants ( up to 50) who do not respond to 1 Hz or 10 Hz rTMS will be offered the 
opportunity to participant in an exploratory, 2 week, trial of iTBS or cTBS based on ICF 
biomarker status (Phase II of the study).  Participants with high baseline ICF (defined as > 1.5) 
will be assigned to cTBS treatment.  Participants with low ICF  (defined ≤ 1.5) will be assigned 
to iTBS. 
 
7 T MRS measures Glutamate and GABA biomarkers in healthy adolescents and depressed 
adolescents. The overall goals are to examine cortical Glutamate and GABA neurochemical 
markers in adolescent depression and the impact of 1 Hz and 10 Hz rTMS on cortical glutamate 
and GABA neurochemical markers when compared to the healthy adolescent cohort.  
 
2.1 Primary Objective 
 
Aim 1 examines the relative efficacy of 6 weeks low frequency (1 Hz) or high frequency (10 Hz) 
left prefrontal rTMS according to a baseline ICF (ICF-15 % MEP amp) measure of 
glutamatergic tone in depressed adolescents.  We will employ a biomarker stratified design.  
Depressed adolescents will be stratified by baseline ICF low (≤ 1.5) or ICF high (>1.5) groups 
prior to randomization.  

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• We expect that 6 weeks of 1 Hz rTMS will have greater efficacy (assessed by improvement in 
CDRS-R) in depressed adolescents with high baseline ICF compared to adolescents with low 
baseline ICF. 
• We expect that 6 weeks of 10 Hz rTMS will have greater efficacy (assessed by improvement in 
CDRS-R) in depressed adolescents with low baseline ICF compared to adolescents with high 
baseline ICF. 
• 6 weeks of 1 Hz rTMS will have greater efficacy (assessed by improvement in CDRS-R) than 
6 weeks of 10 Hz rTMS in depressed adolescents with high baseline ICF. 
• 6 weeks of 10 Hz rTMS will have greater efficacy (assessed by improvement in CDRS-R) than 
6 weeks of 1 Hz rTMS in adolescents with low baseline ICF. 
 
2.2 Secondary Objective 
 
Aim 2 examines changes in weekly ICF and CDRS-R across 6 weeks of either 1 Hz or 10 Hz 
rTMS. 
• We anticipate that ICF measures will decrease in depressed adolescents receiving 6 weeks of 1 
Hz rTMS. 
• We anticipate that ICF measures will increase in depressed adolescents receiving 6 weeks of 
10 Hz rTMS. 
Depressive symptom improvement will have a direct relationship with ICF decrease in depressed 
adolescents receiving 6 weeks of 1 Hz rTMS and an indirect relationship with ICF increase in 
depressed adolescents receiving 10 Hz rTMS. 
Exploratory Aim 3  
 
Aim 3a: To compare 7 T MRS cortical measures of GABAergic tone and glutamatergic 
neurochemistry in depressed adolescents and healthy control adolescents. 
 
Aim3b: To examine potential changes in cortical GABAergic and glutamatergic neurochemistry 
after a six week course of either 1 Hz or 10 Hz rTMS in depressed adolescents. 
 
Hypothesis:  
 
1. Depressed adolescents will have decreased cortical levels of GABA as assessed with 7 T MRS 
compared to healthy control adolescents. 
 
2. Depressed adolescents will have increased cortical levels of Glutamate as assessed with 7 T 
MRS compared to healthy control adolescents. 
 
3. Bilateral cortical 7 T MRS measures of GABA will increase after 6 weeks of 1 Hz rTMS in 
depressed adolescents. 
 
4. Bilateral cortical 7 T MRS measures of Gln/Glu will decrease after 6 weeks of 1 Hz rTMS in 
depressed adolescents. 
 
5. Bilateral cortical 7 T MRS measures of GABA will decrease after 6 weeks of 10 Hz rTMS in 
depressed adolescents. 

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6. Bilateral cortical 7 T MRS measures of Gln/Glu will increase after 6 weeks of 10 Hz rTMS in 
depressed adolescents. 
 
Exploratory Aim 4 examines clinical moderators of treatment (anhedonia and adversity) in this 
sample of adolescents undergoing treatment with 1 Hz and 10 Hz rTMS.  
 
Hypothesis: 
6 weeks of low frequency (1 Hz) rTMS vs. high frequency (10 Hz) rTMS will have greater 
efficacy (as assessed by CDRS-R) in depressed adolescents with anhedonia and adversity 
compared to depressed adolescents without anhedonia and adversity 
 
The proposed project will examine an rTMS dosing, target engagement strategy for adolescent 
depression and refine understanding of GABAergic and glutamatergic contributions to negative 
valence.  Findings will inform the clinical dissemination of rTMS for adolescent depression and 
provide insights to further treatment innovation for disorders of the negative valence systems 
domain early in life.9,52 
 
To our knowledge the NeuroStar® TMS Therapy System in XPLOR research configuration has 
been used most often in prior investigational studies of adolescent depression.33,69 Our group has 
existing and ongoing collaborations with Neuronetics as documented in referenced IDE 
applications: G060269, G110091, G120121.  The present, proposed IDE application would 
deliver investigational, therapeutic TMS therapy (1 Hz, 10 Hz, cTBS, and iTBS) with the 
NeuroStar® TMS Therapy System in XPLOR research configuration. 
 
Although the interventional component of the study (randomized biomarker stratified trial of 1 
Hz or 10 Hz rTMS and extension trial of cTBS or iTBS) is considered more than minimal risk to 
adolescents, TMS treatments offer a potential direct benefit for the individual participants.33,47  
Notably all depressed, adolescent participants will received an active form of TMS.  There is no 
placebo or sham condition.  In addition, the schedule of mood assessments and daily assessments 
during the interventional portion of the study for any adverse events has been developed for the 
purpose of monitoring the participants’ well-being. 
 
All families and participants for this study will be provided with a consent/assent form 
describing this study and providing sufficient information for Participants to make an informed 
decision about their participation in this study.  This consent/assent form will be submitted with 
the protocol for review and approval by the Mayo Clinic IRB. The formal consent/assent of a 
participant, using the approved IRB consent/assent form, must be obtained before that participant 
undergoes any study procedure.  This form must be signed and dated by the participant the 
participant’s legally-authorized representative, and the individual obtaining informed 
consent/assent. 
 
3 Study Design 
3.1 
General Design 
 

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Phase I will enroll a cohort (N=120) of adolescents (ages 12-18) with clinically significant 
depression defined as 40 or greater on the Children’s Depression Rating Scale-Revised (CDRS-
R).  Participants will be stratified according to baseline ICF (high defined as > 1.5 or low defined 
≤ 1.5) and then randomized to 6 weeks of either left prefrontal 1 Hz or 10 Hz rTMS.   The 
research team will collect weekly ICF and CDRS-R measures during treatment. We will assess 
baseline anhedonia with a composite measure from relevant CDRS-R and Beck Depression 
Inventory-II (BDI-II) items. We will assess lifetime adversity with the Childhood Trauma 
Questionnaire (CTQ). Participants will have baseline neurocognitive testing. Participants will 
have a six month follow-up visit with depression severity measures (CDRS-R and BDI-II) and 
neurocognitive assessments. 
 
Up to 100 Depressed adolescents will be offered the opportunity to undergo magnetic resonance 
spectroscopy (MRS) measure at baseline (prior to any Phase I TMS treatment) and posttreatment 
visits (within 2 months after 6 weeks of TMS treatment in Phase I).  A comparison group of 30 
healthy control adolescents will be offered the opportunity to undergo MRS at one time point. A 
subset of up to 50 depressed adolescents who do not respond to Phase I TMS treatment will be 
offered the opportunity to continue in Phase II (within 2 months of completion of Phase I 
treatment) for two weeks of either iTBS if (ICF ≤ 1.5 ) or cTBS if (ICF is >1.5). 

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. 
 
Magnetic Resonance Imaging:  Depressed and control participants will undergo 3 T structural 
MRI and ultra-high field (7 T) MRS (7-T, 90–cm horizontal bore magnet interfaced with a 
Siemens console) to examine GABA, glutamate, and glutamine concentrations in the occipital 
cortex (OCC)  Dr. Malgorzata Marjanska is a co-investigator on this grant and will supervise the 
collection and analyses of all MRI/MRS data at the Center for Magnetic Resonance Research 
(CMRR) at the University of Minnesota.  Please note that travel time from Mayo Clinic 
Rochester to the CMRR is approximately 1 hour.  Participants will be remunerated for travel and 
all study visits.  
 
 Recent work in adult humans with 7 T MRS and short echo time sequences has enhanced the 
detection and resolution of GABA, glutamate and glutamine. Spectra will be acquired from a 
voxel  placed in the OCC  using the STEAM sequence. Voxels will be prescribed using 
anatomical landmarks from T1-weighted images. Spectra will be stored separately for 
subsequent automatic frequency and phase correction (in-house written Matlab routines) using 
the NAA signal at 2.01 ppm. Summed spectra will be analyzed using LCModel 6.1-4A (Stephen 
Provencher Inc., Oakville, ON, Canada) and simulated basis sets with a metabolite-nulled 
macromolecule spectrum measured in vivo.. No baseline correction, zero-filling or apodization 
functions will be applied to the in vivo data prior to the analysis. LCModel fitting will be 
performed over the spectral range from 0.5 to 4.2 ppm. The quantification will be performed 
using the unsuppressed water signal obtained from the same voxel. Concentrations will be 
corrected for cerebrospinal fluid content (the tissue composition will be obtained vial voxel 
segmentation using T1-weighted images acquired at 3 T).   
 
The first MRS will take place following the screening visit but before the baseline/treatment visit 
occurs. Therefore, a 7 day window is the allowed timeframe for the first MRI and MRS scan. 
The second MRS will take place within 2 months of completing all rTMS phase I treatments and 
assessments and before beginning Phase 2 treatments. Screening will include University of 
Minnesota Center for Magnetic Resonance Research  systematic safety assessments for safety to 
undergo both rTMS and ultra-high field (7 T) MRI/MRS.   
 
Please note that travel time from Mayo Clinic Rochester to the CMRR is approximately 1 hour.  
Participants will be remunerated $100.00 per scan for their time and travel expenses. 
 
Research participants: We will enroll participants ages 12 to 18 with the capacity to provide 
informed assent and parents (for participants younger than age 18) with the capacity to provide 
informed consent.  Capacity to consent will be assessed with comprehension assessments.  We 
are budgeted to recruit 120 depressed adolescents over five years for a target of 100 evaluable 
subjects (120 accounts for attrition based on our prior experience).  We are budgeted to recruit 
30 healthy adolescent participants for MRS comparison and test-retest studies.  These goals are 
realistic given our group’s experience with therapeutic rTMS and biomarker studies.  Screening 
will include systematic safety assessments for safety to undergo both rTMS and ultra-high field 
(7 T) MRI/MRS.   
 

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Participants who fail to receive clinical benefit from Phase I (defined as a CDRS-R score of 40 
or greater at post-treatment) will be offered enrollment in Phase II (N=50 max).  The decision to 
enroll in Phase II can be made by the subject no more than 2 months after the last day of Taper 
Week 3.  During phase II, participants will be assigned to 2 weeks of cTBS if their intracortical 
facilitation measure (baseline assessment for TBS extension trial) is >1.5 (building on the current 
speculation that cTBS would be expected to decrease cortical excitability and ICF measures).  
Participants will be assigned to 2 weeks of iTBS if their ICF (baseline assessment for TBS 
extension trial) is < 1.5 (building on current speculation that iTBS would increase cortical 
excitability and ICF measures.  All participants in Phase II will have a six month follow-up visit 
with depression severity measures (CDRS-R and BDI-II) and neurocognitive assessments.   
 
3.2 
Primary Study Endpoints 
 
The primary study endpoint is depression severity (measured by CDRS-R total) over the 6-week 
study period.   
 
3.3     Secondary Study Endpoints. 
 
The secondary study endpoint is intracortical facilitation (ICF) over the 6-week study period. 
 
 
 
 

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3.4 Table 1 Primary Safety Endpoints 
 
 
Assessment 
Description 
Adverse events 
Participants will be evaluated for adverse events at each visit. Serious 
adverse events (SAEs) will be reported as they occur to the Mayo 
Clinic IRB and USA FDA (as per regulations). Systematic data 
collection focused on adverse events will include the Pediatric 
Adverse Event Rating Scale and Physical Symptom Checklist. These 
rating scales will be administered at baseline, weekly (during all 
rTMS, cTBS, and iTBS treatment weeks), at the 6 month follow up 
visit, and at study exit. 
Auditory thresholds 
Participants will undergo audiometry testing at baseline and upon 
completion of 6 week rTMS (1 Hz or 10 Hz) and once again (if 
applicable) after the two week open extension trial (of either cTBS or 
iTBS).  
C-SSRS – Columbia Suicide 
Severity Rating Scale 
This is collected to assess lifetime suicidal ideation and behavior prior 
to participation, reassessed weekly (during 6 week trial of 1 Hz vs 10 
Hz rTMS and if applicable 2 week extension trial of cTBS or iTBS) 
during treatments, posttreatment, and 6 month follow up visit.  
NIH Toolbox Cognition Battery 
http://www.healthmeasures.net/explore-measurement-systems/nih-
toolbox 
 
Cognition measures: http://www.healthmeasures.net/explore-
measurement-systems/nih-toolbox/intro-to-nih-toolbox/cognition 
 
The NIH Toolbox Cognition Battery, recommended for ages 7+, 
consists of tests of multiple constructs. It yields individual measure 
scores and the following summary scores:  Education, Handedness, 
Attention (Flanker Inhibitory Control and Attention Test),  Episodic 
memory (Picture Sequence Memory Test, and Auditory Verbal 
Learning Test), Executive Function (Dimensional Change Card Sort 
Test, Flanker Inhibitory Control and Attention Test), Language 
(Picture Vocabulary Test, Oral Reading Recognition Test), Processing 
Speed (Pattern Comparison Processing Speed Test), Working Memory 
(List Sorting Working Memory Test).  Collected at baseline, 
posttreatment, and 6 month follow up. 
 
Pediatric Adverse Event Rating 
Scale 
This is a 51 item; self-report measure collected at baseline, weekly 
during rTMS treatments, posttreatment, and at 6 month follows up 
visit for adverse event monitoring. 
Physical Symptoms Checklist 
This is a 46 item measure to be collected by the study team (under the 
supervision of the PI) at baseline, weekly during rTMS treatments, 
posttreatment, and at 6 month follow up visit for adverse event 
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Assessment 
Description 
Vital Signs 
(Pulse, blood pressure, height, and weight) will be collected at 
baseline, upon completion of 6 week rTMS (1 Hz or 10 Hz) once 
again (if applicable) after two week open extension trial (of either 
cTBS or iTBS), and at 6 month follow up visit. 
YMRS-Young Mania Rating        
Scale 
This is an 11 item measure used to assess for manic symptoms.  The 
YMRS scale will be completed at baseline and repeated during the 
course of study participation if symptoms of mania occur in a study 
participant.  If the YMRS is positive, A MINI/MINI-Kid will be 
repeated to evaluate for mania.  If the study participant meets full 
DSM-5 criteria for mania or hypomania he or she will be discontinued 
from the study and followed clinically. 
 
4 
Participant Selection, Enrollment and Withdrawal 
 
4.1 
Inclusion Criteria 
 
Inclusion Criteria: 
- ages 12-18, male or female 
-Depressed adolescent participants will have a primary diagnosis of MDD based on a clinical and 
structured interview with the MINI 
-Depression symptoms severity of a 40 or greater based on evaluation with the Children’s 
Depression Rating Scale Revised (CDRS-R) at screening and baseline visits. Further, the total 
score of the baseline CDRS-R score must not have had a 25% or greater decrease from the 
screening CDRS-R score  
-The duration of the current episode of depression must be 4 weeks or more but 3 years or less.  
-For any participant currently receiving antidepressant medication, the referring clinician must 
determine that insufficient benefit is being received from this treatment and it is clinically 
appropriate to discontinue the existing antidepressant. Participants will need to have stopped 
taking antidepressants at least 1 week prior (4 weeks for fluoxetine) to the baseline visit.  
-Participants in psychotherapy are eligible provided that this was initiated 4 weeks prior to 
enrollment and that the frequency of visits will be maintained during study participation.  
4.1.1  Inclusion Criteria Healthy Controls 
-ages 12-18, male or female 
4.2 
Exclusion Criteria 
Exclusion Criteria: 
-The following psychiatric comorbidities are exclusionary: psychotic disorders, bipolar 
disorders, anorexia nervosa, bulimia nervosa, and substance use disorders within the past year 
(with the exception of caffeine and tobacco) 
-A positive urine drug screen at baseline   
-Seizure history 
-Family history of epilepsy in a first degree relative  

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-Head trauma with loss of consciousness for greater than 5 minutes 
-Any true positive findings on the rTMS safety screening form. 
- Contraindications to MRI/MRS (CMRR Subject Safety Screening Form) 
-Any concurrent psychotropic medications (for potential participants receiving antidepressants or 
psychotropic medications, the referring clinician must determine that insufficient benefit is being 
received from the treatment and if clinically appropriate, discontinue existing antidepressants and 
other psychotropic medications). 
-Prohibited concomitant medications (See Appendix A) 
-Pregnancy or suspected pregnancy in female Participants (assessed with urine pregnancy test)  
- Conductive, ferromagnetic, or other magnetic-sensitive metals implanted in the subject’s head 
within 30 cm of the treatment coil excluding the mouth that cannot safely be removed. Examples 
include cochlear implants, implanted electrodes/stimulators, aneurysm clips or coils, stents, 
bullet fragments, jewelry and hair barrettes. 
-Prior brain surgery 
-Risk for increased intracranial pressure such as a brain tumor 
-Any unstable medical condition 
-History of treatment with ECT or TMS Therapy for any disorder 
-Use of any investigational drug within 4 weeks of the baseline visit 
-Initiation of a new psychotherapeutic treatment within the past 4 weeks  
-Suicide attempt within the previous 6 months that required medical treatment or ≥ 2 attempts in 
the past 12 months, or has a clear cut plan for suicide and states that he/she cannot guarantee that 
he/she will inform a family member or call his/her psychiatrist or the investigator if the impulse 
to implement the plan becomes substantial during the study; or, in the investigator's opinion, is 
likely to attempt suicide within the next 6 months. 
4.2.2 Exclusion Criteria Healthy Controls 
-History of depression or any psychiatric treatment 
-Subjects found to be pregnant at time of screening will be ineligible 
-Positive urine drug screening 
-Contraindications to MRI/MRS (CMRR Subject Safety Screening Form) 
4.3 
Participant Recruitment, Enrollment and Screening 
 
Participants will be recruited from the general community and referrals from local providers.  
Currently Dr. Croarkin directs a research program and outpatient clinic for adolescent mood 
disorders. Our group historically has been successful in the recruitment of similar samples.   
 
Additional resources will be utilized for recruitment of potential participants including: 
• from within the clinical and referral practices of  the clinical study site 
• referrals from other care providers within the treatment communities 
• radio advertisements 
• invitation letters sent to parents of potentially eligible participants 
• print advertisements, including but not limited to brochures, flyers, and listings in research 
classifieds 
• trial listing with ClinicalTrials.gov 
• trial listing on university and clinical study site website 

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• social media 
 
All advertising materials will be reviewed and approved by the Mayo Clinic IRB prior to use.  
 
Potentially interested adolescents and their families may be provided with printed participant 
educational materials to aid them in making an informed decision regarding their willingness to 
participate in this study. In addition, parents of potentially eligible patients identified via i2b2 
search will be contacted via IRB-approved email and follow-up telephone calls if necessary. 
 
Institutional Review Board (IRB) approval will be obtained for the consent and assent form.  The 
investigators will describe the study in full and complete a series of written comprehension 
questions to verify an understanding of the discomforts and potential benefits to the study. 
Participants and parents will then be asked to sign the consent and assent forms prior to 
participation.  Dr. Croarkin or a research team member that Dr. Croarkin has trained and 
supervises will explain the details of the study, answer any study related questions, and obtain 
informed assent and consent from the participants and their parents or legal guardians.  Dr. 
Croarkin or a board-certified child and adolescent psychiatrist will be available 24 hours a day to 
address any questions participants or parents have in signing informed consent or in the course of 
study participation.  Dr. Croarkin and the study team will reinforce that declining study 
participation does not impact accessibility to standard psychiatric treatment within the Mayo 
Clinic system or surrounding community.  Dr. Croarkin will offer ongoing standard clinical care 
or appropriate referrals (based on patient preference) to patients who exit the study or complete 
all study procedures. 
 
After providing informed consent and assent, participants will undergo an initial clinical 
assessment with a structured diagnostic interview (MINI), urine drug screen, safety screens, 
symptom rating scales, and a neurocognitive battery with the NIH tool box.86  Participants will 
then undergo TMS neurophysiology testing to generate a baseline ICF (interstimulus interval of 
15 milliseconds) measure for the purpose of stratification.  Baseline visits study procedures can 
be performed on the same date at Screening visit procedures or over 2-3 separate visits based on 
Participant preference and comfort.  Upon completion of baseline measurements and procedures, 
participants will be randomized to 1 Hz or 10 Hz rTMS.   
 
Preventing participant attrition during investigational, therapeutic TMS:  Treatment 
sessions are delivered 5 days per week consistent with prior systematic research.33,47,83, 38 We 
will offer treatment sessions on the weekend (for a total of 5 weekly sessions) when necessary to 
accommodate the participant scheduling constraints over a period of 6 weeks.  Hence 
participants will be given 42 opportunities to complete 30 sessions of rTMS.  During the first 
week of rTMS treatment intensity may be adjusted for participant comfort to a minimum of 80% 
motor threshold and titrated by 10% daily to 120% of resting motor threshold.  We have found 
that these scheduling and titration procedures are highly effective for retaining adolescent 
participants for investigational therapeutic rTMS 
 
It is anticipated that 150 participants will be screened to enroll 120 participants for Phase I.  A 
maximum of 50 participants will be enrolled in Phase II.  Prior clinical experience and research 
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not respond to treatment and thus will be eligible for Phase II. Please note that Phase II is an 
exploratory study and also intended to provide an addition resource for participants who do not 
respond to standard rTMS approaches. Based on prior work it is unlikely that no more than 50 
participants will be eligible and interested in enrollment in Phase II.   
 
 
 
4.4 
Early Withdrawal of Participants 
 
4.4.1 Participant Withdrawal, Data Collection, and Follow-Up 
Participants may withdraw voluntarily from the study at any time. Participants will be withdrawn 
from the study by the PI/Sponsor if a participant: 
 
• experiences a seizure, 
• experiences a DSM-5-confirmed treatment-induced mania, 
• is non-compliant with study procedures; or 
• endorsed illicit drug use or has a positive urine drug screen during the study  
 
The PI may also withdraw a participant if he/she believes that for safety reasons it is in the best 
interest of the participant to be withdrawn. 
 
Discontinuation information [e.g., date and the reason(s) for discontinuation] will be recorded in 
the Participant’s CRF (Case Report Form). Participants who discontinue prematurely should 
complete the Week 6 assessment procedures within 2 days following their last TMS treatment 
session. See the Schedule of Events for the specific procedures to be performed at this 
discontinuation visit.   
 
Participants withdrawn from the study due to an AE will be followed up for 30 days or until 
resolution. Participants withdrawn from the study will not be replaced, regardless of the reason 
for withdrawal. An effort will be made to determine why a participant does not return for the 
required visits or is dropped from the study. This information will subsequently be recorded on 
the participant’s CRF.Participants will be encouraged to remain compliant with all expected 
study visits.  Non-adherence to expected study visits will be documented and may result in 
removal from the study.  This will be clearly discussed during the consent/assent process and 
reinforced throughout the study through regular screening for issues with compliance. 
 
Dr. Croarkin will assist with clinical referral for all participants who voluntarily withdraw from 
the study or are withdrawn by the research team and PI.  Specifically, Dr. Croarkin will offer 
ongoing clinical care or community referrals based on the preference of the participant. 
 

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5 Study Device 
5.1 
Description 
The NeuroStar TMS Therapy® System is a computerized electromechanical instrument that 
produces and delivers brief duration, rapidly alternating (pulsed) magnetic fields to induce 
electrical currents in localized regions of the cerebral cortex.  It is a non-invasive tool used for 
the treatment of Participants with MDD who have not achieved sufficient clinical benefit from 
antidepressant pharmacotherapy.  The NeuroStar TMS Therapy System has been FDA-cleared 
for use in adults.  NeuroStar XPLOR® is a clinical research option for the NeuroStar TMS 
Therapy System that provides features necessary to conduct randomized controlled trials and 
other TMS research.  The active treatment modality is essentially the same for both the 
NeuroStar TMS Therapy System and NeuroStar XPLOR.   
 
The NeuroStar XPLOR TMS System consists of the following equipment and software: 
 
• Mobile Console (includes processor module, power module, mast, gantry, halo, and 
display arm) 
• System Software; the XPLOR option also includes a dedicated system software 
application (software version 1.7.5 or greater) with its own dedicated database of 
participant treatment history, TMS TrakStar® application, and TrakStar database that 
operates only with the corresponding XPLOR Software, maintaining isolation, security, 
and data integrity of the research.  
• TMS TrakStar® Data Management System software 
• Therapy Coils included with the XPLOR option is a set of three TMS coils: 
o a blinded sham or placebo coil; the sham coil is acoustically matched to protect 
the integrity of the blind, 
o a blinded active coil, and 
o a standard treatment coil that can be used for performing motor threshold level 
determination or open-label treatment. 
• Head Support System (includes laser positioning aid and coil positioning guide) 
• Treatment Chair 
• Positioning Cushions (to enhance comfort and positioning of the participant in the 
required posture for the duration of the treatment session) 
 
The NeuroStar TMS Therapy System also requires supplies and disposables for each treatment 
session: 
• Head Cushion Liner 
• Head Side Pad Liner 
• Head Positioning Straps 
• Earplugs 
• SenStar® Treatment Link (a single-use medical device) 
• Used SenStar Treatment Link Return box 
 

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5.2 Method for Assigning Participants to Treatment Groups 
 
Each participant will be assigned a unique identification upon signing the informed consent and 
assent form. This number will consist of an assigned 3-digit identifier. Participants will be 
identified by their assigned number and initials on the CRFs and source documents. The 
PI/Study Sponsor will maintain a master list linking Participant names and the identifying 
information indicated above 
 
A Phase I randomization schedule will be generated by Dr. Nakonezny (Study biostatistician). 
Participants will not be randomized until all entry (inclusion and exclusion) criteria have been 
met and all pre-study procedures have been satisfactorily completed. After stratification based on 
ICF biomarker status, eligible participants will be randomly assigned to receive one of the two 
treatment regimens (1 Hz or 10 Hz rTMS), and the next available randomization number for the 
participant’s stratum will be recorded in the screening log and on the participant’s CRF. 
Randomization numbers may not be reassigned.  A permuted-block procedure will be used to 
randomly assign the treatment conditions, with a fixed block size for each stratum.  Phase II is a 
trial of cTBS or iTBS for Phase I participants who did not have an adequate clinical response in 
Phase I.   Participants will be assigned to 2 weeks of cTBS if their intracortical facilitation 
measure is >1.5 (building on the current speculation that cTBS would be expected to decrease 
cortical excitability and ICF measures).  Participants will be assigned to 2 weeks of iTBS if their 
ICF (baseline assessment for TBS extension trial) is < 1.5.   
 
Collection of ICF and TMS neurophysiology measures:  TMS data will be collected with 
standard procedures published previously.65 Participants are seated in a comfortable chair during 
the procedure.  All participants and research team members wear ear plugs during testing 
sessions. Surface electromyography (EMG) readings are recorded from the abductor pollicis 
brevis (APB) muscle.  The research team will ensure participants maintain relaxation during the 
procedures with audio feedback tests. TMS stimulation will be applied to the hand area of the 
contralateral cortex with a figure-of-eight magnetic coil (with a coil diameter of 70 mm on each 
loop) using the Magstim 200 magnetic stimulator device. The TMS coil is held tangentially on 
the head with the handle backward at 45 degrees laterally from the midline to determine resting 
motor threshold.  The optimal coil position is located by moving the coil in 1-cm increments 
over the motor cortex. The resting motor threshold (RMT) is defined as the stimulation intensity 
which elicits a motor evoked potential (MEP) of > 50 microvolts in 5 of 10 trials with a relaxed 
APB muscle. For ICF measurements, a subthreshold conditioning stimulus (CS) which is set to 
80% of RMT precedes a suprathreshold test stimulus (TS), which is calibrated to produce an 
average MEP of 0.5 to 1.5 millivolt peak-to-peak amplitude in the contralateral APB muscle. 
Conditioning stimuli are delivered to the motor cortex prior to the TS in one of five random 
interstimulus intervals (ISIs): 2 msec, 4 msec for ICI; 10 msec, 15 msec, and 20 msec for ICF. 
Changes in TS MEP amplitude of each ISI are expressed as a percentage of the mean 
unconditioned MEP amplitude. Administration of tests is counterbalanced to prevent order 
effects. Please see Section 16, Appendix B for detailed methodology for collection of ICF and 
TMS neurophysiology measures. 
 

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5.3 Preparation and Administration/Implantation of Investigational Device 
 
Administration of TMS treatment will be consistent with procedures outlined in the NeuroStar® 
User Manual and User training documentation. 
 
Motor Threshold Determination Procedure – per NeuroStar User Manual 
Participants in phase I (1 Hz vs. 10 Hz) will receive treatment parameters that have been safely 
and feasibly utilized in adult and adolescent studies.  For 1 Hz and 10 Hz (Phase I) sessions, 
stimulation will occur at 120% magnetic field intensity relative to the participant’s resting motor 
threshold (MT).  In phase II (cTBS vs. iTBS) stimulations will occur at 80% of the magnetic 
field intensity relative to the participant’s resting motor threshold.  
  
Treatment 
 
Participants in Phase I will be stratified based on ICF testing (high or low) at baseline.  An ICF 
of >1.5 at baseline is considered “high” and an ICF ≤ 1.5 is considered “low”.  Based on our 
prior work and review of literature, a sample of depressed adolescents will have an even 
distribution of high and low ICF values.  After stratification, adolescents are randomized to 
either LDLPFC 1 Hz rTMS with 2400 continuous pulses per session at 120% motor threshold or 
LDLPFC 10 Hz rTMS with 4 seconds on 36 seconds off for 2400 pulses each session at 120% of 
resting motor threshold.  Hence sessions in each treatment arm with two different types of rTMS 
(1 Hz and 10 Hz) will have identical intensities (120% motor threshold) durations (40 minutes), 
number of pulses (2400), and treatment location (LDLFPC).  Up to 50 nonresponders in Phase I 
will be offered to the opportunity to enroll in a Phase II.  The decision to enroll in Phase II must  
be made by the subject no more than 30 days after the last day of Taper Week 3.We will deliver 
therapeutic rTMS sessions with a Neurostar XPLOR system magnetic stimulator.  The research 
team will localize rTMS treatment sites with the Beam F3 method.  Prior research demonstrates 
that this is a valid and reliable method for scalp location of the dorsolateral prefrontal cortex with 
comparable results to more expensive, time intensive, MRI-guided approaches. 87 Our prior 
research demonstrates that the Beam F3 method is a feasible and reliable method for rTMS 
treatment localization in adolescents.69 Efficacy measures (CDRS-R) and TMS biomarkers will 
be collected at baseline and weekly.  The TMS biomarker panel includes ICF, Motor threshold 
(MT) Short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), 
and cortical silent period (CSP). 
 
Participants in Phase II will be assigned to 2 weeks of cTBS if their intracortical facilitation 
measure (baseline assessment for TBS extension trial) is >1.5.  Participants will be assigned to 2 
weeks of iTBS if their ICF (baseline assessment for TBS extension trial) is  < 1.5.  Extension 
trial TBS will be applied to the LDLPFC with the Beam F3 method. Participants receiving cTBS 
will receive 10 daily (5 sessions per week for two weeks) 120 second trains of uninterrupted TBS 
for 1800 pulses at 80% motor threshold. Participants receiving iTBS will receive 10 daily (5 
sessions per week for two weeks) 2 second trains every 10 seconds for a total of 570 seconds for 
1800 pulses at 80% motor threshold.  Efficacy measures (CDRS-R) and TMS biomarkers will be 
collected at baseline, 1 week, and 2 weeks.  The TMS biomarker panel includes ICF, Motor 

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threshold (MT) Short-interval intracortical inhibition (SICI), long-interval intracortical inhibition 
(LICI), and cortical silent period (CSP). 
 
Safety Precautions for Seizures and Cardiogenic Syncope during Phase I and Phase II 
TMS sessions. 
 
We will follow our standard lab procedures for screening to minimize the risk of seizures and 
syncope, monitoring during treatment sessions, and immediately addressing any induced seizures 
or syncope during TMS sessions. 
 
With regard to the potential for seizures, all patients will be carefully screened for current or 
historical factors that may increase the risk of seizures (see Exclusion criteria). The Transcranial 
Magnetic Stimulation Adult Safety Screen (TASS) will be used to specifically query for any 
potential seizure or syncope risks. Neurologic disease which may increase the risk for seizures is 
part of the exclusion criteria.74,75 Patients undergoing TMS in the proposed study will not be 
taking medications which could potentially lower their seizure threshold. All TMS sessions will 
be supervised by a physician located in the treatment suite and all personnel involved will be 
provided with training in the identification of potential prodromal signs or symptoms of a 
seizure, particularly the identification of more subtle behavioral events which may herald the 
occurrence of a frontal lobe seizure, such as changes in level of consciousness or inattention.   
 
All TMS sessions will be conducted in the neurostimulation suite with access (within minutes) to 
medical facilities and life-support equipment in the event a seizure should occur.   
 
Monitoring for Seizures during TMS sessions. 
 
Seizure monitoring will be by continuous visual observation.  This includes visual monitoring for 
signs of seizures and twitching of muscles, including the abductor pollicis brevis and the first 
dorsal interosseous muscles of the contralateral hand. The visual observation monitoring will 
include monitoring for behavioral events such as changes in level of consciousness or 
inattention.  One or more research team members will be in the room with the participant at all 
times during TMS sessions for visual observation.  At a minimum one TMS technician (with 
specialized onsite and national training on the delivery of TMS, visual monitoring for signs of a 
seizure, and training in seizure management) will be in the room with the participant at all times 
during the TMS session with a study physician in the TMS treatment suite.  
 
Seizure Management 
 
The TMS technician and physician investigators have the capability to manage a seizure if it 
were to occur. The Mayo Clinic Neurostimulation Lab has direct access (within minutes as it is 
in the same hospital) to emergency medicine services. 
 
In the event of a seizure or syncopal event, the supervising physician will initiate appropriate 
clinical care as defined within the clinical rTMS practice.  The Pediatric Code Team will also be 
called immediately. Attention must be taken to minimize the risk of aspiration, and when 
possible guiding the patient into the left lateral decubitus position is desirable.  Because seizures 

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in the context of TMS are brief (typically <60 seconds) and without serious physical sequelae, 
efforts will be focused on preventing complications of the seizure rather than initiating any 
specific medication that is not required unless a seizure is prolonged.  The Pediatric Code Team  
is a hospital-based pediatric rapid response team who will arrive within minutes with life-support 
equipment 
(oxygen, 
suction, 
blood 
pressure 
monitor, 
CPR 
equipment) 
and 
anticonvulsant/antiepileptic  medications.  The Pediatric Code Team and the supervising TMS 
study physician will escort the participant to the emergency medicine department upon 
stabilization (located in the same hospital as the TMS suite).  To date, status epilepticus has 
never been described following rTMS.47,74,75 However, in the rare event this occurs, the 
participant will be treated in the emergency medicine department with access (within minutes) to 
neurological consultation. 
 
If a seizure occurs during the study, TMS treatment as part of the study will be discontinued.  
Ongoing monitoring of mood and neurocognitive symptoms per the study protocol will be 
offered.  Any seizure will be reported to the Mayo Clinic IRB, Data and Safety Monitoring 
Board (DSMB), Neuronetics, and the FDA as required per agreements, regulations, and policies. 
 
5.4 Packaging and Labeling 
The NeuroStar XPLOR® Therapy System will be clearly labeled with the following warning: 
 
“CAUTION – Investigational Device. Limited by Federal (or United States) law to 
investigational use”  
 
5.5 Blinding of Study 
 
In both phases of the study (phase I and phase II) participants and study team members 
completing clinical rating scales (Drs. Croarkin, Romanowicz, or other designated and trained 
clinical raters) will be blinded to treatment assignment.  The study team member completing 
clinical rating scales will not be allowed in the treatment suite during therapeutic rTMS sessions 
(10 Hz, 1 Hz, iTBS, or cTBS).  We will recruit adolescent participants with no prior TMS 
exposure or experience and maintain blind to rTMS treatment assignment (1 Hz or 10 Hz for 
phase I and cTBS or iTBS for phase II).  A pre-post treatment expectancy and experience form 
will ask that participants and parents guess which treatment (1 Hz, 10 Hz, iTBS, or cTBS) was 
received.88 
 
5.6 Receiving, Storage, Distribution and Return 
5.6.1 Receipt of Investigational Devices 
NeuroStar 
XPLOR® 
TMS 
Therapy 
System 
will 
be 
delivered 
to 
the 
Principal 
Investigator/Sponsor and installed by Neuronetics. 
 
Upon receipt of the NeuroStar and study treatment supplies, an inventory will be performed and 
a device accountability log completed by designated study staff.  The designated study staff will 

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count and verify that the shipment contains all the items noted in the shipping invoice.  Any 
discrepancies or damaged or unusable devices in a given shipment will be documented in the 
device accountability log.  The Investigator at each study site will notify Neuronetics 
immediately of any discrepancies or damaged or unusable products.   
5.6.2 Storage 
The supplies and disposables required for each treatment will be stored in a supply station 
separate from clinical practice stock at each site. 
5.6.3 Distribution of Study Device 
All participants will be treated using a new single-use treatment disposable, or SenStar® 
Treatment Link, from their treatment site at the start of every new treatment.  The treatment 
packs and SenStar Treatment Links will be stored in an area that is separate from clinical 
practice stock.  Regular reconciliation of SenStar Treatment Links received from Neuronetics, 
SenStars used during study treatments, and SenStars remaining will be performed.  This 
reconciliation of the inventory will be logged in the Device Accountability Log, signed, and 
dated.  Any discrepancies noted will be documented, Neuronetics will be notified, and an 
investigation will be conducted to determine the cause of the discrepancy.  Any SenStars 
disposed of for any reason other than use for the study will be documented in the Device 
Accountability Log at the time of disposal. 
5.6.4 Return or Destruction of Study Device 
NeuroStar devices and/or XPLORs that are loaned to the study site for purposes of this study will 
be returned to Neuronetics at conclusion of the study by Neuronetics personnel.  SenStars® that 
are remaining in the site study research inventory at the completion of the study will be packaged 
and returned to Neuronetics. 
 
5.7 Participant Compliance Monitoring 
 
Non-adherence to the assigned treatment regimen is defined as missing  ≥3 treatments in daily 
sequence, or missing more than 20% of the total number of treatment sessions occurring during 
the 6 weeks of acute treatment (does not include taper treatments) as outlined in the schedule of 
events (i.e., 100% compliance = 30 total treatments).  However, if the participant does miss a 
treatment, the participant must not go more than 3 calendar days without a treatment session.  
Treatments missed during the taper visits are considered protocol deviations.  Participants who 
are unable to comply with this schedule may be withdrawn from the investigational treatment 
portion of the study.  If a participant receives more than the prescribed number of pulses (i.e. 
2400 pulses of good contact), this would be considered an overdose and documented on the SAE 
form and reported to the IRB and US FDA. 
 
5.8 Prior and Concomitant Therapy 
 
5.8.1 Documenting Prior and Concomitant Therapy 
 

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Reasonable efforts will be made to determine all somatic therapies for depression received by the 
participant in the past 2 years.  All other medications and therapies received within six months of 
study enrollment will also be determined.  All relevant information will be recorded on the 
Participants CRF.  The antidepressant treatment history form (ATHF) will be completed to 
quantify treatment history. 
5.8.2 Permitted Concomitant Therapy 
Zaleplon, zolpidem, or zopiclone (1 dose nightly) as needed for treatment emergent insomnia or 
lorazepam (up to 2 mg daily) for treatment emergent anxiety, may be administered for up to 14 
doses during Phase I and an additional 5 doses during Phase II.  The use of alternative hypnotics 
or anxiolytic compounds requires prior approval from the PI/Sponsor (Dr. Croarkin).  Hormonal 
contraceptives are allowed if the participant has been on a stable dose for at least 3 months.  
Short-term treatments for headaches, allergies, colds, and flu symptoms will be allowed during 
the study provided the medications utilized have no established psychotropic effects that would 
be expected to confound interpretation of study outcome measures.  These medications may 
include non-sedating, over-the-counter, or prescription antihistamines, analgesics and 
decongestants.  All questions regarding the acceptability of specific medications must be 
approved by the PI/Sponsor (Dr Croarkin). Please see appendix A for further information.  
5.6.3 Prohibited Concomitant Therapy 
Any medication administered for the treatment of any psychiatric or neurologic disorder or any 
other known CNS active drugs, including herbal, over-the-counter, and homeopathic 
medications, MAOIs, other antidepressants, antipsychotics, stimulants and mood stabilizers are 
prohibited during this study (See Appendix A, Concomitant Medication Exclusion List).  Use of 
Zaleplon, zolpidem, zopiclone or lorazepam for more than the permitted days (see above) or 
beginning a new regimen of hormonal contraception may lead to excluding the participant from  
the study. 
6 Study Procedures 
 
6.1 Phase I Visit 1 (Screening) 
 
Table 2 describes all study assessments.  Table 3 describes a schedule of events. The first visit is 
a screening visit. Informed consent and assent will be completed. A physical exam, vital signs, 
urine drug screen, and urine pregnancy test (if applicable) will be completed. Baseline 
assessments may be completed at this time as well in the interest of decreasing patient burden 
related to study procedures (see Table 3). 
 
Once eligibility criteria are met and interest in the MRI/MRS is indicated, the subject will report 
to the University of Minnesota Center for Magnetic Resonance Imaging for the 3 and 7 Tesla 
MRI Scans.  This procedure needs to be completed prior to the Baseline Visit. 
 
6.2 Phase I Visit 2 (Baseline) 
 
Assessments will be completed (see Table 3),  TMS neurophysiology measures are collected,   
and the participant is stratified as described previously based on ICF (ICF-15 % MEP amp) 

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biomarker status.  The participant is randomized to 1 Hz or 10 Hz rTMS.  Based on participant 
preference, the baseline visit can be scheduled on a Monday to facilitate the initiation of 
investigational rTMS treatment (1 Hz or 10 Hz based on randomization). Otherwise, the 
participant will be scheduled to initiate the first investigational rTMS treatment day as 
appropriate based on the patient’s schedule and staffing availability. 
 
6.3 Phase I Daily Treatment Visits 
 
On each treatment visit 1 Hz or 10 Hz rTMS will be delivered as described previously. 
Additionally, for the first week of Phase I treatment, a pre-treatment checklist will be completed  
by 2 members of study staff prior to initiating treatment to ensure treatments are performed 
properly and accurately. The 2nd member of study staff may assist telephonically if necessary.  
Participants will undergo weekly depression severity measures and TMS neurophysiological 
measures (see Table 3).  
 
Table 2. Description of Assessments  
 
Assessment 
Description 
Abnormal Involuntary 
Movement Scale (AIMS) 
Collected at the screening visit and at weekly treatment visits, 
posttreatment, and 6-month follow up visit.  This assessment is to 
screen and monitor twitching, trembling, and dyskinesias.  
Antidepressant Treatment 
History Form (ATHF) 
Collected at baseline to systematically document prior psychotropic 
medication exposure and for quantification of treatment resistance 
(number of failed antidepressant trials with an adequate dose and 
duration). 
Adverse events 
Participants will be evaluated for adverse events at each visit. Serious 
adverse events (SAEs) will be reported as they occur to the Mayo 
Clinic IRB and USA FDA (as per regulations). Systematic data 
collection focused on adverse events will include the Pediatric 
Adverse Event Rating Scale and Physical Symptom Checklist. These 
rating scales will be administered at baseline, weekly (during all 
rTMS, cTBS, and iTBS treatment weeks), at the 6 month follow up 
visit, and at study exit. 
Auditory thresholds 
Participants will undergo audiometry testing at baseline and upon 
completion of 6 week rTMS (1 Hz or 10 Hz) and once again (if 
applicable) after the two week open extension trial (of either cTBS or 
iTBS).  
Beck Depression Inventory-II 
This is a validated, 21-item, self-report measure with a range of 0-63. 
Collected at baseline, weekly during treatment, posttreatment, and 6 
month follow up visit. 
CDRS-R – Childhood 
Depression Rating Scale – 
Revised 
This is a validated, 17-item, clinical rating tool to assess severity of 
depression. Parents provide input into 14 of the items. Total possible 
scores range from 17 to 113. Collected at baseline, weekly during 
treatment, posttreatment, and 6 month follow up visit. 

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Assessment 
Description 
CGI-S– Clinical Global 
Impressions Severity Scale 
A standard measure of symptom severity and treatment response.  
Collected at baseline, weekly during treatment, posttreatment, and 6 
month follow up visit. 
Center for Magnetic Resonance 
Research Safety Screen 
(CMRR) 
This assesses subject safety to go in the magnet room and undergo 3T 
and 7 MRI/MRS.  This will be completed at Mayo Clinic and CMRR 
C-SSRS – Columbia Suicide 
Severity Rating Scale 
This is collected to assess lifetime suicidal ideation and behavior prior 
to participation, reassessed weekly during 6 week trial of 1 Hz vs 10 
Hz rTMS (phase I) and if applicable 2 week extension trial of cTBS or 
iTBS (phase II) during treatments, posttreatment, and 6 month follow 
up visit.  
CTQ – Childhood Trauma 
Questionnaire  
A 28 item self-report scale used to screen for a history of adversity. 
Collected at baseline. 
Edinburgh Inventory for 
Handedness  
Used to assess handedness of all Participants. Collected at baseline. 
Mini International 
Neuropsychiatric Interview 
(M.I.N.I) 
A structured psychiatric interview (M.I.N.I. for age 18 and M.I.N.I 
Kid for ages 12-17). Collected at baseline. 
 
NIH Toolbox Cognition Battery 
http://www.healthmeasures.net/explore-measurement-systems/nih-
toolbox 
 
Cognition measures: http://www.healthmeasures.net/explore-
measurement-systems/nih-toolbox/intro-to-nih-toolbox/cognition 
 
The NIH Toolbox Cognition Battery, recommended for ages 7+, 
consists of tests of multiple constructs. It yields individual measure 
scores and the following summary scores:  Education, Handedness, 
Attention (Flanker Inhibitory Control and Attention Test),  Episodic 
memory (Picture Sequence Memory Test, and Auditory Verbal 
Learning Test), Executive Function (Dimensional Change Card Sort 
Test, Flanker Inhibitory Control and Attention Test), Language 
(Picture Vocabulary Test, Oral Reading Recognition Test), Processing 
Speed (Pattern Comparison Processing Speed Test), Working Memory 
(List Sorting Working Memory Test).  Collected at baseline, 
posttreatment, and 6 month follow up. 
 
PDS – Pubertal Development 
Scale and Tanner Staging 
A self-report questionnaire and line-drawings used to evaluate level of 
pubertal development. Collected at baseline. 
Pre/Post Treatment Expectations 
and Experience Questionnaire 
(Adolescent and Parent) 
Assesses adolescent and parent blinding to treatment arm (1 Hz or 10 
Hz) and expectations for treatment outcome. Collected at baseline and 
posttreatment. 
SHAPS-Snaith-Hamilton 
Pleasure Scale 
This is a 14 item, self-report measure of validated measure of hedonic 
capacity. Collected at baseline. 

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Assessment 
Description 
Pediatric Adverse Event Rating 
Scale 
This is a 51 item; self-report measure collected at baseline, weekly 
during rTMS treatments, posttreatment, and at 6 month follows up 
visit for adverse event monitoring. 
Physical Symptoms Checklist 
This is a 46 item measure to be collected by the study team (under the 
supervision of the PI) at baseline, weekly during rTMS treatments, 
posttreatment, and at 6 month follow up visit for adverse event 
monitoring. 
SIT-R3 – Slosson Intelligence 
Test – Revised  
A rapid, validated index of intellectual ability. Its items cover six 
cognitive domains: Information, Comprehension, Quantitative, 
Similarities and Differences, Vocabulary, and Auditory Memory. 
Collected at baseline, if PI the determines there are concerns about 
cognitive functioning. 
TASS – Transcranial Magnetic 
Stimulation Safety Screen 
This safety screen is completed prior to TMS for confirmation patient 
safety. Collected at baseline. 
UCSD Brief Assessment of 
Capacity to Consent (UBACC) 
This will be given to patients that are 18 years of age who are interested in 
participating in the MRI/MRS scans at CMRR of age during informed 
consent. This assesses the patient’s understanding of the MRI/MRS portion 
of the study.  
Vital Signs 
(Pulse, blood pressure, height, and weight) will be collected at 
baseline, upon completion of 6 week rTMS (1 Hz or 10 Hz) once 
again (if applicable) after two week open extension trial (of either 
cTBS or iTBS), and at 6 month follow up visit. 
YMRS-Young Mania Rating        
Scale 
This is an 11 item measure used to assess for manic symptoms.  The 
YMRS scale will be completed at baseline and repeated during the 
course of study participation if symptoms of mania occur in a study 
participant.  If the YMRS is positive, A MINI/MINI-Kid will be 
repeated to evaluate for mania.  If the study participant meets full 
DSM-5 criteria for mania or hypomania he or she will be discontinued 
from the study and followed clinically. 
TMS Neurophysiology 
Measures (MT, SICI, ICF, LICI, 
CSP) 
Single (motor threshold and cortical silent period) and paired-pulse 
(intracortical facilitation, short-interval cortical inhibition, long-
interval cortical inhibition).  TMS neurophysiology measures will be 
collected in depressed adolescent participants at baseline, weekly 
during six weeks of rTMS treatment with 1Hz or 10 Hz rTMS (phase 
I), posttreatment, and weekly for 2 weeks for depressed adolescent 
participants in a, trial of cTBS or iTBS (phase II).   
 
 
 

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Table 3 Phase I Assessments 
 
 
Phase I 
1-Week  
Prestudy 
6-Week  
Treatment (1 Hz vs. 10 Hz) 
3-Week  
Post-
Treatment 
Taper  
6- 
Mont
h  
Follo
w Up 
Week 
Wk –2 to -
1a 
(Screening) 
Wk 0a 
(Baselin
e) 
W
k 
1b 
W
k 
2b 
W
k 
3b 
W
k 
4b 
W
k 5 
b 
Wk 
6b,c/E
T 
Wk 
1 
Wk 
2 
W
k 
3 
 
Day(s) 
-7a 
0a 
1-5 
8-
12 
15-
19 
22-
26 
29-
35 
36-42 
43-
49 
50-
56 
57
-
63 
 
Informed 
Consent/Assent/HIPA
A 
X 
 
 
 
 
 
 
 
 
 
 
 
CMRR Safety Screen 
(prior to MRI/MRS) 
X 
 
 
 
 
 
 
X 
 
 
 
 
UCSD 
Brief 
Assessment 
of 
Capacity to Consent 
(UBACC) 
(only 
patients 
age 
18 
participating 
in 
MRI/MRS scans at 
CMRR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MRI/MRS 
Study(Before Baseline 
Appt.) 
X 
 
 
 
 
 
 
X 
 
 
 
 
Transcranial 
Magnetic Stimulation 
Adult Safety Screen 
(TASS) 
X 
 
 
 
 
 
 
 
 
 
 
 
Antidepressant 
Treatment History 
Form (ATHF) 
X 
 
 
 
 
 
 
 
 
 
 
 
Abnormal 
Involuntary 
Movement Scale 
(AIMS) 
X 
 
X 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
MINI / MINI-Kids 
X 
 
 
 
 
 
 
 
 
 
 
 
CTQ 
 
X 
 
 
 
 
 
 
 
 
 
 
PDS 
 
X 
 
 
 
 
 
 
 
 
 
 

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Phase I 
1-Week  
Prestudy 
6-Week  
Treatment (1 Hz vs. 10 Hz) 
3-Week  
Post-
Treatment 
Taper  
6- 
Mont
h  
Follo
w Up 
Week 
Wk –2 to -
1a 
(Screening) 
Wk 0a 
(Baselin
e) 
W
k 
1b 
W
k 
2b 
W
k 
3b 
W
k 
4b 
W
k 5 
b 
Wk 
6b,c/E
T 
Wk 
1 
Wk 
2 
W
k 
3 
 
Day(s) 
-7a 
0a 
1-5 
8-
12 
15-
19 
22-
26 
29-
35 
36-42 
43-
49 
50-
56 
57
-
63 
 
SHAPS 
 
X 
 
 
 
 
 
 
 
 
 
 
Pre/Post-TEEQ-P 
 
X 
 
 
 
 
 
X 
 
 
 
 
Pre/Post-TEEQ-A 
 
X 
 
 
 
 
 
X 
 
 
 
 
Efficacy Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
BDI-II 
X 
X 
 
 
 
X  
 
Xc,d 
X 
 
Xd 
 
CDRS-R 
X 
X 
X 
X 
X 
Xd 
X 
Xc,d 
X 
X 
Xd 
X 
CGI-S 
X 
X 
 
 
 
X  
 
Xc,d 
X 
 
Xd 
X 
Neuropsychological 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
  
NIH Toolbox 
 
X 
 
 
 
 
 
 
Xc,d 
 
 
 
X 
SIT-R3 
 
X 
 
 
 
 
 
 
 
 
 
 
YMRSd 
 
X 
 
 
 
 
 
  
 
 
 
 
C-SSRS 
X 
X 
Xd 
Xd 
Xd 
Xd 
Xd 
Xc,d 
Xd 
Xd 
Xd 
X 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
  
 
 
 
 
 
Xc 
X 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy teste 
X 
 
 
 
 
 
 
 
 
 
 
 
Audiometry 
assessment 
 
X 
 
 
 
 
 
Xc 
 
 
 
X 
Physical Symptom  
Checklist 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
   Pediatric Adverse 
Event Rating 
         Scale 
 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 X 
Adverse Events 
X ---------------------------------------------------------------------------------------------------X 
 
Prior/Concomitant 
Treatment 
X ---------------------------------------------------------------------------------------------------X 
 

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Phase I 
1-Week  
Prestudy 
6-Week  
Treatment (1 Hz vs. 10 Hz) 
3-Week  
Post-
Treatment 
Taper  
6- 
Mont
h  
Follo
w Up 
Week 
Wk –2 to -
1a 
(Screening) 
Wk 0a 
(Baselin
e) 
W
k 
1b 
W
k 
2b 
W
k 
3b 
W
k 
4b 
W
k 5 
b 
Wk 
6b,c/E
T 
Wk 
1 
Wk 
2 
W
k 
3 
 
Day(s) 
-7a 
0a 
1-5 
8-
12 
15-
19 
22-
26 
29-
35 
36-42 
43-
49 
50-
56 
57
-
63 
 
Motor Threshold 
Determinationg 
  
X 
 
 
 
 
 
 
 
 
 
 
TMS Treatment 
Session 
(daily  5 
weekdays/week) 
 
 
X--
-Xb 
X--
-Xb 
X--
-Xb 
X--
-Xb 
X---
Xb 
X---Xb 
 
 
 
 
TMS neurophysiology 
measures (MT, SICI, 
ICF, LICI, CSP) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Post-Treatment Taper 
TMS Session(s) 
(3X/Wk1, 2X/Wk 2, 
1X/Wk 3) 
 
 
 
 
 
 
 
  
X 
X 
 
X 
 
  
a. A maximum of 7 days may elapse between the screening and baseline visits; a maximum of 5 days may elapse between the baseline visit 
and the first treatment day of Week 1.  All baseline assessments must be completed before 1st TMS treatment. 
b. The first visit during each week of treatment should occur on a Monday, with daily treatment sessions occurring on Monday through Friday 
of each week. 
c. Participants who prematurely discontinue should complete all Week 6 procedures within 2 days after their last TMS treatment session. 
d. Efficacy and neuropsychological assessments to be performed after last TMS treatment session on last day of the treatment week when 
assessments are required. YMRS to be completed if symptom indicating mania occurs.  If positive, a MINI/MINI-Kid must be repeated to 
determine if Participant meets full DSM-5 criteria for mania or hypomania.  If positive, participant to be discontinued from the study and 
followed clinically. 
e. If Participant is female of childbearing potential, a urine pregnancy test will be performed at screening.  Note that parents or guardians will 
not be told the results of the pregnancy test without the participant’s permission. But if the participant’s doctor believes that being pregnant 
may cause serious health problems, they may need to tell the parent/guardian the pregnancy test results. 
f. Adverse events occurring prior to randomization will be recorded as part of each patient’s medical history. Those AEs occurring following 
the first TMS treatment session through 30 days after last TMS treatment session will be collected. 
g. In addition to the indicated day, Motor Threshold Determination (MT) may be repeated at any time during the course of the active TMS 
treatment sessions based on clinical assessment of the supervising physician.   
Medication treatment for emergent insomnia and emergent anxiety is permitted (refer to protocol for usage allowance).  Refer to 
Appendix A for the Concomitant Medication List. 
h. The following assessments will be completed once only for healthy controls at the Mayo Clinic site: Urine testing (drugs and pregnancy if 
female), vitals (blood pressure, pulse, height and weight), GUID (demographics) form, physical examination record,  Transcranial Magnetic 
Stimulation Adult Safety Screen, M.I.N.I. Kid, Children’s Depression Rating Scale, Columbia - Suicide Severity Rating Scale, Childhood 
Trauma Questionnaire, Clinical Global Impressions, Center for Magnetic Resonance Research Screening Form, Edinburgh Handedness 
Inventory, Scale for Pubertal Development, Beck Depression Inventory-II, Authorization to Release Information (if applicable) 
 
Table 4 Phase II Assessments 

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Every treatment day of Phase II treatment a pre-treatment checklist will be completed  by 2 members of study staff 
prior to initiating treatment to ensure treatments are performed properly and accurately. The 2nd member of study staff 
may assist telephonically if necessary. 
7 Statistical Plan 
 
7.1 
Sample Size Determination 
 
Sample Size Estimation and Power Analysis for the Primary Aim of the Study  
 
Using a putative estimate of effect size (d~0.61) as it relates to the Primary Aim, an a priori 
sample size estimation and power analysis was performed for the repeated measures design in 
the proposed study. The results suggest that a sample size of 25 participants per group (N=120) 
achieves 80% power, at a 0.05 alpha level (two-tailed), to detect standardized group mean 
differences (Cohen’s d) as small as 0.61 in a 2-treatment by 2-biomarker status between-
Participants group design with 6 (within-Participants) repeated measurements of the primary 
outcome (depression severity) having a compound symmetry covariance structure, when the 
assumed within-Participant correlation between observations (depression severity) on the same 
Participant is ≤0.50 (0.50 was based on guidance from our preliminary rTMS work).  We 
anticipate some dropouts (~20% based on treatment discontinuation results from our previous 
rTMS studies). Thus, ~120 participants will be enrolled to allow for this expected rate of attrition 
with the intent of capturing a range of evaluable data for 100 participants. The Power Analysis 
and Sample Size (PASS) 2016 software, version 14.0.7, was used to carry out the sample size 
and power analysis. 89 
Week  
Week 1 
Week 2 
6 Month 
Follow-up 
Days  
1-5 
8-12 
 
Informed Consent/Assent 
       X 
 
 
Motor Threshold 
X 
 
 
CDRS-R 
X 
X 
X 
CGI 
X 
X 
X 
C-SSRS 
X 
X 
X 
TMS neurophysiology measures  
(MT, SICI, ICF, LICI, CSP) 
X 
X 
 
AIMS 
X 
X 
X 
Vital Signs 
X 
X 
 
Physical Symptom  Checklist 
X 
X 
X 
Pediatric Adverse Event Rating  Scale 
X 
X 
X 
Audiometry assessment 
 
X 
X 
NIH toolbox 
 
X 
X 
Adverse Eventsf 
Daily 
Daily 
 
Prior/Concomitant Treatment 
Daily 
Daily 
 

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We recognize that to definitively evaluate the relationship between rTMS Treatment (low 
frequency 1 Hz rTMS vs. high frequency 10 Hz rTMS) by biomarker status (high baseline ICF 
vs. low baseline ICF) on depression severity—since this relationship has not been previously 
studied, we have no previous findings to guide effect size selection for the present effort, and the 
current study would be the first of its kind to examine this effect in depressed youth—we will 
possibly need a larger sample size than the 100 participants put forth in this proposal.  The 
selection of 100 participants was, in part, resource-driven.  The sample size is designed, in part, 
to detect a moderate effect and to establish a proof of concept so as to expand to a subsequent, 
larger-scale multi-center study.  Nevertheless, the current proposal will permit an evaluation of 
whether receiving low frequency (1 Hz) rTMS vs. high frequency (10 Hz) rTMS treatment 
according to patients’ baseline biomarker status (ICF) shows initial evidence of a relationship 
with improvement in depression severity in a depressed adolescent population.  
 
7.2 
Statistical Methods 
 
 
Statistical Methods 
All statistical analyses will be carried out using SAS software, version 9.4. The level of 
significance will be set at α = .05 (two-tailed) and, to address multiple testing (where applicable), 
p-values will be adjusted using the False Discovery Rate.  
 
Primary Aim  
Data Analysis Plan for Primary Aim 1 (Hypotheses 1a ̶ 1d)  
 
Primary Continuous Outcome: CDRS-R Total Score 
Depression severity (measured by CDRS-R total) over the 6-week study period will be the 
primary continuous outcome measure.  A linear mixed model analysis of repeated measures will 
be used to evaluate the rTMS Treatment (low frequency 1 Hz rTMS vs. high frequency 10 Hz 
rTMS) by biomarker status (high baseline ICF vs. low baseline ICF) interaction effect on 
depression severity (CDRS-R total) over 6 weeks of rTMS in depressed adolescents. The model 
will contain fixed effects terms for rTMS treatment, biomarker status, time, rTMS treatment × 
biomarker status interaction, and baseline CDRS-R total score as a covariate.  We will consider 
the inclusion of pubertal state and treatment resistance (as defined by Antidepressant Treatment 
History Form [ATHF] score) during the study period as additional covariates in the mixed 
model.  Restricted maximum likelihood estimation, Type 3 tests of fixed effects, and generalized 
least squares will be used, with the Kenward-Roger correction applied to the appropriate and best 
fitting covariance structure. The sandwich (robust covariance matrix) estimator will also be 
considered. Least squares (LS) means will be estimated as part of the mixed model. Tests of 
Simple Effects will be examined so as to partition the interaction LS means effects; i.e., simple 
group main effects of biomarker status at each level of rTMS treatment (Hypotheses 1a, 1b) and 
simple group main effects of rTMS treatment at each level of biomarker status (Hypotheses 1c, 
1d) will be examined.  Cohen’s d and Hedges' g will be calculated and interpreted as the effect 
size estimator for the between-Participants group main effects. A separate linear mixed model 
repeated measures analysis similar to that described above will also be implemented over 6 
weeks of acute rTMS treatment and throughout the 6-month follow-up period.  The PROC 

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MIXED procedures (mixed model approach) in SAS software will make use of all available data 
from all participants from the efficacy analysis set, and provide a robust mechanism for handling 
data that are assumed missing at random (see sensitivity analysis section below for MNAR).   
 
Secondary Aim  
Data Analysis Plan for Secondary Aim 2 (Hypotheses 2a ̶ 2d)  
 
Secondary Continuous Outcome:  Intracortical Facilitation (ICF)  
Intracortical Facilitation over the 6-week study period will be the secondary continuous outcome 
measure.  A within-Participants linear mixed model analysis of repeated measures will be used to 
examine the change in ICF over 6 weeks of rTMS treatment in depressed adolescents.  We will 
consider the inclusion of pubertal state and treatment resistance (as defined by ATHF score) 
during the study period as a covariate in the mixed model.  A mixed model analysis will be 
conducted on ICF for those who receive 6 weeks of low frequency (1 Hz) rTMS treatment 
(Hypothesis 2a) and, in a separate model, for those who receive 6 weeks of high frequency (10 
Hz) rTMS treatment (Hypothesis 2c).  Restricted maximum likelihood estimation, Type 3 tests 
of fixed effects, and generalized least squares (LS) will be used, with the Kenward-Roger 
correction applied to the appropriate and best fitting covariance structure. The sandwich (robust 
covariance matrix) estimator will also be considered.  LS mean contrasts (between ICF 
measurement time periods) from the mixed model will also be examined.  A separate linear 
mixed model analysis similar to that described above will also be implemented over 6 weeks of 
acute rTMS treatment and throughout the 6-month follow-up period.  A nonlinear mixed model 
will be considered (e.g., exponential decay/growth model) to estimate ICF over the 6 weeks of 
rTMS treatment (if the pattern of ICF values suggests that a nonlinear model is deemed 
necessary).  
 
A linear mixed model repeated measures analysis similar to that described above will also be 
used to examine the relationship between measures of ICF (as the response variable) and 
depressive symptoms (CDRS-R total as a time-varying covariate) over the 6 weeks of rTMS 
treatment.  We will consider the inclusion of pubertal state and treatment resistance (as defined 
by ATHF) during the study period as a covariate in the mixed model.  The parameter estimates 
(regression coefficients) will be interpreted from the solution for fixed effects in the mixed 
model analysis for those who receive 6 weeks of low frequency (1 Hz) rTMS treatment 
(Hypothesis 2b) and for those who receive 6 weeks of high frequency (10 Hz) rTMS treatment 
(Hypothesis 2d).  A separate linear mixed model analysis similar to that described above will 
also be implemented over 6 weeks of acute rTMS treatment and throughout the 6-month follow-
up period. A nonlinear mixed model will be considered to estimate ICF over the 6 weeks of 
rTMS treatment from CDRS-R total (if the pattern of ICF and CDRS-R total suggests that a 
nonlinear model is deemed necessary). 
 
Data Analysis Plan for Exploratory Aim 3  (MRI/MRS)  
 
A within-participants linear mixed model analysis of repeated measures will be used to examine 
baseline differences between depressed adolescents and healthy control adolescents (Hypotheses 
1 and 2); and the change in cortical MRS measures of GABA and Gln/Glu over 6 weeks of 
rTMS treatment in depressed adolescents.  Separate mixed models will be conducted on cortical 
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(Hypotheses 3 and 4) and for those who receive 6 weeks of high frequency (10 Hz) rTMS 
treatment (Hypotheses 5 and 6).  A nonlinear mixed model will be considered (if the pattern of 
GABA and Gln/Glu values suggests that a nonlinear model is deemed necessary). 
 
Data Analysis Plan for Exploratory Aim4   
 
Moderator Effects of Anhedonia and Adversity on Treatment Outcome of Depression Severity 
The multiple mediation/moderation path analytic model, as described in Preacher and Hayes will 
be used to estimate the direct effect as well as the total and specific indirect effects of rTMS 
treatment on depression severity (at the 6-week endpoint) through each of the potential baseline 
moderators (anhedonia and adversity) operating in parallel and, via a separate model, in serial, 
while controlling for any potential demographics/patient characteristics (not designated as 
mediators/moderators), including pubertal state and treatment resistance (as defined by ATHF 
score).  A test of the indirect effects will be conducted by bootstrapping standard errors and 
confidence intervals (95% bias-corrected) from 5,000 bootstrap samples. The procedures of the 
PROCESS computational SAS macro developed by Hayes will be used to implement the path 
analytic-based multiple mediation/moderation model. 
 
Sensitivity Analysis  
In this section we present a brief sensitivity analysis plan to address incomplete response patterns 
according to a missing not at random mechanism.  First, we will follow the outcome-based 
model framework of for longitudinal data with non-random missingness along with a model-
based approach proposed for modeling both the treatment response and the missing data 
process.90 That is, if deemed necessary, we will build longitudinal models for the data which 
includes a model for the dropout (or missing data) process so as to assess the sensitivity of the 
results about the dependence between dropout (or missingness) and treatment response.  
Additionally, if deemed necessary, we will consider implementing the semi-parametric shared 
parameter model approach as described in Tsonaka et al. (2009) to handle nonmonotonic 
nonignorable missingness for mixed-effects models.  A Pattern-Mixture Model will also be 
considered (if necessary). 90 The results from such (non-random dropout/missingness) models 
will then be compared with the results of the proposed standard methods (dropout or missing at 
random models) so as to assess the sensitivity of the results to the effect of dropouts (or 
incomplete response patterns according to a missing not at random mechanism).    
 
8 
Safety and Adverse Events 
8.1 
Definitions 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is 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 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 participants. 
 
Adverse Effect (Event) 

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Any untoward medical occurrence in a participant involved in clinical study of an investigational 
device; regardless of the causal relationship of the problem with the device or, if applicable, 
other study related treatment(s). 
 
Associated with the investigational device:  there is a reasonable possibility that the adverse 
effect may have been caused by the investigational device. 
 
Life-threatening adverse effect: Any adverse effect that places the participant, in the view of 
either the investigator or the sponsor, at immediate risk of death from the effect as it occurred.  
It does not include a reaction that, had it occurred in a more severe form, might have caused 
death. 
 
Serious adverse effect: An adverse effect is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes:  
• death  
• a life-threatening AE 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability/incapacity 
• a congenital anomaly/birth defect. 
 
Unanticipated adverse effect: Any adverse effect, the nature, specificity, severity, or frequency 
of which is not consistent with the risk information in the clinical study protocol or elsewhere in 
the current IDE application. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as an unanticipated adverse device effect unless specifically instructed 
otherwise in this protocol.  Any condition responsible for surgery should be documented as an 
adverse event if the condition meets the criteria for an adverse event. 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances 
 
• 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery will not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful 
• 
Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 

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Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the Participant is lost to follow-up, or the adverse event is otherwise explained.  At the 
last scheduled visit, the research team will instruct each participant to report any subsequent 
event(s) that the participant, or the participant’s personal physician, believes might reasonably be 
related to participation in this study.   
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
Unanticipated Problems Involving Risk to Participants or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets all of the following three criteria: 
• 
Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
Participant or others (including individuals who are not research Participants). These 
include: (1) death; (2) life threatening adverse experience; (3) hospitalization - inpatient, 
new, or prolonged; (4) disability/incapacity - persistent or significant; (5) birth 
defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or new 
information (i.e. publications, DSMB reports, interim findings, product labeling change) 
that in the opinion of the local investigator may adversely affect the rights, safety, or 
welfare of the Participants or others, or substantially compromise the research data, AND 
• 
Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• 
Related: A problem or event is "related" if it is possibly related to the research 
procedures. 
 
An adverse event is any untoward, undesired, or unplanned event in the form of signs, 
symptoms, disease, or laboratory or physiological observations occurring in a person who has 
received NeuroStar TMS therapy (1 Hz, 10 Hz, cTBS, or iTBS).  The event need not be causally 
related to the NeuroStar device or the present clinical trial. An AE includes, but is not limited to: 
 
• Any clinically significant worsening of a pre-existing condition; 
• An AE occurring from overdose (i.e., a dose higher than that described in the protocol) of a 
NeuroStar TMS device, whether accidental or intentional; 
• An AE occurring from abuse (e.g., use for non-clinical reasons) of a NeuroStar TMS device; 
• An AE that has been associated with the discontinuation of the use of a NeuroStar TMS 
device; a preexisting condition is a clinical condition (including a condition being treated) 

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that is diagnosed before an informed consent form is signed and is documented as part of the 
Participant’s medical history. 
 
The questions concerning whether the condition existed before the start of the active phase of the 
study and whether it has increased in severity and/or frequency will be used to determine 
whether an event is a treatment-emergent AE (TEAE). An AE is considered to be a TEAE if (1) 
it was not present when the active phase of the study began and is not a chronic condition that is 
part of the Participant’s medical history, or (2) it was present at the start of the active phase of 
the study or as part of the Participant’s medical history, but the severity or frequency increased 
during the active phase. 
 
Additionally, important medical events that may not result in death, be life-threatening, or 
require hospitalization, may be considered SAEs, based upon appropriate medical judgment. 
 
Life threatening refers to immediate risk of death as the event occurred or use or continued use 
of the device or other medical product might have resulted in the death per the reporter. A life-
threatening event does not include an event that, had it occurred in a more severe form, might 
have caused death, but as it actually occurred, did not create an immediate risk of death.  
 
Hospitalization is to be considered only as an admission. Hospitalization or prolongation of a 
hospitalization constitutes an AE to be classified as serious. 
 
Note that hospitalizations planned before the start of the study, for a preexisting condition that 
has not worsened, do not constitute an SAE (e.g., elective hospitalization for surgery due to a 
preexisting condition that has not worsened during the study). 
 
If there is any doubt whether the information constitutes an SAE, the information should be 
treated as an SAE for the purpose of this study. 
 
8.2 
Recording of Adverse Events 
 
All adverse events occurring during the study, including those not meeting the criteria of an 
Unanticipated Adverse Device Effect (UADE) will be recorded on the appropriate case report 
form on the day of the occurrence.  Records of these events will be maintained and reports 
submitted to the FDA and IRB according to the regulatory requirements.  Expected clinical 
adverse events and nonsignificant (not serious) clinical adverse events will not be reported. 
Expected clinical adverse events and anticipated adverse device effects are those listed in Section 
1.4.1.  The PI/Sponsor (Dr. Croarkin) and research team will follow all AEs, SAEs, and other 
reportable events until the event has subsided or values have returned to baseline, or in case of 
permanent impairment, until the condition stabilizes.  
8.3 
Reporting Procedures 
At each required study visit, all AEs that have occurred since the previous visit will be recorded 
in the adverse event record of the Participant’s CRF. The information recorded should be based 
on the signs or symptoms detected during the physical examination and clinical evaluation of the 

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Participant. In addition to the information obtained from those sources, the Participant should be 
asked the following nonspecific question:  "How have you been feeling since your last visit?" 
Signs and symptoms should be recorded using standard medical terminology. On the case report 
form the treating physician will record the event, sign with their initials and enter the current 
date.  After the treatment is completed, this process will be repeated.  The PI or a Co PI will 
review the Adverse Events on a daily basis and will determine the event to be “Clinically 
Significant” or “Not Significant.” This process can be completed by phone, email or face to face.   
 
The following AE information must be included (when applicable): the specific condition or 
event and direction of change; whether the condition was preexisting (i.e., an acute condition 
present at the start of the study or history of a chronic condition) and, if so, whether it has 
worsened (e.g., in severity and/or frequency); the dates and times of occurrence; severity; causal 
relationship to the investigational device; action taken; and outcome.  
Causal relationship options and definitions are as follows: 
• Definitely related: Event can be fully attributable to administration of the investigational 
device. 
• Probably related: Event is most likely to be explained by administration of the 
investigational device, rather than the Participant’s clinical state or other agents/therapies. 
• Possibly related: Event is as likely explained by administration of the investigational device, 
as by the Participant’s clinical state or other agents/therapies. 
• Probably not related: Event is most likely to be explained by the Participant’s clinical state 
or other agents/therapies, rather than the investigational device. 
• Definitely not related: Event can be fully explained by the Participant’s clinical state or other 
agents/therapies, rather than the investigational device. 
When assessing the relationship between an investigational product/protocol and an AE, the 
following parameters are considered: 
• Temporal relationship between the investigational device/protocol and the AE 
• Biologic plausibility of relationship 
• Participants’ underlying clinical state or concomitant agents/therapies 
• Where applicable, whether the AE abates on discontinuation of the investigational device 
(dechallenge) 
• Where applicable, whether the AE reappears on repeat exposure to the investigational device 
(rechallenge) 
SAEs that are not investigational device-related may nevertheless be considered by the 
participating Investigator or the medical monitor (or designee) to be related to the conduct of the 
clinical study, i.e., to a Participant's participation in the study. 
For this study, the treatment follow-up period for adverse events is defined as 30 days following 
the last study visit.  Follow up will be documented in the Participants study file. 
 

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Per Mayo Clinic policy: “All health care providers in the State of Minnesota are mandated 
reporters under the Minnesota Maltreatment of Minors Act.” All study staff are made aware of 
this policy and will remain in compliance with associated reporting procedures when necessary. 
8.3.1 Sponsor-Investigator Reporting, Notifying Mayo IRB 
 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
 
8.3.2  Sponsor-Investigator Reporting: Notifying the FDA 
 
The sponsor-investigator will report to the FDA all unanticipated adverse device effects 
according to the required reporting timelines, formats and regulations. 
 
Additionally, per FDA request, all blurred vision adverse events will be reported to the FDA 
within 5 business days. 
 
The sponsor-investigator will submit a completed FDA Form 3500A to the FDA’s Center for 
Devices and Radiological Health for any observed or reported adverse effect that is determined 
to be an unanticipated adverse device effect.  A copy of this completed form will be provided to 
the DSMB and all participating sub-investigators. 
 
The completed FDA Form 3500A will be submitted to the FDA as soon as possible and, in no 
event, later than 10 working days after the sponsor-investigator first receives notice of the 
adverse effect. 
 
If the results of the sponsor-investigator’s follow-up evaluation shows 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 sponsor-investigator will submit a completed FDA Form 
3500A as soon as possible, but in no event later than 10 working days, after the determination 
was made. 
 
For each submitted FDA Form 3500A, the sponsor-investigator will identify all previously 
submitted reports that that addressed a similar adverse effect experience and will provide an 
analysis of the significance of newly reported adverse effect in light of any previous, similar 
report(s). 
 
Subsequent to the initial submission of a completed FDA Form 3500A, the sponsor-investigator 
will submit additional information concerning the reported adverse effect as requested by the 
FDA. 
 
 
Reporting Process 
Unanticipated Adverse Device Effect reports will be submitted on FDA Form 3500A. 
The contact information for submitting reports is: 

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Food and Drug Administration 
Center for Devices and Radiological Health 
Document Mail Center - WO66-G609 
10903 New Hampshire Avenue 
Silver Spring, Maryland 20993-0002 
 
8.3.3 Deviations from the investigational plan. 
 
The sponsor-investigator shall notify Mayo IRB (see 21 CFR 56.108(a) (3) and (4)) of any 
deviation from the investigational plan to protect the life or physical well-being of a Participant 
in an emergency. Such notice shall be given as soon as possible, but in no event later than 5 
working days after the emergency occurred. Except in such an emergency, prior approval by the 
sponsor-investigator is required for changes in or deviations from a plan, and if these changes or 
deviations may affect the scientific soundness of the plan or the rights, safety, or welfare of 
human Participants, FDA and IRB notification in accordance with 21 CFR 812.35(a) also is 
required. 
 
8.4 
Unblinding Procedures (Breaking the Blind) 
While the safety of the participant always comes first, it is still important to seriously consider if 
unblinding the study therapy is necessary to ensure a Participant’s safety.  In the event of a 
serious adverse device effect, the Investigator will carefully assess whether breaking the blind 
will critically affect how a Participant is treated in response to the adverse effect and whether this 
knowledge outweighs the implications to the scientific soundness of the study.  In the case of 
most serious adverse effects, treatment would be discontinued and symptoms treated 
symptomatically.  In these instances, having this information would not significantly alter the 
treatment of the adverse effect(s).   
 
As an additional safeguard against bias, the DSMB has been charged with making the final 
recommendations for breaking the study blind 
 
If the decision to break the blind is made immediately upon learning of the adverse event, this 
information will be reported to the FDA and reviewing IRB at the time of initial adverse event 
reporting.  If the unblinding occurs after the initial reporting, the FDA will be notified of the 
action within ten working days from the time of breaking the blind.  The reviewing IRB will be 
notified according to their reporting guidelines if the decision is made to break the study blind 
after the initial reporting. 
 
8.5 
Stopping Rules 
Specific occasions when study treatment may be stopped are explained Section 4.4.1 in the 
discussion of Anticipated Risks.  
 

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Because of the anticipated low level of adverse events of TMS, the DSMB will be charged with 
reviewing adverse events at least every six months. Serious adverse events will be reviewed on a 
monthly basis, unless a more urgent review is requested.  Only under extreme circumstances or if 
it were determined that a high level of side effects was due to TMS, would the DSMB be 
charged with breaking the study mask.  
 
Specific Study Stopping Rules 
The study will be stopped should any of the following occur: 
 
- Two participants experience seizures 
-One or more participant experiences status epilepticus 
 -One or more participant attempts or commits suicide during treatment weeks in Phase I or II. 
 -Two or more Serious Adverse Events in one or more participants. 
-Two or more participants have blurred vision associated with rTMS treatment (confirmed by an 
ophthalmologist.)  
8.6 
Medical Monitoring 
 
The PI/sponsor (Dr. Croarkin) has oversight and accountability for the overall safety of the study 
participants.  PI/sponsor safety monitoring will include careful assessment and appropriate 
reporting of adverse events as noted above, as well as the construction and implementation of a 
data and safety-monitoring plan.  Medical monitoring will include a regular assessment of the 
number and type of serious adverse events. 
8.6.1 Independent Data and Safety Monitoring Board 
A Data and Safety Monitoring Board will be assembled to oversee the safety of the study, 
Participants, and the scientific validity and integrity of data collected as part of the study.  This 
DSMB will include members from academic sites independent of the study sites and will consist 
of at least one non-study, board-certified psychiatrist and one biostatistician. 
 
The responsibilities and decision points for the DSMB will be captured in the DSMB charter. 
 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study Participants will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed Participant authorization informing the Participant of the 
following: 
• What protected health information (PHI) will be collected from Participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research Participant to revoke their authorization for use of their PHI. 
In the event that a Participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 

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Participant authorization.  For Participants that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (long term survival 
status that the Participant is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
 
Source data comprise all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, Participants’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, Participant files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. When applicable, information recorded on the CRF shall match the Source 
Data recorded on the Source Documents. 
 
All clinical notes and discussions regarding the patient will be appropriately captured, signed and 
documented. 
 
9.3 
Case Report Forms 
 
An eligibility form will be completed for each Participant enrolled into the clinical study.  As 
needed, an adverse event worksheet will be completed for study Participants experiencing AEs.  
The site investigator or designated study staff will review, approve, and sign/date each 
completed CRF; the signature serving as attestation that all clinical and laboratory data entered 
on the CRF are complete, accurate, and authentic.  Data will be entered into an excel database. 
 
9.4   Data Management 
 
a) Data is entered into an excel spreadsheet 
b) Study data will be reviewed regularly by the Investigator and Study Coordinator for the 
following:  
a. Participant inclusion criteria has been met 
b. Transcription of data is accurate and complete 
c. Units of measure are recorded appropriately 
c) Details of the study treatments including treatment parameters, such as percent of MT for 
each treatment, will be retained within the TMS device by the TrakStar software.  In 
addition, a daily summary of the treatment will be created and stored in the Participant’s 
source document. 
d) Case files will be created for each Participant where completed visit CRFs will be stored.  
Any adverse event CRFs will also be stored in the case file. 
 
9.5   Data Security and Confidentiality 
 

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a) Non-electronic source document data will be stored in a locked cabinet in a secure office. 
Only authorized study staff will have access. 
b) Electronic data will be stored on a secure database. Only authorized users will have 
access. All users will have unique identifiers and passwords. Sharing of log-in 
information is not permitted. 
 
9.6 Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include Participant case histories and regulatory documents. 
 
 
The sponsor-investigator will retain the specified records and reports for: 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy”
,  
whichever is longer. 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
This study will be monitored by the Mayo Clinic Office of Research Regulatory in accordance  
with standard operating procedures. 
 
10.2 Auditing and Inspecting 
The sponsor-investigator will permit study-related monitoring, audits, and inspections by the 
IRB, the monitor, and government regulatory agencies, of all study related documents (e.g., 
source documents, regulatory documents, data collection instruments, study data etc.).  The 
sponsor-investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
 
Participation as a sponsor-investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 

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Although this study is considered more than minimal risk to adolescents, TMS treatments (1 Hz, 
10 Hz, cTBS, and iTBS) offer a potential direct benefit for the individual Participant.  In 
addition, the schedule of mood assessments and daily assessment during the interventional 
portion of the study for any adverse events has been developed for the purpose of monitoring the 
Participant's well-being.   
 
This protocol and any amendments will be submitted to a properly constituted local IRB, in 
agreement with local legal prescriptions, for formal approval of the study at each participating 
site.  The decision of the IRB concerning the conduct of the study at MUSC will be documented 
in writing to the regulatory sponsor before commencement of this study. 
 
All families and Participants for this study will be provided a consent/assent form describing this 
study and providing sufficient information for Participants to make an informed decision about 
their participation in this study.  This consent/assent form will be submitted with the protocol for 
review and approval by the site IRB for the study.  The formal consent of a Participant, using the 
approved IRB consent/assent form, must be obtained before that Participant undergoes any study 
procedure.  This form must be signed and dated by the Participant, the Participant’s legally-
authorized representative, and the individual obtaining informed consent/assent. 
 
12 Study Finances 
12.1 Funding Source 
 
The study will be funded by a National Institute of Mental Health Grant 1R01MH113700.  
Neuronetics, Inc. will provide grant-in-kind support for NeuroStar magnetic stimulators and 
disposable SenStar Shields. 
 
12.2 Participant Stipends or Payments 
 
Participants will be remunerated $10 per visit to assist with costs related to travel. 
 
13 Publication Plan 
 
The PI/Sponsor (Dr. Croarkin) holds the primary responsibility for publications of results from 
the proposed study.  The PI/Sponsor will register the study on ClinicalTrials.gov 
(https://register.clinicaltrials.gov/) prior to participant recruitment and enrollment.  Results will 
be posted to ClinicalTrials.gov within 12 months of final data collection form the primary 
outcomes.  
 
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seizure of a patient with adolescent-onset depression: a case report and literature review. 
The Journal of international medical research. 2011;39(5):2039-2044. 
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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 Stimul. 2013;6(5):830-831. 
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Cullen KR, Jasberg S, Nelson B, Klimes-Dougan B, Lim KO, Croarkin PE. Seizure 
Induced by Deep Transcranial Magnetic Stimulation in an Adolescent with Depression. J 
Child Adolesc Psychopharmacol. 2016;26(7):637-641. 
81. 
Wu SW, Shahana N, Huddleston DA, Lewis AN, Gilbert DL. Safety and tolerability of 
theta-burst transcranial magnetic stimulation in children. Developmental medicine and 
child neurology. 2012;54(7):636-639. 
82. 
Wu SW, Maloney T, Gilbert DL, et al. Functional MRI-navigated repetitive transcranial 
magnetic stimulation over supplementary motor area in chronic tic disorders. Brain 
Stimul. 2014;7(2):212-218. 
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Allen CH, Kluger BM, Buard I. Safety of Transcranial Magnetic Stimulation in Children: 
A Systematic Review of the Literature. Pediatric neurology. 2017;68:3-17. 
84. 
Chung SW, Hoy KE, Fitzgerald PB. Theta-burst stimulation: a new form of TMS 
treatment for depression? Depress Anxiety. 2015;32(3):182-192. 

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Li CT, Chen MH, Juan CH, et al. Efficacy of prefrontal theta-burst stimulation in 
refractory depression: a randomized sham-controlled study. Brain : a journal of 
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Mir-Moghtadaei A, Caballero R, Fried P, et al. Concordance Between BeamF3 and MRI-
neuronavigated Target Sites for Repetitive Transcranial Magnetic Stimulation of the Left 
Dorsolateral Prefrontal Cortex. Brain Stimul. 2015;8(5):965-973. 
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15. Appendix A Concomitant Medication List 
 
CONCOMITANT MEDICATION LIST 
 
This list should not be considered exhaustive. Drugs that are categorized into one of the drug 
categories listed in the table below will be treated similarly.   
 
CLASS:  
    Drug 
PRN 
Chronic 
ANTIASTHMA DRUGS 
 
 
 
 
Theo-Dur (theophylline)  
N 
N 
 
Bronchodilators 
 
 
 
 
Alupent (metaproterenol), Proventil (albuterol), Ventolin (albuterol) 
Y 
Y 
 
Steroids  
 
 
 
 
Inhaled 
(Beclovent 
[beclomethasone], 
Azmacort 
[triamcinolone], 
Vanceril [beclomethasone]) 
Y 
Y 
 
 
Oral 
Y 
Y 
 
Leukotriene antagonists 
 
 
 
 
Accolate (zafirlukast), Zyflo (zileuton), Singulair (monoleukast)  
N 
Y 
 
 
 
 
 
ANTICOAGULANTS 
 
 
 
 
Coumadin (warfarin) 
N 
Y  
(w/ stable 
protime) 
 
 
 
 
 
ANTICHOLINGERGICS 
 
 
 
 
Cogentin (benztropine), Artane (trihexyphenidyl), etc. 
N 
N 
 
 
Phenylpropanolamine (PPA) and pseudoephedrine 
N 
N 
 
 
 
 
 
ANTIHISTAMINE and DECONGESTANTS 
 
 
 
Sedating 
 
 
 
 
Anticholinergic 
(Benadryl 
[diphenhydramine], 
chlorpheniramine, 
brompheniramine, Atarax [hydroxyzine]) (not for psychiatric indications) 
N 
N 
 
Non-sedating 
 
 
 
 
Allegra (fexofenadine), Claritin (loratadine), Zyrtec (cetirizine) 
Y 
Y 
 
 
Hismanal (astemizole) 
N 
N 
 
 
 
 
 
ANTI-INFECTIVE AGENTS 
 
 
 
Antibacterial antibiotics (Penicillin, sulfa, etc.) 
Y 
Y 
 
Antifungal agents (ketoconazole, fluconazole, etc.) 
 
 
 
 
Topical creams and ointments 
Y 
Y 
 
 
Oral antifungals (single-dose for vaginitis OK)  
Y 
N 
 
Antiviral agents 
 
 
 
 
Zovirax (acyclovir), Famvir (famcyclovir), Valtrex (valacyclovir) 
Y 
Y 
 
 
Antiretroviral drugs (e.g. AZT, protease inhibitors) 
N 
N 
 
 
 
 
 
ANTI-NEOPLASTIC AGENTS  
N 
N 
 
 
 
 
 
SKELETAL MUSCLE RELAXANTS 
 
 
 
 
Lioresal 
(baclofen), 
Flexeril 
(cyclobenzaprine), 
Parafon 
Forte 
(chlorzoxazone), Robaxin (methocarbamol), Soma (carisoprodol) 
N 
N 

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CLASS:  
    Drug 
PRN 
Chronic 
ANALGESICS AND ANTIPYRETICS 
 
 
 
 
Nonsteroidal anti-inflammatory agents (aspirin, ibuprofen, naproxen)  
Y 
Y 
 
 
Opiate Agonists / Partial Agonists (including Ultram [tramadol])  
N 
N 
 
 
Miscellaneous analgesics & antipyretics (acetaminophen, paracetamol)  
Y 
Y 
 
CARDIOVASCULAR DRUGS (All drugs in this category must be stable for at least 3 months) 
CARDIAC DRUGS 
 
 
 
 
Calcium Channel Blockers  for coronary disease or angina (see also 
"Antihypertensives") (Calan [verapamil], Cardizem [diltiazem], Norvasc 
[amlodipine], Procardia [nifedipine])  
N 
Y 
 
Antiarrhythmics 
 
 
 
 
Cordarone (amiodarone), lidocaine (note: local anesthesia injection OK), 
Mexitil (mexiletine), Norpace (disopyramide), Procan (procainamide), 
quinidine, Tambocor (flecainide) 
N 
N 
 
 
Digoxin (blood levels must be monitored)  
N 
Y 
 
 
 
 
 
ANTI-HYPERTENSIVE AGENTS  (All anti-hypertensives must be stable dose x 1 month) 
 
 
ACE Inhibitors (Vasotec, Capoten, Zestril) 
N 
Y 
 
 
Angiotensin receptor blockers (Cozaar)  
N 
Y 
 
 
Calcium Channel Blockers 
N 
Y 
 
 
Diuretics  
Y 
Y 
 
 
Phentolamine  
N 
N 
Beta-Adrenergic Blockers (see also Anti-Migraine) 
 
 
 
 
Low lipid solubility/CNS penetration (Corgard [nadolol], Tenormin 
[atenolol]) 
Y 
Y 
 
 
High lipid solubility/CNS penetration (Inderal [propranolol], Lopressor 
[metaprotereno]), (low lipid solubility preferred) 
Y 
Y 
 
Peripherally-acting alpha adrenergic agents 
 
 
 
 
Cardura (doxazosin), Hytrin (terazosin), Minipress (prazosin)  
Y 
Y 
 
Centrally-acting alpha adrenergic agents 
 
 
 
 
Aldomet (methyldopa), Catapres (clonidine)  
N 
N 
 
All others (quanethidine, reserpine, etc.)  
N 
N 
 
 
 
 
 
ANTILIPEMIC AGENTS 
 
 
 
 
Niacin (no slow-release preparations), Lipitor (atorvastatin), Lopid 
(gemfibrozil), Mevacor (lovastatin), Zocor (simvastatin) 
N 
Y 
 
 
 
 
 
VASODILATING AGENTS 
 
 
 
 
Hydralazine  
N 
Y 
 
 
minoxidil (topical OK) 
N 
C 
 
 
 
 
 
ANTI-CONVULSANTS 
N 
N 
 
 

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CLASS:  
    Drug 
PRN 
Chronic 
PSYCHOTHERAPEUTIC AGENTS 
 
 
 
 
Antidementia drugs (donepezil, etc.), Antidepressants, Antipsychotics 
(Thorazine, Prolixin, etc.), Miscellaneous Psychotherapeutic Agents 
N 
N 
 
Anxiolytics (per protocol) 
Y 
N 
 
Stimulants 
N 
 
 
Sedatives and Hypnotics 
 
 
 
 
Barbiturates, Benzodiazepines (except those allowed per the protocol), 
Other hypnotic agents 
N 
N 
 
 
Ambien (zolpidem; per protocol), chloral hydrate (per protocol), Sonata 
(zaleplon; per protocol), Lunesta (eszopiclone; per protocol), Rozerem 
(ramelteon; per protocol) 
Y 
N 
 
 
 
 
 
ANTIMANIC AGENTS 
 
 
 
 
Anticonvulsants, lithium 
N 
N 
 
 
 
 
 
HORMONES & SYNTHETIC SUBSTITUTES 
 
 
 
 
Corticosteroids (methylprednisolone, prednisone)  
Y 
N 
 
 
Mineralocorticoids (Florinef [fludrocortisone]) 
N 
N 
 
 
Topical steroids (creams, ointments, eyedrops)  
Y 
Y 
 
 
pregnenolone 
N 
N 
 
Androgens 
N 
N 
 
 
DHEA, testosterone, danazol  
N 
N 
 
Contraceptives  
 
 
 
 
Hormonal (dose must be stable for at least 3 months): Oral, Vaginal 
Ring, Patch, Injections, Norplant (levonorgestrel)  
N 
Y 
 
 
Intrauterine device 
Y 
Y 
 
 
Latex condom, diaphragm and or cervical cap with spermicide 
Y 
Y 
 
Estrogen replacement (postmenopausal, stable dose for 3 months)  
N 
Y 
 
Thyroid (stable dose for 3 months and thyroid function tests within normal 
limits.  Clinical significance to be determined by the physician) 
N 
Y 
 
 
 
 
 
ANTIDIABETIC AGENTS 
 
 
 
 
Oral hypoglycemic agents 
N 
Y 
 
 
Insulin’s 
Y 
Y 
 
 
 
DERMATOLOGIC AGENTS 
 
 
 
 
Topical steroid preparations, Rogaine (topical minoxidil), Miscellaneous 
creams, ointments, etc. 
Y 
Y 
 
 
 
 
 
VITAMINS  
Y 
Y 
 
 
 
OVER-THE-COUNTER SUPPLEMENTS 
 
 
 
 
chromium picolinate, DHEA, melatonin, pregnenolone, St. John’s Wort 
N 
N 
 
 
 
 
 
 
 
 

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CLASS:  
    Drug 
PRN 
Chronic 
GASTROINTESTINAL DRUGS 
 
 
 
 
Cisapride (propulsid)  
Y 
Y 
 
Antiemetics 
 
 
 
 
Over-the-counter (e.g., Emetrol [dextrose], Coke syrup) 
Y 
Y 
 
 
Phenothiazines & related drugs (Compazine [prochloroperazine], 
Phenergan 
[promethazine], 
Reglan 
[metoclopramide], 
Tigan 
[trimethobenzamide]), Anzemet (dolasetron), Kytril (granisetron), Zofran 
(ondansetron) 
Y 
N 
 
 
Marinol (dronabinol), 
N 
N 
 
Antacids 
 
 
 
 
AlternaGel (aluminum hydroxide), Amphojel (aluminum hydroxide), 
Basaljel (aluminum carbonate), Bicitra (sodium citrate), Maalox (calcium 
carbonate), 
MagOX 
(magnesium 
oxide), 
Mylanta 
(magnesium 
hydroxide), Tums (calcium carbonate), UroMag (magnesium oxide) 
Y 
Y 
 
Antidiarrhea agents  
 
 
 
 
Arco-Lase (trizyme), Furoxone (furazolidone), Motofen (difenoxin), 
Sandostatin (octreotide acetate) 
N 
N 
 
 
Imodium (loperamide), Lomotil (diphenoxylate), Pepto-Bismol (bismuth 
subsalicylate) 
Y 
N 
 
Cathartics & Laxatives  
 
 
 
 
Colace (docusate), enemas, Metamucil, Perdiem, Senokot, Soflax, 
Unifibre 
Y 
Y 
 
 
Dialose (docusate) 
Y 
Y 
 
Antisecretory agents 
 
 
 
H2 Blockers 
N 
N 
 
 
Axid (nizatidine), Pepcid (famotidine), Zantac (ranitidine)  
Y 
Y 
 
Proton pump inhibitors 
 
 
 
 
Prevacid (lansoprazole), Prilosec (omeprazole) 
Y 
Y 
 
Miscellaneous gastrointestinal drugs 
 
 
 
 
Carafate (sucralfate) 
Y 
Y 
 
 
Reglan (metoclopramide)  
N 
N 
 
 
Levsin (L-hyoscyamine sulfate) 
Y 
Y 
 
 
 
 
 
ANTI-MIGRAINE  
 
 
 
 
DHE 45 (dihydroergotamine), Imitrex (sumatriptan), methysergide, 
Midrin (isometheptene mucate), Zomig (zolmitriptan) 
N 
Y 
 
 
Fiorinal (butalbital, ASA, caffeine), Cafergot (ergotamine) 
Y 
Y 
 
 
Nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen, Toradol, 
etc.) 
Y 
Y 
 
Beta-blocking drugs 
 
 
 
 
Corgard (nadolol), Tenormin (atenolol), Other beta-blockers (e.g., 
Inderal [propranolol]) 
Y 
Y 
 
 
 
 
 
SKIN & MUCOUS MEMBRANE AGENTS  
Y 
Y 
 
 
 
 
 
 
 

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CLASS:  
    Drug 
PRN 
Chronic 
MISCELLANEOUS DRUGS 
 
 
 
 Accutane, All over-the-counter diet pills,  Ionamin (phentermine resin), 
Lioresal (baclofen), Wellbutrin (bupropion), Zyban (bupropion) 
N 
N 
 
 Allopurinol, colchicine 
Y 
Y 
 
 Fosamax (alendronate) 
N 
Y 
 
 Gold compounds, hydroxychloroquine, and methotrexate for severe 
arthritis 
N 
Y 
 
 Smoking cessation aids (Nicorette, nicotine patches) 
Y 
Y 
 
 Chantix (varenicline) 
N 
N 
 
 
 
 
 
ENDNOTES 
 
 
N = Never to be used in this study. 
Y = Can be used in this study for either PRN or Chronic use as indicated in the table. 
C = Call for Sponsor approval.  Approval for these medications is generally granted if the patient is 
otherwise acceptable, including stable medical condition, no undue risk, no other "marginal" 
considerations in the medical history or concomitant medications. Or may be used during the long-term 
maintenance phase with certain restrictions. 
 
16 Appendix B  ICF and TMS Measures 
 
Collection of ICF and TMS Neurophysiology Measures 
 
1) The subject is greeted and seated comfortably. 
 
2) Details of the subject’s session will be recorded in the study file. 
 
3) Subjects, technicians, and the study physician (who will always be present) will be provided with 
earplugs, which are to be worn at all times. Subjects will be instructed to turn off all cell phones 
and pagers. Eyeglasses will be removed. Subjects should not have any metal above their 
neckline (with the exception of orthodontics), specifically hairpins or large metallic earrings. 
Subjects will be instructed to sit quietly with their eyes open throughout the measurements. 
 
4) The TMS coil will be wiped with an alcohol swab before and after each session. 
 
5) EMG set up includes a 1k gain, HPF 30, and LPF 500 or 1000. When the operator is doing 
calibration setting, the isolated bioamp must be on the lowest setting. When collecting data the 
operator must ensure that the switch of the bioelectric amplifier is on. 
 
Connecting EMG Leads: 
 
a. EMG leads are connected to the right hand.  
b. The white wire goes in the red circle. 
c. The black wire goes in the green circle. 
d. The green wire goes in the white circle (this is the ground). 
e. Place one electrode on abductor pollicis brevis (white wire). 
f. 
Place one lead on the middle joint of the index finger (black wire). 
g. Place ground lead on the hand that you are measuring (green wire). 
h. On the computer, the red line refers to the right hand.  

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6) At the start of each session, the operator must check the plastic casing of the stimulating coil for 
any signs of external damage. If any cracks are visible in the housing, the stimulating coil must 
not be used and should be serviced. 
 
7) Connect the coil to the main Magstim unit. Switch on, select the desired stimulating power by 
using the output power knob, and press the run switch on the front panel of the Magstim to arm 
the unit. The Magstim will charge and the “ready” display will be illuminated. 
 
8) Position the stimulating coil on the desired area to be stimulated. Press and hold down one or 
both of the safety switches at the baseline of the stimulating coil. Triggering the Magstim results 
in a magnetic pulse being delivered by the stimulating coil, stimulating the nerves beneath it. 
 
9) When necessary, reposition the stimulating coil and/or modify the stimulating power level to suit 
the requirements for the next stimulus. Meanwhile, the Magstim will have recharged and can be 
triggered once again in the normal manner. 
 
10) When the tests have been completed, press the “stop” switch on the front panel of the Magstim 
and replace the stimulating coil on the coil hanger. The Magstim will then revert to standby mode 
and cannot be triggered until it is armed once more. 
 
11) The TMS coil is held tangential to the subject’s head at 45 degrees. 
 
12)  Single-pulse measures (MT and CSP): 
 
a. When giving pulses, always wait 5-10 seconds between pulses. 
b. Start at 30% intensity and administer a few pulses to acclimate the subject to the test 
conditions. 
c. Increase to 40% intensity and then by 10 at a time to get motor responses, and then 
decrease intensity. 
d. Administer 10 successive pulses at each intensity. If 6 of 10 pulses are not sufficient, this 
is the threshold point. If 5 of 10 pulses elicit a motor response, decrease the intensity until 
6 of 10 do not elicit a motor response. 
e. Measure optimal site laterally and posterior from the vertex. 
f. 
Single-pulse measures are performed with submaximal, tonic, hand muscle contraction. 
This reduces variability in the CSP (Mathis et al. 1998, Bajbouj et al. 2006). 
g. The duration of the CSP is measured from the onset of the corticospinal mediated EMG 
response, to the end of the silent period. The end is the point at which averaged tonic 
EMG activity reaches the amplitude of mean EMG activity prior to TMS. 
 
13) Paired-pulse measures (ICI and ICF): 
 
a. The figure of eight coil and the bistim module are utilized for these measurements. 
b. Two stimulations are given in succession, as described previously (Kujirai et al. 1993, 
Nahas et al. 2007). The first pulse is the conditioning stimulus. The second pulse is the 
test pulse. 
c. Stimulations for ICI are spaced 1-5 msec apart, and 100-200 msec apart.  
d. Stimulations for ICF are spaced 7-20 msec apart. 
e. Complete 10 trials of the test stimuli, each administered 10 seconds apart. Peak to peak 
amplitudes of the conditioned response are averaged and expressed as a percentage of 
the average of the test response amplitudes.