Utilizing Changes in Human Brain Connectivity to Establish a Dose-response Relationship Involved in the Therapeutic Actions of Prefrontal Brain Stimulation on Depression Symptoms
Phase: NA
Conditions: Treatment Resistant Depression
Sponsor: Stanford University

Utilizing Changes in Human Brain Connectivity to Establish a 
Dose-Response Relationship Involved in the Therapeutic 
Actions of Prefrontal Brain Stimulation on Depression 
Symptoms 
Protocol Number:  54909 
i 
 
 
National Clinical Trial (NCT) Identified Number:  NCT04243798 
Principal Investigator: Nolan Williams, MD 
Funded by: National Institute of Mental Health 
Version Number:  3.5 
JAN  30 2025 
 
 
 
Summary of Changes from Previous Version (Version 3.4): 
 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
- 
Table of Contents page numbers 
Organization 
1.3 
Removed HDRS-17 from Screening 
Visit. Visit Names. Removal of NTF 
for screening sharing 
Update 
2.3.1 
Referenced 8.3.3.3 for all AEs 
Clarification 
4.1 
Added clarification around goal of 
treatment and explanation around 
depth corrections and 120% RMT 
limit 
Clarification 
4.3 
120% RMT limit clarification added. 
Clarification 
5.1 - 5.2 
Visit naming. Moved timepoint table 
for eligibility criteria 
Clarification 
5.4 
Visit naming 
Clarification 
5.5 
Removed Mandarin from 
recruitment materials 
Clarification 
6.1.2 
90 - 120% RMT limit clarification 
added 
Clarification 
6.3 
added link to recent RCT 
 
7.2 
Clarification that subjects may 
withdraw at any time 
Clarification 

Utilizing Changes in Human Brain Connectivity to Establish a 
Dose-Response Relationship Involved in the Therapeutic 
Actions of Prefrontal Brain Stimulation on Depression 
Symptoms 
Protocol Number:  54909 
i 
 
8.1 
Updated screening process to reflect 
current practices. Removed HDRS 
17. Re-named visits. 
Clarification 
8.2 
Added emergency escalation 
language 
Update 
8.3.3.3 
Compiled list of AEs 
Clarification 
8.3.5 
Updated frequency to bi-annual 
DSMB  
Update 
9 - 9.4.5 
Clarified language 
Clarification 
9.4.9 
Updated exploratory analyses 
Update 
10.1.1.2 
Clarified plan for review of consent 
documents 
Clarification 
10.1.5 
Updated study psychiatrist contact 
info. Removed outdated advisory 
committee info. 
Update 
10.1.7 
Clarified Dr. Spiegel is medical 
monitor. 
Clarification 
10.1.8 
Referenced Quality Management 
SOP 
Update 
10.1.9.1 
Added documentation of blood draws 
Update 
10.3 
Removed GRID/HAMD17 
Update 
10.4 
Added updates from Protocol 3.4 
Update 
11.0 
Added citations 
Update 
 
 

Utilizing Changes in Human Brain Connectivity to Establish a 
Dose-Response Relationship Involved in the Therapeutic 
Actions of Prefrontal Brain Stimulation on Depression 
Symptoms 
Protocol Number:  54909 
i 
 
Table of Contents 
STATEMENT OF COMPLIANCE 
11  PROTOCOL SUMMARY
 
11.1  Synopsis
 
1 
1.2  Schema 
3 
1.3  Schedule of Activities (SoA) 
5 
2  INTRODUCTION 
7 
2.1  Study Rationale 
7 
2.2  Background 
122.3  Risk/Benefit Assessment
 
12 
2.3.1  Known Potential Risks 
12 
2.3.2  Known Potential Benefits 
142.3.3 Assessment of Potential Risks and Benefits
 
143  OBJECTIVES AND ENDPOINTS
 
144  STUDY DESIGN
 
164.1  Overall Design
 
16 
4.2  Scientific Rationale for Study Design 
174.3  Justification for Dose
 
184.4  End of Study Definition
 
20 
5  STUDY POPULATION 
20 
5.1  Inclusion Criteria 
20 
5.2  Exclusion Criteria 
215.3  Lifestyle Considerations
 
245.4  Screen Failures
 
245.5  Strategies for Recruitment and Retention
 
256  STUDY INTERVENTION
 
266.1  Study Intervention(s) Administration
 
266.1.1  Study Intervention Description
 
266.1.2  Dosing and Administration
 
276.2  Preparation/Handling/Storage/Accountability
 
286.2.1  Acquisition and accountability
 
27 
6.2.2  Formulation, Appearance, Packaging, and Labeling 
286.2.3  Product Storage and Stability
 
286.2.4  Preparation
 
286.3  Measures to Minimize Bias: Randomization and Blinding

Utilizing Changes in Human Brain Connectivity to Establish a 
Dose-Response Relationship Involved in the Therapeutic 
Actions of Prefrontal Brain Stimulation on Depression 
Symptoms 
Protocol Number:  54909 
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286.4  Study Intervention Compliance
 
296.5  Concomitant Therapy
 
296.5.1  Rescue Medicine
 
307  STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
 
307.1  Discontinuation of Study Intervention
 
307.2  Participant Discontinuation/Withdrawal from the Study
 
30 
7.3  Lost to Follow-Up 
31 
8  STUDY ASSESSMENTS AND PROCEDURES 
31 
8.1  Efficacy Assessments 
33 
8.2  Safety and Other Assessments 
348.3  Adverse Events and Serious Adverse Events
 
368.3.1  Definition of Adverse Events (AE)
 
368.3.2  Definition of Serious Adverse Events (SAE)
 
378.3.3  Classification of an Adverse Event
 
37           8.3.3.1  Severity of Event
 
37 
           8.3.3.2  Relationship to Study INTERVENTION 
38 
           8.3.3.3  Expectedness 
38 
8.3.4  Time Period and Frequency for Event Assessment and Follow-Up 
39 
8.3.5  Adverse Event Reporting 
40 
8.3.6  Serious Adverse Event Reporting 
41 
8.3.7  Reporting Events to Participants 
42 
8.3.8  Events of Special Interest 
42 
8.3.9  Reporting of Pregnancy 
43 
8.4  Unanticipated Problems 
43 
8.4.1  Definition of Unanticipated Problems (UP) 
43 
8.4.2  Unanticipated Problem Reporting 
43 
8.4.3  Reporting Unanticipated Problems to Participants 
44 
9  STATISTICAL CONSIDERATIONS 
449.1  Statistical Hypotheses
 
449.2  Sample Size Determination
 
45 

Utilizing Changes in Human Brain Connectivity to Establish a 
Dose-Response Relationship Involved in the Therapeutic 
Actions of Prefrontal Brain Stimulation on Depression 
Symptoms 
Protocol Number:  54909 
i 
 
9.3  Populations for Analyses 
45 
9.4  Statistical Analyses 
46 
     9.4.1  General Approach 
46 
     9.4.2  Analysis of the Primary Efficacy Endpoint(s) 
46 
     9.4.3  Analysis of the Secondary Endpoint(s) 
47 
     9.4.4  Safety Analyses 
48 
     9.4.5  Baseline Descriptive Statistics 
48 
     9.4.6  Planned Interim Analyses 
48 
     9.4.7  Sub-Group Analyses 
49 
     9.4.8  Tabulation of Individual participant Data 
49 
     9.4.9  Exploratory Analyses 
49 
10  SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
50 
10.1  Regulatory, Ethical, and Study Oversight Considerations 
50 
10.1.1  Informed Consent Process 
50 
10.1.1.1  Consent/assent and Other Informational Documents Provided to participants 
50 
10.1.1.2  Consent Procedures and Documentation 
51 
10.1.2  Study Discontinuation and Closure 
52 
10.1.3  Confidentiality and Privacy 
52 
10.1.4  Future Use of Stored Specimens and Data 
54 
10.1.5  Key Roles and Study Governance 
54 
10.1.6  Safety Oversight 
55 
10.1.7  Clinical Monitoring 
56 
10.1.8  Quality Assurance and Quality Control 
5610.1.9  Data Handling and Record Keeping
 
5710.1.9.1  Data Collection and Management Responsibilities
 
5710.1.9.2  Study Records Retention
 
5910.1.10  Protocol Deviations

Utilizing Changes in Human Brain Connectivity to Establish a 
Dose-Response Relationship Involved in the Therapeutic 
Actions of Prefrontal Brain Stimulation on Depression 
Symptoms 
Protocol Number:  54909 
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5910.1.11  Publication and Data Sharing Policy
 
60 
10.1.12  Conflict of Interest Policy 
61 
10.2  Additional Considerations 
61 
10.3  Abbreviations 
61 
10.4  Protocol Amendment History 
6511   REFERENCES
 
70 
12   APPENDICES 
81 

Utilizing Changes in Human Brain Connectivity to Establish a Dose-Response Relationship  
Version 3.5 
Involved in the Therapeutic Actions of Prefrontal Brain Stimulation on Depression Symptoms 
Protocol 54909 
30JAN2025 
 
1 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for 
the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the protocol 
and the consent form must be obtained before any participant is enrolled.  Any amendment to the 
protocol will require review and approval by the IRB before the changes are implemented to the study.  
In addition, all changes to the consent form will be IRB-approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a previously 
approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
 
1.1 
SYNOPSIS  
Title: 
Utilizing Changes in Human Brain Connectivity to Establish a Dose-
Response Relationship Involved in the Therapeutic Actions of Prefrontal 
Brain Stimulation on Depression Symptoms 
 
Study Description: 
 
This double-blind, randomized, sham-controlled mechanistic study aims to 
establish a resting-state functional connectivity (RS FC) dose-response curve 
associated with the therapeutic actions of our accelerated intermittent theta-
burst stimulation (aiTBS) neuromodulation approach in outpatients 
diagnosed with Major Depressive Disorder (MDD) as defined by DSM-5 
criteria. We will accomplish this by applying the aiTBS protocol (10 daily 
interventions of aiTBS to a customized target within the left dorsolateral 
prefrontal cortex identified with fMRI for five consecutive days) and 
measuring RS FC between the subgenual anterior cingulate cortex (sgACC) 
and the default mode network (DMN) after each day of intervention. We then 
will determine the relationship between changes in the RS FC and both 
changes in clinical symptoms of depression (24 hour version of the 
Montgomery-Asberg Depression Rating Scale-Self Report [MADRS-S]) and 
acute mood state (Immediate Mood Scaler [IMS-12]). Our mechanistic 
hypothesis is that the nature of the improvement in mood will be linear, 
related to session number (accumulated pulse dose), and correlated with 
degree of change in RS FC between the sgACC and DMN. 
 
Objectives: 
 
Primary Objective:   

Utilizing Changes in Human Brain Connectivity to Establish a Dose-Response Relationship  
Version 3.5 
Involved in the Therapeutic Actions of Prefrontal Brain Stimulation on Depression Symptoms 
Protocol 54909 
30JAN2025 
 
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The primary objective of this investigation is to establish a resting state 
functional connectivity (RS FC) dose-response curve of active versus sham 
aiTBS.  
 
 
Secondary Objectives:  
 
(a) To determine the relationship between active versus sham aiTBS-induced 
clinical improvement (as measured by reduction of the MADRS-S) and 
changes in RS FC between the sgACC and DMN. 
 
(b) To determine the relationship between acute mood state (as measured by 
the IMS-12) and changes in RS FC between the sgACC and DMN in those 
receiving active versus sham aiTBS. 
 
 
 
Endpoints: 
 
Primary Endpoint:  
 
Change in RS FC between the sgACC and DMN over 5-days of active aiTBS 
as compared to sham aiTBS.   
 
Secondary Endpoints:  
 
(a) Relationship between clinical improvement (measured by the MADRS-
S) and RS FC between the sgACC and DMN.  
 
(b) Relationship between acute mood state (measured by the IMS-12) and RS 
FC between the sgACC and DMN.  
 
Study Population: 
 
We will enroll 100 participants and employ a two-arm design with 50 
subjects per arm. The target population is adults of all genders and ethnicities 
who are between 22 and 65 years of age with treatment-resistant major 
depressive disorder and who are otherwise in good general health. 
Participants must be without contraindications to Magnetic Resonance 
Imaging (MRI) or transcranial magnetic stimulation (TMS) and must be able 
to attend all study visits.   
 
Phase: 
 
This is a mechanistic study similar to a phase 2 trial. 
 
 
Description of 
Sites/Facilities 
Enrolling Participants: 
 
1. The Stanford Department of Psychiatry and Behavioral Sciences: This 
study will be conducted within the Stanford Department of Psychiatry and 
Behavioral Sciences outpatient building. The outpatient building will provide 
both the office space and infrastructure for the screening / enrollment of 
participants, the delivery of study intervention, and the assessment of clinical 
outcomes.  
2. The Stanford Center for Cognitive and Neurobiological Imaging: The 
Stanford Center for Cognitive and Neurobiological Imaging (CNI) provides 
a research-dedicated 3T MRI scanner, a GE Ultra-High Performance MR 
system  that will be used with a Nova Medical 32-channel head and neck coil. 
Improvements in fMRI technology are implemented from time to time at 

Utilizing Changes in Human Brain Connectivity to Establish a Dose-Response Relationship  
Version 3.5 
Involved in the Therapeutic Actions of Prefrontal Brain Stimulation on Depression Symptoms 
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major academic research environments. Fidelity to sequences used at the 
beginning of the study will be maintained to ensure that changes in signal-to-
noise ratio do not take place during the course of the study. 
 
Description of Study 
Intervention: 
 
We will deliver both active and sham study intervention via a MagPro X100 
(MagVenture, Skovlunde, Denmark) TMS device equipped with a Cool-B65 
A/P coil. The intervention paradigm consists of 10 daily sessions (50 total 
over 5 days) of intermittent theta-burst (iTBS) stimulation (3-pulse 50-Hz 
bursts at 5-Hz for 2-second trains, with trains every 10 seconds), delivered 
with 50-minute inter-session intervals (10-minute sessions, 50-minutes in 
between sessions). Stimulation will be delivered at 90% of the resting motor 
threshold (with depth correction to account for the distance between the scalp 
and cortex). An operator entered code (derived from randomization) will 
instruct the device to deliver active or sham magnetic stimulation.  
 
Custom MATLAB scripts will be used to identify the portion of the left 
DLPFC maximally anticorrelated with the sgACC, which will serve as the 
target for both active and sham stimulation. The intervention target will be 
located via a Localite TMS Navigator (Localite, Bonn, Germany). More 
specifically, the left dorsolateral prefrontal cortex is located according to 
routine, FDA-approved clinical rTMS practice. Our scripts then further 
discern functional subregions within the left DLPFC. 
 
Study Duration: 
 
The entire project is estimated to take approximately 60 months, broken 
down into 48 months of data collection and an additional 12 months of 
analysis. 
 
Participant Duration: 
 
The total duration for each participant from the time of baseline assessment  
to study completion is approximately 6-weeks. 
 
 
1.2 
SCHEMA 

Utilizing Changes in Human Brain Connectivity to Establish a Dose-Response Relationship  
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
 
 
 

Utilizing Changes in Human Brain Connectivity to Establish a Dose-Response Relationship  
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Assessment 
Visit 1 - 
Remote 
Screening*X  
 
Visit 2 - In-
person 
Screening 2  / 
Baseline*  
Visit 3-7 
MRIs & 
Intervention 
Visit 8 
Next day 
 
Visit 9 
1 Month 
Follow Up* 
Screening Informed 
Consent 
x 
 
 
 
 
Demographics 
x 
 
 
 
 
MRI Safety Screening 
Form 
x 
 
x 
 
 
TASS1 
x 
 
 
 
 
Medical History 
x 
 
 
 
 
ATHF-Current2 
x 
 
 
 
 
ATHF-Lifetime 
x 
 
 
 
 
Current Medications 
x 
x 
x 
x 
x 
Study Informed Consent 
 
xa 
 
 
 
Capacity to Consent 
 
xa 
 
 
 
Urine Drug Screen 
 
xa 
x 
x 
 
Urine Pregnancy Test 
 
xa 
 
 
 
Inclusion/ 
Exclusion Criteria 
x 
x 
 
 
 
Enrollment/ 
Randomization 
 
x 
 
 
 
COVID19 screener 
 
x 
x 
x 
 
Stimulation log 
 
 
x 
 
 

Utilizing Changes in Human Brain Connectivity to Establish a Dose-Response Relationship  
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Motor threshold 
 
xa 
x 
 
 
Adverse Events 
 
 
x 
x 
x 
SCID Overview 
x 
 
 
 
 
MINI 
x 
 
 
 
 
BPD diagnostic module 
from SCID for DSM-5⍦ 
x 
 
 
 
 
MSM3 
x 
 
 
 
 
MSSI#4 
x 
xa 
 
 
 
Columbia-Suicide 
Screening Rating Scale 
(C-SSRS) 
x 
 
 
 
 
MADRS-S 
x 
xa 
x (Visit 3) 
 
x 
MADRS-S (24-h 
version) 
 
 
x (Visits 4-7) 
x 
 
YMRS 
x 
xa 
x 
 
 
MADRS-CR 
x 
 
 
 
 
IMS-125 
 
x 
x 
x 
 
Pittsburgh Sleep Quality 
Index (PSQI) 
x 
x 
 
 
 
FIGS^ 
 
x 
 
 
 
CTQ^ 
 
x 
 
 
 
MRI Scan 
 
 
x 
x 
 
      Blood Draw^ 
 
x 
 
x 
x 
 
*Indicates a participant encounter that occurs remotely via video call and/or online data capture. 
⍦If a participant meets the screening threshold on the self-reported BPD prescreening questions from 
SCID for DSM-5, then the diagnostic module will be performed 
#The MSSI will be administered at screening and baseline and then as part of any clinical consultation 
with the study psychiatrist or their designee at any other study visit if a participant scores a 3 on item 9 

Utilizing Changes in Human Brain Connectivity to Establish a Dose-Response Relationship  
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of the MADRS-S (‘Zest for life’ item). 
^Only applicable if participants opts into optional additional blood marker substudy 
X- Subjects who have provided screening data for another study in Stanford University’s Brain 
Stimulation Laboratory (BSL) may have their screening data used for this study. Additionally, screening 
data used in this study may be used in another study in BSL. The purpose of this is to reduce 
unnecessary burden to the subject. The discretion of which screening data is accepted is up to the 
discretion of the investigator. Data will be manually re-entered within BSL’s RedCap system from the 
previous study into the new study. 
aRefers to measures required to confirm study eligibility that occur at the In-person Screening 2 / 
Baseline (Visit 2). 
*Study activities associated with Visits 1, 2, and 9 may or may not occur on the same day. 
 
 
 
2 
 
INTRODUCTION 
 
 
 
2.1 
STUDY RATIONALE  
 
The Challenge (Clinical): Treatment-Resistant Depression (TRD) is an escalating problem in the US. Major 
depressive disorder (MDD) is the leading cause of disability worldwide6,7 with lifetime prevalence in the 
US >20%8. Combating TRD will require improvements in treatments; however, treatment development is 
limited by insufficient understanding of the mechanism of disease remission. Discovering the network-
level mechanisms of remission has been particularly challenging due to treatments requiring weeks-to-
months to induce remission9, limited effectiveness of available treatments10,11, and potential disease 
heterogeneity12,13.  
 
Depression as a Condition of Dysfunctional Emotion Regulation Networks: Some of the earliest MDD 
neuroimaging studies reported reduced activity in the left dorsolateral prefrontal cortex (L-DLPFC) of 
patients with MDD14–16, which is restored with effective treatment17–20. This early data suggested a major 
role of top-down dysfunction in the pathophysiology of depression21,22. Similarly, concomitant increases 
in activity in subgenual anterior cingulate cortex (sgACC) long have been observed in patients during 
depressive episodes23, and this has been hypothesized to be causally related to reductions in L-DLPFC 
activity24. This hypothesis has been reinforced by observations that antidepressants lead to reductions in 
sgACC activity17,18,25–30. This led to the conception of depression as dysregulation in corticolimbic 
systems22. In recent years, this conceptualization has evolved to include neural networks and their 
interactions. Several lines of evidence suggest dysfunction of emotion regulation (ER) in MDD31 with 
neural correlates observed with fMRI32,33. The neural basis of ER includes emotional reactivity: amygdala 
and striatum; explicit control of emotion – central executive network (CEN): DLPFC, ventrolateral PFC 
(vlPFC); and implicit ER – default mode network (DMN), salience network (SN) and insula. Dysfunction 
within the DMN, CEN, and SN has repeatedly been reported in MDD34–38. 
 
Depression as a Condition of Dysfunctional Connectivity within and between Emotion Regulation 
Networks: Numerous resting-state functional connectivity (RS FC) MRI studies have demonstrated that 
individuals with MDD have altered within network and cross network connectivity39,40. The hyper 
activity/connectivity within DMN has been considered as evidence of dysfunction of rumination and self-

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referential processing, and treatment is hypothesized to normalize DMN activity/connectivity36,41–
44.Depression is associated with increased fc between DMN and sgACC34,35,39,45–49. The degree of 
treatment-resistance has been correlated with the degree of sgACC-DMN connectivity where higher 
connectivity is associated with more treatment resistance34. Depression is also associated with increased 
fc between DMN and amygdala50–54; DLPFC and amygdala55; and, PFC and striatum56–59. Increased DLPFC-
striatum fc correlates with increased depression severity and fc between DLPFC-striatum connectivity 
decreases following treatment56. There are also alterations in salience network (SN) fc in MDD and more 
specifically insular fc with multiple relevant nodes39,60,61. Insula has a well-known role in interoception62,63, 
and insula activity is correlated with abnormal interoception in MDD64. Increased SN fc has been reported 
to be associated with decreased anticipated pleasure65 and MDD66. Individuals with depression have 
reduced fc between amygdala-precuneus67 and DLPFC-insula68. 
 
Excitatory repetitive transcranial magnetic stimulation (rTMS) applied to the L-DLPFC is a therapeutic 
non-invasive brain stimulation technique for TRD: Excitatory rTMS (≧5 pulses/second) increases cortical 
excitability over a cortical target69,70. Following the emotional dysregulation hypothesis of depression, 
stimulation of the CEN at the L-DLPFC node via rTMS1–3 has been hypothesized to produce antidepressant 
effects via enhanced regulation of emotion. This is in line with the observation that increased activity in 
CEN results in suppression of DMN71, and this has led others to hypothesize that improved accuracy of 
targeting these networks might produce better treatment efficacy72–77. This fits well with the hypothesis 
that L-DLPFC has reduced activity in depression, preventing suppression of sgACC activity, and that 
restoring L-DLPFC activity with treatment inhibits sgACC activity. When applied to the L-DLPFC, this 
approach was originally conceived to normalize hypoactivity in L-DLPFC78, reduce sgACC hyperactivity and 
strengthen indirect inhibitory connections between the L-DLPFC and sgACC. For some patients, rTMS to 
L-DLPFC has been demonstrated to be an effective and durable79 antidepressant treatment which has 
been FDA-approved for TRD80. Traditional rTMS produces its antidepressant effect during the later part of 
a treatment course which involves 90,000 pulses applied at 3000 pulse sessions five days per week for 6 
weeks. Remission rates from depression with conventional rTMS remain low at 35%81,82.    
 
Properties of rTMS Dosing:  
Session Dosage and Total Dosage: Total dose of stimulation appears to be important for rTMS therapeutic 
effects83. 60,000-90,000 pulses are used for the 6-week standard high frequency rTMS course81,82. In cases 
where higher pulse dosages have been used, there is evidence of greater efficacy84,85. There also is 
evidence that there are a number of responder trajectories that are related to the level of TRD86. In the 
case of the FDA-approved iTBS protocol87, 600 pulses are applied during each session such that 18,000 
pulses are delivered over a six-week treatment course. While there had been a question as to whether 
>600 pulses per session might result in a reversal in the cortical excitability of a prefrontal target88, there 
is now evidence in depressed89,90 and normal healthy controls that 1800 pulses of iTBS per session 
(iTBS1800) produces long-lasting effects in the intended direction91. In fact, iTBS1800 is the only pulse dose 
that has yielded a positive result in a blinded TBS trial92–95 and that has been shown to produce the 
intended resting-state effects96. Additionally, the 1800 pulse dose has been shown to produce long-lasting 
changes in cortical excitability97  and resting-state functional connectivity96 .  
 
Stimulation Intensity Adjustments for Differential Prefrontal Cortical Atrophy and Induced E-Field: 
Intermittent theta-burst stimulation applied <100% rMT produces the optimal change in prefrontal 
cortical excitability98 and resting state changes99,100 when compared to suprathreshold stimulation. This 
convergent data suggests that unlike traditional rTMS101, there appears to be an inverse U-shaped curve 
with TBS intensities requiring an optimal intensity directly over a target. This finding would explain why, 

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Involved in the Therapeutic Actions of Prefrontal Brain Stimulation on Depression Symptoms 
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of the blinded iTBS trials for TRD, the only positive trials were found in those studies utilizing subthreshold 
%MT93, while those trials utilizing >100% %MT did not separate from sham95.  
 
Furthermore, with age there is differential atrophy of PFC and PMC102. Depth correction103 historically has 
been applied to the resting motor threshold to adjust for differences in the cortical depth of the 
individual’s functional target compared to the primary motor cortex in order to consistently achieve the 
intended rMT at the target. In the OPT TMS trial it was determined that a standard %MT could be used 
(120% avg of depth adjustment), but with traditional HF rTMS104 there is no inverted U-shaped curve101 
like there may be with iTBS98,100. Accordingly, it is very unlikely that an average multiplier can be used with 
iTBS given its principles. 
 
Patterning: 
Pattern of Stimulation Session (Intermittent Theta-Burst Stimulation (iTBS)): Theta-burst stimulation 
(TBS), a patterned form of rTMS modeled after endogenous hippocampal discharge patterns105,106, has 
been shown to be more efficient than standard rTMS in modulating cortical excitability107 and last ~60 
min108. Recent clinical trials indicate non-inferiority of 600 pulses/day of iTBS given over 3 min versus 3,000 
pulses/day of conventional rTMS given over 37 min in treating depression (now FDA-approved)80 and 
notable efficacy in treating TRD90. What is unknown is the ideal timing of when each session should be 
applied, and currently 24 hours is the default109. It is unclear if this approach is ideal110.  
 
Pattern of stimulation course (Intersession interval (ISI)): An accumulation of TBS effects can occur when 
TBS stimulation is applied in a neurobiologically-informed, patterned manner (compared to en-masse 
stimulation)111 allowing for a dose-response curve to be constructed112. Previous work has demonstrated 
that iTBS sessions delivered to hippocampal slices with inter-session intervals of 50-90 min have a 
cumulative effect on dendritic spine enlargement, a process involved in synaptic strengthening. In 
comparison, iTBS sessions delivered with inter-session intervals of ≦40 min do not have a cumulative 
effect on dendritic spines113–115. Two iTBS sessions delivered to the motor cortex110,116 or prefrontal 
cortex117 with a 15-minute inter-session interval have been shown not to result in an incremental increase 
in cortical excitability over a single iTBS session, while two applications of iTBS with a 30-min ISI does result 
in an increase in cortical excitability110,116. When 1800 pulses of iTBS is applied at a subthreshold %MT at 
the 15 min post time point, there is an initial increase in fc between ACC and DMN (in the pathological 
direction). At the 30 min time point, there is a decrease in fc between ACC and DMN and these changes 
are maximal at the 50 min time-point. Interestingly, Nettekoven et al. similarly reported that the 30 min 
time point does result in changes in RS FC110,116, but the 50 min time point is optimal for engaging the 
entire mood regulatory network. This could explain the limited efficacy of a previously reported 
accelerated iTBS protocol that used an inter-session interval of only 15 min118,119. This work provides 
further support for an ISI that is ≧50 min96. Studies that have applied TBS to cortical targets have shown 
that two spaced stimulation sessions produce greater110,120,121 and longer lasting121,122 changes in cortical 
excitability than single sessions. This finding holds for other cortical targets in diseased123  and normal 
subjects124. Recent attempts at this have demonstrated that multiple sessions of iTBS per day increase 
efficacy compared to single applications/day both clinically125 as well as physiologically105.  
 
Network-Level Targets and Stimulation Effects:  
Effective Treatment Requires Precise Targeting: Neuroimaging data suggest the higher the anti-
correlation between the stimulated region of the L-DLPFC & sgACC, the better the clinical outcome77. This 
finding has since been confirmed in other cohorts72,77. A recent TMS-fMRI study used resting-state fMRI 
to target the region of the L-DLPFC which showed greatest fc with the sgACC and showed stimulation 
propagated to the sgACC in all participants126. In comparison, another study which targeted L-DLPFC using 

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anatomical MRI coordinates (the border of BA9 & BA46), stimulation propagated to the sgACC in only 44% 
of participants127. These data suggest that using resting-state fMRI to identify and stimulate the region of 
the L-DLPFC which is most anti-correlated with the sgACC in each individual could increase the efficacy of 
TMS protocols96,128 and may explain why attempts at accelerated iTBS (without fc targeting) may have not 
have demonstrated efficacy from sham96,118,119.  
 
Prestimulation Connectivity is Predictive of Post-Stimulation Efficacy: The effects of rTMS/iTBS on cortical 
excitability are linked to its effects on resting state functional connectivity110,116. Past studies have found 
that fc between stimulation site L-DLPFC & striatum129,130 and between downstream targets (ACC/VMPFC, 
dACC & l-insula)131,132,132 predicts TMS efficacy, and several groups have reported that fc between 
stimulation site & sgACC that is more negative results in greater reductions in depressive symptoms with 
rTMS72,74,77.  
 
rTMS/TBS is a Functional Connectivity (FC) Modulator: Stimulation of L-DLPFC can result in fc changes. 
rTMS to L-DLPFC reduces fc between DMN & striatum in normal healthy controls (NHCs)128,133. 
Improvement in depression is correlated with more reduction in L-DLPFC-striatum fc after therapeutic L-
DLPFC rTMS134,135. Excitatory rTMS to L-DLPFC also has been shown to modulate sgACC activity/fc41,42,133 
and reduce fc between sgACC & DMN when targeted to the anticorrelated fc91 and increase fc between 
DLPFC & sgACC when no fc targeting is used136 in NHCs. iTBS to L-DLPFC reduces fc/effective connectivity 
(ec) between L-DLPFC & r-insula137,138 with baseline fc/ec between L-DLPFC & r-insula predicting degree of 
network changes137,138. iTBS/rTMS to L-DLPFC potentiates upstream neural circuits77 to normalize sgACC-
DMN connectivity36,43,44,76,139. Prior studies have reported significant reductions in fc between sgACC & 1-2 
nodes of DMN36,42–44,140 as well as FPN fc139 after active but not sham rTMS/iTBS139.  
 
Properties Required for iTBS-induced Network-Level Changes:  
First, the intensity in which iTBS is applied affects its modulation of fc98,100. Second, the network 
configuration (amount of pre-stimulation fc between target pairs) of the pre-stimulation targeted network 
is associated with post-stimulation efficacy120,132,138,141–143. Third, when applying multiple stimulation 
applications, the ISI must be sufficient for changes in fc to occur99,144 or there is no incremental 
change98,144. Fourth, in order to achieve consistent target engagement, the cortical & downstream target 
must be identified and targeted126,145,146 or the stimulation will not be consistently distributed into the 
downstream target127. Fifth, the position of the rTMS coil must be superimposed over the cortical 
target147,148 to exert intended effects. Sixth, the intensity of the stimulation must be adjusted to 
differential depth of prefrontal target103 as under/over stimulation results in no change98,100. 
 
The Challenge (Methodological):  
Our lab’s accelerated intermittent theta-burst stimulation (aiTBS) protocol is a form of neuromodulation 
that induces remission in 90% of individuals with TRD within 1-5 days149. This study addresses our current 
limitations of understanding the MOA of aiTBS’s dramatic therapeutic149 and network-level effects150. This 
study will provide an opportunity to iteratively assess changes in RS FC after each day of stimulation (i.e., 
every 18,000 pulses - which is equivalent to an entire conventional 6-week course of iTBS80) and thereby 
establish a dose-response relationship between stimulation and change in RS FC at our target (sgACC-
DMN)86. This study is the only way to accomplish this because if one assumes that the rate of decrease is 
linear, recent data demonstrate a 12 point per day decrease in the HDRS-1786, and given that the high end 
of the scale is a 52, it would take 5 days to reduce the score from 52 to remission range. To apply 7.5 
months (5X dose of traditional) of once per day of rTMS would be infeasible from a clinical study 
standpoint. Otherwise, there would be a high expected regression to the mean of a sample receiving 5 
times the conventional 6-week course (7.5 months long duration of therapy if given by conventional 

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means)151. We recently demonstrated a significant reduction in mean sgACC-DMN connectivity after aiTBS 
with significant reductions in fc between sgACC and 3 of 4 DMN nodes150. Individual changes in fc 
magnitude showed that participants with the lowest magnitude reductions in fc between sgACC and 
midline DMN experienced the best clinical improvements. This makes sense in the context of the 
longitudinal fc changes induced by ECT where an early fc decrease significantly predicted a later increase 
in fc152. These findings may suggest that less or more sessions of aiTBS would result in differential 
fc/clinical outcomes and illustrate the need for this study to construct an fc-based dose-response curve. 
 
Innovation:       
This study is innovative technologically in its approach to rapidly modulate the neural circuitry underlying 
depression and measure the functional connectivity changes resulting from that modulation using 
precision medicine. This efficacy and rapidity is achieved via several technological innovations over 
conventional rTMS: 1) The number of pulses given per day (18,000) is higher than any other known 
application, and this may address potential under dosing of rTMS in treatment of depression84,90. 2) iTBS 
is more efficient than rTMS at a pulse ratio of 1:5 with 1 pulse of iTBS equivalent to 5 10Hz rTMS pulses 
and at a time ratio of 1:12.3 with every 1 min of iTBS being equivalent to 12.3 min of 10Hz rTMS81. 3) We 
space iTBS sessions at 60-min intervals, which may be optimal for producing long-term potentiation via 
iTBS as shown by studies of synaptic potentiation153. Notably, theta-burst trains that are spaced by 60 min 
result in over twice the magnitude of potentiation as trains spaced by 30 min, and trains spaced by 60 min 
induce the same magnitude of synaptic potentiation as those spaced by 90 min153. 4) We account for the 
significant variability in head anatomy154. 5) We employ an automated personalized targeting approach 
based a hierarchical clustering algorithm to identify functional subregions of the L-DLPFC & sgACC. A 
separate decision-making algorithm then evaluates the size, shape, and the functional connectivity 
relationships between each L-DLPFC subregion and each sgACC subregion in order to identify the optimal 
L-DLPFC target with an existing anti-correlation functional connectivity relationship with the sgACC. The 
advantages of aiTBS also include more rapid delivery of treatment, more rapid improvement in symptoms, 
and fewer needed visits; thus, likely enhancing retention and treatment completion. aiTBS provides a new 
opportunity to begin investigating the network alterations underlying MDD remission. Fc changes that 
occur with aiTBS may reflect generalized network-level changes associated with remission from 
depression. Given that we found that fc significantly decreases between several of these regions following 
aiTBS-induced remission from MDD, the magnitude of fc change often correlating with symptom 
improvement, and the pre-treatment connectivity between several regions to be predictive of the 
magnitude of this improvement, this study will allow for an opportunity to study the nature of the 
trajectory of the fc changes in relation to clinical changes5,86. 
 
aiTBS is a reimagination of the original engineering conditions of the first rTMS depression 
experiment78. In constructing aiTBS, we understood that multiple variables were being modified 
concurrently155, but we decided to construct a stimulation methodology which retained those variables 
demonstrated to be correct: [target (DLPFC)82,156–160, laterality (left)82,157–159,161,162, direction of stimulation 
(excitation82,157,159,162,163, biological and clinical efficacy of iTBS81,164 ]  while simultaneously addressing those 
variables which continue to be uncertain (intersession interval (ISI)109,144,165, targeting within DLPFC166, 
nature100 of pulse dose84,85). We are emulating the approach taken by all those who have successfully 
developed an innovative new therapeutic intervention167–170. Three parameters of particular note are: 
within node (L-DLPFC) targeting99,128,171, dose (amount84,85 and nature110,116), and pattern110,116. We 
independently conceptually addressed these variables and, after careful consideration, we constructed a 
stimulation strategy that reflects the modern understanding of the neuroscientific principles of 
neuromodulation172. Targeting the placement of neuromodulation devices is crucial16,168,  and given recent 
advances in fc-based targeting, we decided to utilize the only candidate brain target for rTMS therapy for 
TRD (L-DLPFC-sgACC)72,77,99,128,175 ᠆ all others are skull targeting approaches resulting in a variably positioned 

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brain target104,171,176, which may have resulted in previous failed attempts119,177. Further, the doses of rTMS 
applied per day are several orders of magnitude less than other more effective forms of 
neuromodulation178 (600-3,000 pulses/day87 versus 500,000 pulses/day for DBS179). Additionally, new data 
suggest that the intensity of the dose may be subthreshold98,100. We sought to produce as rapid-acting of 
effects as possible, as conventional rTMS studies are plagued by the potential for individuals receiving 
sham to experience regression to the mean151  due to the extended timeframe of the therapy180. Further, 
an ISI (as conventionally applied) is 24 hrs which has no known physiological evidence109 and other 
investigators have utilized ISIs119,177 which are not consistent with known physiology96,98,110,115,128. Hence, an 
accelerated protocol makes sense from a clinical trial design perspective as well as the basic neuroscience 
perspective. 
 
2.2 
BACKGROUND  
 
Preliminary Data 
 
aiTBS acute efficacy: Numerous past reports have found iTBS of the L-DLPFC to be an effective treatment 
for depression87,164,177. In our first open-label study of aiTBS for treatment of the most severe, treatment-
resistant depression (MSM score of every patient was 14)181,182, we found a 76% reduction in depression 
symptoms (HDRS-17) with 5/6 participants showing >50% reduction in symptoms and 4/6 remitting from 
depression after 5 days of aiTBS, despite having failed ECT, conventional rTMS, numerous medications 
(including ketamine), and psychotherapy.  
 
We recently published our open-label follow-up study149. We have treated 31 participants with highly 
treatment resistant depression (Maudsley Staging Method score ≥11) with only 1 drop-out during the 5-
day treatment course. We observed an extremely high rate of remission (28/31, 90%, MADRS <10) in less 
than 5 days of treatment (mean days to remission = 2.96±1.48). After 5 days of aiTBS there was an 88% 
reduction in mean MADRS with scores from 37.71±7.24 to 4.65±6.46. Notably, our results are nearly 
identical for the subset of 22 patients with major depressive disorder (MDD, the 9 other patients had 
bipolar depression or Parkinson’s-related depression), as this MDD sample is more reflective of the 
population we plan to target in this study.  Mean Hamilton Depression Rating Scale-6 (HDRS-6) scores 
decreased with each additional day of stimulation over the entire 5 day stimulation course. None of the 
participants who had previously not responded to an FDA-approved rTMS treatment course responded 
after the first day of aiTBS, when the equivalent amount of stimulation as an FDA-approved treatment 
course was administered. However, 76.92% of the rTMS non-responders in our study did respond to aiTBS, 
suggesting that FDA-approved protocols may be underdosing. Mean HAMD-17 significantly decreased 
from 26.280 (±4.909, range 20-35) at baseline to 4.722 (±4.599, range 0-16) after treatment (t (17)=11.275, 
p<.001). Mean MADRS significantly decreased from 33.220 (±5.208, range 27-44) at baseline to 4.833 
(±5.813, range 0-19) after treatment (t (17)=14.915, p<.001). Baseline HAMD-17 and MADRS scores were 
highly correlated (r=.817, p<.001), as were the percent-change scores from baseline to post-treatment 
(r=.948, p<.001). MADRS was used as the primary clinical outcome for all fc analyses, and all results are 
equivalent for HAMD-17.  
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
 
2.3.1  
KNOWN POTENTIAL RISKS  
 

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Immediate Risks: 
aiTBS: Seizure risk is generally the most significant immediate concern associated with rTMS, at 
approximately 1:30,000 sessions for traditional high frequency rTMS183. However, there are no reported 
seizures with the iTBS (excitatory) parameters that will be used in this study184. Only one case of TBS has 
resulted in seizure, and this case was associated with the use of continuous (inhibitory) TBS at >/=100% 
resting motor threshold184,185, whereas we will use iTBS at 90%. Any seizure that theoretically could occur 
would likely be self-limited and lead to no residual neurological impairment. Seizures induced by rTMS 
are rare, brief and don’t result in sequelae, with no events of status epilepticus ever being reported183. 
Another potential immediate risk is that of induction of mania. Although there have been no such cases 
of mania induced by iTBS, there have been at least 13 cases of rTMS-induced mania reported from fixed-
frequency rTMS186. The rTMS-induced mania rate reported by Xia et al was 0.84% as compared to 0.73% 
for sham, which were not significantly different from each other. Most of the reported cases of rTMS-
induced mania were in individuals with bipolar disorder, a population that will not be included in the 
current study. Nevertheless, it is possible that patients could develop symptoms of hypomania or mania 
following stimulation. Patients' symptoms will be monitored carefully by both members of the research 
team and clinical staff. The YMRS will be administered daily to check for mania symptoms. If patients show 
hypomanic/manic symptoms, no further stimulation will be administered and the patient's clinician will 
be notified. 
Another potential risk is mild pain at the site of stimulation, which occurs during stimulation only, and 
which wanes with each session. There is also a risk of psychological distress related to this pain, should it 
occur, though discomfort associated with rTMS is typically mild, and not distressing when participants are 
reassured it is not dangerous. 
Finally, expected AEs have been reported in association with iTBS in a recent large RCT187, and a full list of 
expected AEs can be found in Section 8.3.3.3. 
MRI: There are some contraindications that may prevent a participant from having a scan; however, all 
participants will be screened prior to scanning to evaluate these risk factors188. Due to the strength of the 
magnetic field, contraindications include participants with heart pacemakers, metallic foreign bodies in 
their eye, and brain aneurysm clips, as the magnetic field may dislodge the metal leading to injury184,188 
Possible 
side 
effects 
of 
undergoing 
an 
MRI 
are 
listed 
in 
8.3.3.3. 
 
Lidocaine: 
Possible 
side 
effects 
associated 
with 
Lidocaine 
are 
mentioned 
in 
8.3.3.3. 
 
Confidentiality: A risk of all clinical studies is that they collect personal  information that may be seen by 
individuals not associated with the study. This could lead to psychological, social, cultural and legal risks. 
To protect participants’ confidentiality, a numerical system will be used as unique identifiers, and 
identifying information will not be stored with the data. Electronic data will be stored on shared computer 
drives and in REDCap, a HIPAA compliant electronic data capture software, maintained by the university 
under rigorous firewall and password protection. Secured information linking participant’s ID with 
protected health information will be separated from the unidentified data.  
 
Long-range Risks: No long-range risks associated with iTBS or routine MRI have been reported, and none 
are anticipated for this study.  
 

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Alternative Treatments and Procedures: There are several other treatments for severe depression; 
however, none carry the optimal low risk/benefit ratio or quick action of aiTBS. The most realistic 
alternatives would be electroconvulsive therapy, conventional rTMS, and/or medications. Although the 
current FDA-approved form of conventional rTMS is effective, a typical treatment course takes 6 weeks 
to complete and the open label efficacy rates are lower then this approach and participation in this 
protocol does not preclude a subsequent traditional rTMS82 . Similarly, an acute course of 
electroconvulsive therapy takes typically 1 month to complete, carries greater risks than rTMS189, and 
cultural acceptance is low190 . Medications take months to begin working and their efficacy is severely 
limited compared to ECT or rTMS9,191. Esketamine/Ketamine could also be considered given their rapid 
onset of action, but their effects are short-lived192. 
 
 
2.3.1 
KNOWN POTENTIAL BENEFITS  
 
Based on our previous open-label studies172,193, many of the research participants who receive active aiTBS 
are likely to achieve rapid improvements in their depression symptoms, with associated improvement in 
their social and occupational functioning. Identifying an efficacious treatment for a subject’s depression 
may have long-range benefits as well, in that treatment effects may be sustained and the subject will have 
identified an effective potential treatment after multiple treatment failures. 
 
Furthermore, the information gained from this study will inform further optimization and personalization 
of rTMS therapy for TRD. Specifically, this study will provide invaluable data on the transition from the 
depressed network configuration to the remission network configuration and how this transition relates 
to aiTBS and depression symptoms. Our results might provide a neurobiological basis for L-DLPFC 
inhibition of sgACC as a causative factor in the development of TRD, allowing for potentially more effective 
mood control.  
 
2.3.2 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Given the high degree of safety of MRI and rTMS183, there is a low risk to high benefit ratio for this 
intervention. rTMS will be performed and monitored according to widely accepted principles that 
maximize safety183. Based on our previous open-label studies172,193, many of the research participants who 
receive active aiTBS are likely to achieve rapid improvements in their depression symptoms, with 
associated improvement in their social and occupational functioning.  
 
Furthermore, the information gained from this study will inform further optimization and personalization 
of TMS therapy for TRD. Specifically, this study will provide invaluable data on the transition from the 
depressed network configuration to the remission network configuration and how this transition relates 
to aiTBS and depression symptoms. Our results might provide a neurobiological basis for L-DLPFC 
inhibition of sgACC as a causative factor in the development of TRD, allowing for potentially more effective 
mood control. Hence, we believe that the risks associated with this study are minimal compared to the 
knowledge gained. 
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR 
ENDPOINTS 
Primary 
 
 
To establish a resting state 
functional connectivity (RS FC) 
dose-response curve of active 
versus sham aiTBS. 
 
 
Change in RS FC between the 
sgACC and DMN over 5-days of 
active aiTBS as compared to 
sham aiTBS. RS FC will be 
measured on the morning of 
each intervention day and the 
day following intervention.  
 
We 
hypothesize 
that 
participants (n=50) receiving 
active aiTBS applied to DLPFC-
sgACC 
will 
demonstrate 
a 
significant attenuation of RS FC 
between 
sgACC 
and 
DMN 
compared to sham (n=50) after 
each day of stimulation and 
these effects will accumulate 
linearly over the course of the 5 
days of aiTBS. The central, 
consistent 
change 
in 
neurocircuitry 
observed 
in 
depression is hyperconnectivity 
between the SCC and DMN43 
and 
our 
preliminary 
data 
involving RS FC changes from 
aiTBS 
demonstrates 
highly 
significant changes194. 
Secondary 
 
 
(a) 
To 
determine 
the 
relationship 
between 
active 
versus 
sham 
aiTBS-induced 
clinical 
improvement 
(as 
measured by reduction of the 
MADRS-S) and changes in RS FC 
between the sgACC and DMN. 
 
(b) 
To 
determine 
the 
relationship 
between 
acute 
mood state (as measured by the 
IMS-12) and changes in RS FC 
between the sgACC and DMN in 
those receiving active versus 
sham aiTBS. 
 
 
 
(a) Relationship between clinical 
improvement (measured by the 
MADRS-S) and RS FC between 
the sgACC and DMN.  
 
MADRS-S will be collected at 
baseline,  the end of each 
intervention 
day, 
the 
day 
following intervention, and 1-
month after intervention. RS FC 
will 
be 
measured 
on 
the 
morning of each intervention 
day and the day following 
intervention. 
 
(b) Relationship between acute 
mood state (measured by the 
IMS-12) and RS FC between the 
sgACC and DMN.  
 
IMS-12 will be collected at 
baseline, on the morning of each 
intervention day, and the day 
following intervention. RS FC will 
 
Our mechanistic hypothesis is 
that active versus sham aiTBS-
induced improvement in mood 
will be linear, related to session 
number 
(accumulated 
pulse 
dose), and will be associated 
with (accumulated) decrease in 
sgACC- 
DMN 
resting 
state 
functional 
connectivity, 
as 
compared to sham. 

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be measured on the morning of 
each intervention day and the 
day following intervention.  
Exploratory 
 
 
(a) 
To 
determine 
the 
relationship 
between 
active 
versus 
sham 
aiTBS-induced 
clinical 
improvement 
(as 
measured by reduction of the 
MADRS-S) and changes in RS FC 
in an unbiased, whole-brain 
analysis. 
 
(b) 
To 
determine 
the 
relationship 
between 
acute 
mood state (as measured by the 
IMS-12) and changes in RS FC in 
an 
unbiased, 
whole-brain 
analysis in those receiving active 
versus sham aiTBS. 
(a) Relationship between active 
versus 
sham 
aiTBS-induced 
clinical 
improvement 
(as 
measured by reduction of the 
MADRS-S) 
and 
changes 
in 
whole-brain RS FC. 
 
MADRS-S will be collected at 
baseline, on each intervention 
day, and the day following 
intervention. Whole-brain RS FC 
will 
be 
measured 
on 
the 
morning of each intervention 
day and the day following 
intervention. 
 
(b) Relationship between acute 
mood state (as measured by the 
IMS-12) and changes in whole-
brain RS FC in those receiving 
active versus sham aiTBS 
 
IMS-12 will be collected at 
baseline, on the morning each 
intervention day, and the day 
following intervention. Whole-
brain RS FC will be measured on 
the 
morning 
of 
each 
intervention day and the day 
following intervention. 
Our hypothesis is that greater 
network segregation will be 
detected for better clinical 
outcomes 
and 
that 
a 
combination of the functional 
connectivity features involving 
emotion regulation will have 
better prediction accuracy for 
clinical 
outcomes. 
This 
alternative approach will allow 
us to identify other RS FC 
changes with especially large 
effect sizes, which would be 
important candidates for further 
investigation in future studies. 
 
 
 
 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 

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Hypothesis: Participants (n=50) receiving active aiTBS applied to DLPFC-sgACC will demonstrate a 
significant attenuation of RS FC between sgACC and DMN compared to sham (n=50) after each day of 
stimulation and these effects will accumulate linearly over the course of the 5 days of aiTBS. 
 
Phase: This is a mechanistic study similar to a phase 2 trial. 
 
Trial Design: Randomized, sham-controlled, double-blinded mechanistic study. 
 
Methods to Minimize Bias: This study will achieve robust and unbiased results via several design features 
including: explicit inclusion/exclusion criteria; randomization of intervention condition; the use of a 
validated sham control; blinding; use of validated laboratory and interview/self-report measures and 
methods; explicit hypotheses and corresponding planned statistical analyses; power estimates; planned 
handling of retention/attrition and missing data; and, careful consideration of potential confounds. All 
experimental details will be reported in a fully transparent manner to support replication. 
 
Dose Escalation: TMS stimulation dose will be individually determined according to 90% rMT plus depth 
correction, and then the aiTBS protocol will be administered with a consistent dose across all participants 
receiving active stimulation of 18,000 pulses/day and 90,000 pulses/course. 
 
The goal of treatment in this study is to ensure the correct amount of treatment (90% of motor threshold) 
is received in the target location (L-DLPFC) rather than under-stimulating and under- treating participants. 
Depth correction accounts for the variable distances between the scalp and motor hotspot and scalp and 
treatment target from person to person. In other words, this is a personalized treatment intensity that 
takes into account individual variability. However, to ensure safety we never treat higher than 120% of 
the person’s resting motor threshold, which is the standard TMS treatment intensity in routine clinical 
practice. 
 
Study Arms: Two arms, active vs sham in 50:50 randomization 
 
Site(s): Single Site (Department of Psychiatry & Behavioral Sciences, Stanford University) 
 
Name of Study Intervention: Accelerated intermittent theta-burst stimulation (aiTBS). 
 
Interim Analysis: N/A 
 
Stratification: We will attempt to assess the role of gender in our analyses to determine the potential 
utility of additional follow-up projects that focus on any discovered gender-based observations. However, 
it may not be feasible to run sub-group analyses in this study because of potentially insufficient sub-group 
sample sizes. 
 
Sub-Studies: 
None 
 
 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 

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This is a double-blinded, randomized, controlled mechanistic study using a 1:1 ratio between active and 
sham intervention. During the blinded period, the investigator, participants, clinical assessors, and 
treaters will be blinded to active or sham intervention delivery. Participants with a higher level of 
treatment resistance, who will be the focus of this study, tend to be less susceptible to placebo effects of 
iTBS therapy90. Nevertheless, the use of a sham controlled group is essential to ensuring that our 
outcomes of interest can be properly attributed to active aiTBS.   
 
The aiTBS intervention will be administered with an ‘A/P’ coil (MagVenture, Denmark) which has both an 
active and sham side that are identical in appearance. The intervention condition is determined based on 
a code assigned at randomization. Based on the assigned code the magnetic stimulation is either directed 
towards or away from the head (i.e., when the randomization code assigns sham stimulation then the 
magnetic stimulation ends up being directed away from the head). During sham stimulation, however, 
the magnet still activates. Accordingly, the sound, appearance, and sensation of sham stimulation 
operation is the same as it is for active stimulation. Thus, there is no way for the operator to know if the 
patient is getting sham or active stimulation. Similarly, raters will have no knowledge of which ID 
corresponds to which intervention. This type of sham has been demonstrated to be indistinguishable from 
real TMS, has been well tolerated195,196, and successfully used in clinical trials157,197. 
 
4.3 
JUSTIFICATION FOR DOSE 
 
Total dose of stimulation appears to be important for rTMS therapeutic effects83. 60,000-90,000 pulses 
are used for the 6-week standard high frequency rTMS course81,82. In cases where higher pulse dosages 
have been used, there is evidence of greater efficacy84,85. There also is evidence that there are a number 
of responder trajectories that are related to the level of TRD86. In the case of the FDA-approved iTBS 
protocol87, 600 pulses are applied during each session such that 18,000 pulses are delivered over a six-
week treatment course. While there had been a question as to whether >600 pulses per session might 
result in a reversal in the cortical excitability of a prefrontal target88, there is now evidence in 
depressed89,90 and normal healthy controls that 1800 pulses of iTBS per session (iTBS1800) produces long-
lasting effects in the intended direction91. In fact, iTBS1800 is the only pulse dose that has yielded a positive 
result in a blinded TBS trial92–95 and that has been shown to produce the intended resting-state effects96. 
Additionally, the 1800 pulse dose has been shown to produce long-lasting changes in cortical excitability97  
and resting-state functional connectivity96 .  
 
Stimulation Intensity Adjustments for Differential Prefrontal Cortical Atrophy and Induced E-Field: 
Intermittent theta-burst stimulation applied <100% rMT produces the optimal change in prefrontal 
cortical excitability98 and resting state changes99,100 when compared to suprathreshold stimulation. This 
convergent data suggests that unlike traditional rTMS101, there appears to be an inverse U-shaped curve 
with TBS intensities requiring an optimal intensity directly over a target. This finding would explain why, 
of the blinded iTBS trials for TRD, the only positive trials were found in those studies utilizing subthreshold 
%MT93, while those trials utilizing >100% %MT did not separate from sham95.  
 
Furthermore, with age there is differential atrophy of PFC and PMC102. Depth correction103 historically has 
been applied to the resting motor threshold to adjust for differences in the cortical depth of the 
individual’s functional target compared to the primary motor cortex in order to consistently achieve the 
intended rMT at the target. In the OPT TMS trial it was determined that a standard %MT could be used 
(120% avg of depth adjustment), but with traditional HF rTMS104 there is no inverted U-shaped curve101 

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like there may be with iTBS98,100. Accordingly, it is very unlikely that an average multiplier can be used with 
iTBS given its principles. 
 
Patterning: 
Pattern of Stimulation Session (Intermittent Theta-Burst Stimulation (iTBS)): 
Theta-burst stimulation (TBS), a patterned form of rTMS modeled after endogenous hippocampal 
discharge patterns105,106, has been shown to be more efficient than standard rTMS in modulating cortical 
excitability107 and last ~60 min108. Recent clinical trials indicate non-inferiority of 600 pulses/day of iTBS 
given over 3 min versus 3,000 pulses/day of conventional rTMS given over 37 min in treating depression 
(now FDA-approved)80 and notable efficacy in treating TRD90. What is unknown is the ideal timing of when 
each session should be applied, and currently 24 hours is the default109. It is unclear if this approach is 
ideal110.  
 
Pattern of stimulation course (Intersession interval (ISI)):  
An accumulation of TBS effects can occur when TBS stimulation is applied in a neurobiologically-informed, 
patterned manner (compared to en-masse stimulation)111 allowing for a dose-response curve to be 
constructed112. Previous work has demonstrated that iTBS sessions delivered to hippocampal slices with 
inter-session intervals of 50-90 min have a cumulative effect on dendritic spine enlargement, a process 
involved in synaptic strengthening. In comparison, iTBS sessions delivered with inter-session intervals of 
≦40 min do not have a cumulative effect on dendritic spines113–115. Two iTBS sessions delivered to the 
motor cortex110,116 or prefrontal cortex117 with a 15-minute inter-session interval have been shown not to 
result in an incremental increase in cortical excitability over a single iTBS session, while two applications 
of iTBS with a 30-min ISI does result in an increase in cortical excitability110,116. When 1800 pulses of iTBS 
is applied at a subthreshold %MT at the 15 min post time point, there is an initial increase in fc between 
ACC and DMN (in the pathological direction). At the 30 min time point, there is a decrease in fc between 
ACC and DMN and these changes are maximal at the 50 min time-point. Interestingly, Nettekoven et al. 
similarly reported that the 30 min time point does result in changes in RS FC110,116, but the 50 min time 
point is optimal for engaging the entire mood regulatory network. This could explain the limited efficacy 
of a previously reported accelerated iTBS protocol that used an inter-session interval of only 15 min118,119. 
This work provides further support for an ISI that is ≧50 min96. Studies that have applied TBS to cortical 
targets have shown that two spaced stimulation sessions produce greater110,120,121 and longer lasting121,122 
changes in cortical excitability than single sessions. This finding holds for other cortical targets in 
diseased123  and normal subjects124. Recent attempts at this have demonstrated that multiple sessions of 
iTBS per day increase efficacy compared to single applications/day both clinically125 as well as 
physiologically105.  
 
Intervention Regimen: We will employ a spaced, intermittent theta-burst technique that is capable of 
providing a significant change in neural activity: 10 minutes of stimulation followed by a 50 min inter-
sessional interval with no stimulation. In total, participants will receive 10 sessions of this 10-minute aiTBS 
per day for a total of 100 minutes of aiTBS stimulation per day. 
Name and Justification: The aiTBS protocol was developed to utilize the accelerated neuromodulatory 
application of 90,000 pulses of intermittent theta-burst stimulation at 90% of the resting motor threshold 
(rMT), as this has been demonstrated to be effective in producing a prolonged change in cortical 
excitability124 as well as safe198. The %rMT will be adjusted based on skull-to-cortex distance. The 50-
minute inter-sessional interval is essential, as it has been demonstrated that prolonged stimulation 
approaches without spacing in between can cause a reversal of intended effect, as described above88. This 
spacing also has been utilized in animal models of LTP/LTD induction199. 

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Route: The spaced theta-burst stimulation approach will be applied to the left dorsolateral prefrontal 
cortex (L-DLPFC) in the region of the L-DLPFC that has the highest functional anticorrelation with the 
subcallosal cingulate cortex (SCC). This sub-region of the L-DLPFC will be identified by utilizing 
neuronavigation hardware and coupling this with the latest in cutting-edge rTMS targeting 
methodology147. 
Dosage: 90% of the resting motor threshold adjusted to target depth will be utilized as the dose of aiTBS 
because this dose has been demonstrated effective in modulating the desired cortical target across 
several studies, as described above121,124. 1800 pulses of iTBS with 3-pulse 50 Hz bursts given at 5Hz every 
200 ms will be utilized, as this is the optimal approach for producing stimulation199. This study approach 
will utilize 60 stimulation trains of 30 pulses with 800 ms spacing in between each train of iTBS, as has 
been reported previously121,124. This stimulation approach will be applied for 10 minutes every hour for 10 
sessions a day. Each participant will receive a total of 50 sessions (of 10-minute aiTBS) by the end of the 5 
stimulation days for a total of 90, 000 pulses of aiTBS. To ensure safety we never treat higher than 120% 
of the person’s resting motor threshold, which is the standard TMS treatment intensity in routine clinical 
practice. 
 
A depth-adjusted aiTBS treatment dose >65% of maximal stimulator output is an exclusion criterion. The 
rationale is that at doses >65% of maximal stimulator output, a phenomenon known as magnetic roll-off 
may occur, such that the actual iTBS stimulation dose delivered may be less than the intended dose. 
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the study 
including the last scheduled procedure shown in the Schedule of Activities (SoA), Section 1.3. Here, the 
end of the study is defined as completion of visit 9 as shown in the SoA. 
 
5 
STUDY POPULATION 
 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Male or Female, between the ages of 22 and 65 at the time of screening (Visit 1). 
 
2.   Able to read, understand, and provide written, dated informed consent prior to screening. Proficiency 
in English sufficient to complete questionnaires / follow instructions during fMRI assessments and aiTBS 
interventions.  Stated willingness to comply with all study procedures, including availability for the 
duration of the study, and to communicate with study personnel about adverse events and other clinically 
important information. 
 
3.  Currently diagnosed with Major Depressive Disorder (MDD) and meets criteria for a Major Depressive 
Episode, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth 
Edition, Text Revision (DSM-5). 
 

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4.  Medical records confirming a history of moderate to severe treatment-resistance as defined by a score 
of 7-14 on the Maudsley Staging Method (MSM3). 
 
5.  MADRS score of ≥20 at screening (Visit 1). 
 
6. TMS naive. 
 
7.  Access to ongoing psychiatric care before and after completion of the study. 
 
8.  The dose of the primary antidepressant medication (if applicable) must be stable for 6 weeks prior to 
baseline (Visit 2), and participant must agree to continue at this dose throughout the study period. 
 
9.  In good general health, as evidenced by medical history. 
 
10.  For females of reproductive potential: use of highly effective contraception for at least 1 month prior 
to baseline (Visit 2) and agreement to use such a method during study participation.  
 
11. Agreement to adhere to Lifestyle Considerations (see section 5.3) throughout study duration. 
 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Pregnancy 
2. Primary psychiatric condition other than MDD requiring treatment except stable comorbid 
anxiety disorder  
3. History of or current psychotic disorder or bipolar disorder 
4. Severe borderline personality disorder. 
5. Diagnosis of Intellectual Disability or Autism Spectrum Disorder  
6. Current moderate or severe substance use disorder or demonstrating signs of acute substance 
withdrawal 
7. Urine screening test positive for illicit substances 
8. Active suicidal ideation (defined as an MSSI > 8) or a suicide attempt (as defined by the C-SSRS) 
within the past one year 
9. Any history of ECT (greater than 8 sessions) without meeting responder criteria 
10. Recent (within 4 weeks of any clinical effect) or concurrent use of rapid acting antidepressant 
agent (i.e., ketamine or a course of ECT) 
11. History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, 
brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant 
head trauma 
12. Untreated or insufficiently treated endocrine disorder. 
13. Contraindication to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion) 
14. Contraindication to MRI (ferromagnetic metal in their body) 
15. Treatment with another investigational drug or other intervention within the study period 
16. Depth-adjusted aiTBS treatment dose > 65% maximum stimulator output (MSO) 

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17. Unstable symptoms between screening (Visit 1) and baseline (Visit 2) as defined by a > 30% 
change in MADRS-S score. 
18. Any other condition deemed by the PD to interfere with the study or increase risk to the 
participant 
 
For clarity, the visit(s) that each eligibility criterion is determined are provided in the following table: 
 
 
Inclusion or 
Exclusion Criterion 
# 
 
Form Name 
 
Assessment Timepoint 
Inclusion Criteria 
1 
Demographic Information  
Remote Screening Visit 1 
2 
Capacity to Consent 
Remote Screening Visit 1 
3 
MINI DSM5 
Remote Screening Visit 1 
4 
Maudsley Thase Rush 
Remote Screening Visit 1 
5 
MADRS-C 
Remote Screening Visit 1 
6 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
7 
Demographic Information  
Remote Screening Visit 1 
8 
ATHF 
Remote Screening Visit 1 
9 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
10 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
11 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
Exclusion Criteria 
1 
Urine Pregnancy Screen 
In-Person Screening 2/Baseline - Visit 2 
2 
MINI DSM5 
Remote Screening Visit 1 
3 
MINI DSM5; YMRS 
Remote Screening Visit 1; 

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In-Person Screening 2/Baseline - Visit 2 
4 
SCID For DSM-5 Borderline Personality 
(Clinician Module) 
Remote Screening Visit 1 
5 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
6 
SCID Overview 
Remote Screening Visit 1 
7 
Urine Toxicity Screen 
In-Person Screening 2/Baseline - Visit 2 
8 
C-SSRS - Baseline/Screening; MSSI 
Remote Screening Visit 1; 
In-Person Screening 2/Baseline - Visit 2 
9 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
10 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
11 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
12 
Stanford Medical And Psychiatric Review 
Remote Screening Visit 1 
13 
Stanford Medical And Psychiatric Review;  
TASS TMS Safety Form 
Remote Screening Visit 1 
14 
Stanford Medical And Psychiatric Review; 
MRI Safety Form 
Remote Screening Visit 1 
15 
Main Study Consent 
In-Person Screening 2/Baseline - Visit 2 
16 
Log of Motor Thresholds 
In-Person Screening 2/Baseline - Visit 2 
17 
MADRS-S 
Remote Screening Visit 1; 
In-Person Screening 2/Baseline - Visit 2 
18 
All forms 
All visits 
 
The effects of rTMS on the developing human fetus are unknown200. Accordingly, we will not be enrolling 
pregnant women to this study. Women of childbearing potential must agree to use adequate 
contraception (hormonal / barrier method of birth control or abstinence) prior to study entry and for the 
duration of study participation. Females of childbearing-age will have a pregnancy test prior to starting 
the rTMS stimulation course. Should a woman become pregnant or suspects she is pregnant while 
participating in this study, she should inform study staff. 
Participants taking certain psychoactive medications will be assessed for safety by the PD, due to potential 
for increase of seizure risk182 and change in cortical excitability200.  
Individuals older than 65 years of age will be excluded for the following reasons: 
1) Dementia can present as depression prior to cognitive symptoms (both vascular and 
neurodegenerative)201, and a significant battery of neuropsychological tests would be required to 

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accurately discern cognitive dysfunction from depression from dementia202. Given that this is a 
mechanistic grant, inclusion would increase potential of false negatives.  
2) Even though the study depth adjusts individuals with greater prefrontal over primary motor 
cortex atrophy, the safety limit is at 120% and some individuals require greater than 120% depth 
adjustment to reach PFC102. With this, there is evidence of reduced efficacy in those individuals 
with advanced age203,204.  
3) There is evidence of reduced plasticity in individuals with advanced age with a reduction in the 
duration of the effects of TBS205,206 which may impact the response to the approach. 
 
 
Screening (Visit 1 - Remote Screening) must be completed within 3 months of formal study 
enrollment and baseline assessment (Visit 2 - In-person Screening 2 / Baseline), otherwise 
screening measures will need to be repeated prior to moving forward with enrollment and 
baseline assessment. Inclusion criteria 8 + 10 are relative to the date of first treatment 
administration. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
During this study, participants are asked to: 
● Abstain  from becoming pregnant from the screening visit (Visit 1 - Remote Screening) until after 
the final study visit (Visit 9). 
● Continue usual intake patterns of caffeine- or xanthine-containing products (e.g., coffee, tea, cola 
drinks, and chocolate) without significant change for the duration of the study. 
● Abstain from alcohol for at least 24 hours before the start of each MRI and TMS session. 
● Participants who use tobacco products will be informed that use will be allowed only in between 
intervention sessions. 
 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who sign the screening ICF and/or the study ICF and complete 
some or all of the V1 - Remote Screening and/or Visit 2 - In-person Screening 2 / Baseline visit(s) but are 
not subsequently enrolled in the study due to not meeting study entry criteria. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any serious adverse event (SAE).  
 
Individuals who do not meet the criteria for participation in this study (screen failure) due to a specific 
modifiable factor may be rescreened at a later date once appropriate study criteria are met. Rescreened 
participants will be assigned a modified version of the same participant number as for the initial screening 
(e.g., s001, s001a, s001b, etc.). 
 
In the case of screen failure, screening data of such patients will be electronically stored in our REDCap 
database.  
 

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5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Target Study Sample: 
Racial 
Categories 
Ethnic Categories 
Not Hispanic or Latino 
Hispanic or Latino 
Total 
Female 
Male 
Female 
Male 
American 
Indian/Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
10 
6 
0 
0 
16 
Native 
Hawaiian or 
Other Pacific 
Islander 
4 
2 
0 
0 
6 
Black or 
African 
American 
6 
4 
0 
0 
10 
White 
60 
40 
24 
26 
150 
More than 1 
race 
10 
6 
2 
0 
18 
Total 
90 
58 
26 
26 
200 
 
 
Anticipated accrual rate: Participants will be recruited through the current Stanford Brain Stimulation 
Laboratory clinical trial recruitment pipeline and the Stanford Depression Research Clinic (Dr. Williams is 
a member). Based on our random sampling via chart reviews, there are approximately >110 participants 
who meet inclusion criteria each year at Stanford. These numbers exceed our power analysis, which 
indicates a plan of recruiting 25-30 participants per year at Stanford. 
 
Anticipated number of sites: We will have a single study site and  anticipate enrolling 100 participants 
from the U.S. 
 
Source of participants:  Participants will be recruited from the general public as well as outpatient clinics 
at Stanford Healthcare, private practice clinics, and the student health center at Stanford University. 
 
Recruitment venues & how potential participants will be identified and approached:  Participants will 
be recruited through the Stanford Brain Stimulation Lab online recruitment pipeline (online portal for 
referrals) and the Stanford Depression Research Clinic (Dr. Williams is a member). Potential participants 
will then be invited via email or phone to consent to and participate in screening with a study team 
member (over zoom) for further assessment of eligibility. 
 

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Types of recruitment strategies planned: Recruitment strategies include social media campaigns and in-
services with outpatient clinics at Stanford Healthcare’s psychiatry department as well as private practices 
in the community. Patient advocacy groups will be targeted for recruitment such as National Alliance on 
Mental Illness.  
 
Participant retention plan: Participants will provide best contact information including telephone, email, 
and up to two emergency contacts, all of which will be utilized as needed to ensure participant retention. 
Additionally, participants will be compensated $50 USD for study visits 2 to 8 (baseline to follow-up), for 
a total of $350 USD. They will be compensated at their last study visit.  
 
Specific strategies that will be used to recruit and retain historically under-represented populations: We 
will make every effort to recruit an ethnically and racially representative sample who meet our study 
criteria, such as being depressed and able to undergo an fMRI scan and TMS interventions. The data in 
the Inclusion Enrollment Report are based on extrapolations from our random sample of patients who 
meet inclusion criteria who have undergone clinical rTMS at Stanford. Overall, 37% of our sampled 
patients who met inclusion criteria were non-White, and we will work towards staying as close as possible 
to these diversity numbers. We expect a similar proportion of non-White patients. Our staff will be trained 
and sensitive to the issues related to recruitment and retention of diverse populations. Culturally sensitive 
retention of participants in the study for all of the assessments will be practiced. We have three decades 
of experience in conducting such research studies and have trained our research staff to provide warm 
and caring interactions with our research participants, expressing ongoing appreciation for their 
participation, and responding immediately and supportively to any questions or issues that emerge from 
them or their families. In our experience, this approach has improved ongoing research participant 
adherence to protocols. We make every effort to ensure that our research participants feel respected for 
their important contribution to our research. 
 
In order to facilitate recruitment of diverse populations, recruitment materials will be made available in 
English and Spanish. The Stanford Hospital and Clinics have 24hr per day access to interpreters – in person, 
by video, or by phone – and this will be available to all of our participants. We will also leverage the 
expertise in the Office of Community Engagement in the School of Medicine to target diverse patient 
populations. 
  
 
6 
STUDY INTERVENTION  
 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
 
Active aiTBS Intervention: We have previously discussed this stimulation approach with the FDA and the 
FDA deemed the approach nonsignificant risk (NSR). aiTBS will be delivered similarly to our past172207 aiTBS 
studies using the MagVenture MagPro X100 (Skovlunde, Denmark) TMS device equipped with a Cool-B65 
A/P coil.  The L-DLPFC functional target will be localized for each participant using a Localite TMS Navigator 
(Localite, Bonn, Germany). Participants will then be treated with 1,800 pulses of iTBS (3-pulse 50-Hz bursts 
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depth-adjustment to the personalized functional target103. Each session will last 10 min followed by a 50-
minute intersession interval. Ten sessions will be applied per day (18,000 pulses/day) for 5 consecutive 
days (90,000 total pulses).  
 
Sham aiTBS Intervention:  Intervention will be administered with an ‘A/P’ coil (MagVenture, Denmark) 
which has both an active and sham side that are identical in appearance. The intervention condition is 
determined based on a code assigned at randomization. Based on the assigned code the magnetic 
stimulation is either directed towards or away from the head (i.e., when the randomization code assigns 
sham stimulation then the magnetic stimulation ends up being directed away from the head). During sham 
stimulation, however, the magnet still activates. Accordingly, the sound, appearance, and sensation of 
sham stimulation operation is the same as it is for active stimulation. Thus, there is no way for the operator 
to know if the patient is getting sham or active stimulation. Similarly, raters will have no knowledge of 
which ID corresponds to which intervention. This type of sham has been demonstrated to be 
indistinguishable from real TMS, has been well tolerated194,195, and successfully used in clinical trials. 
 
6.1.2 
DOSING AND ADMINISTRATION 
 
The goal of treatment in this study is to ensure the correct amount of treatment (90% of motor threshold) 
is received in the target location (L-DLPFC) rather than under-stimulating and under- treating participants. 
Depth correction accounts for the variable distances between the scalp and motor hotspot and scalp and 
treatment target from person to person. In other words, this is a personalized treatment intensity that 
takes into account individual variability. However, to ensure safety we never treat higher than 120% of 
the person’s resting motor threshold, which is the standard TMS treatment intensity in routine clinical 
practice. 
 
In scenarios where the cortical target depth is more superficial than the hotspot depth, the intensity will 
only be adjusted upwards. In no case will the stimulation be below 90% of the resting motor threshold. 
 
Following the baseline MRI scan, participants will present to the clinic for the first of their 5-day course of 
aiTBS interventions (Visits 3-7). We will deliver both active and sham study intervention via a MagPro X100 
(MagVenture, Skovlunde, Denmark) TMS. The intervention paradigm consists of 10 daily sessions (50 total 
over 5 days) of intermittent theta-burst (iTBS) stimulation (3-pulse 50-Hz bursts at 5-Hz for 2-second 
trains, with trains every 10 seconds), delivered with 50-minute inter-session intervals (10-minute sessions, 
50-minutes in between sessions). Stimulation will be delivered at 90% of the resting motor threshold (with 
depth correction to account for the distance between the scalp and cortex). aiTBS protocol will be 
administered with a consistent dose escalation across all subjects receiving active stimulation of 18,000 
pulses/day and 90,000 pulses/course. An operator entered code (derived from randomization) will 
instruct 
the 
device 
to 
deliver 
active 
or 
sham 
magnetic 
stimulation.  
 
  
Custom MATLAB scripts will be used to identify the portion of the left DLPFC maximally anticorrelated 
with the sgACC, which will serve as the target for both active and sham stimulation. The intervention 
target will be located via a Localite TMS Navigator (Localite, Bonn, Germany). More specifically, the left 
dorsolateral prefrontal cortex is located according to routine, FDA-approved clinical rTMS practice. Our 
scripts then further discern functional subregions within the left DLPFC. 
 

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6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
 
The intervention device has been purchased by the investigative team, and its use will be closely 
monitored by the PD and Co-I’s. 
 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Because we will use the same device and coil for both active and sham study intervention (but merely 
change the coil side based on active or sham stimulation, as described in 6.1.1), the two study 
interventions will be indistinguishable.  
 
6.2.3 
PRODUCT STORAGE AND STABILITY 
 
The study equipment will be stored in the Brain Stimulation Lab space, with routine and any additionally 
needed maintenance completed per manufacturer standards by the manufacturer themselves (through 
the purchase of a ‘platinum warranty’). 
 
 
6.2.4 
PREPARATION 
 
The MRI, TMS, and neuronavigation devices will be used according to the manufacturer’s instructions. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
In this study, participants will be randomized to active vs. sham aiTBS in a 1:1 ratio in randomly selected 
block sizes of 2, 4, or 6 as based on a random number generator and without stratification. Blinding will 
be achieved via a sham rTMS coil (Cool-B65 A/P) used with the device (MagPro X100, MagVenture, 
Skovlunde, Denmark). This coil can deliver either active or sham iTBS in a manner that is randomized by 
the system itself and therefore blinded to the treater. The sham setting on this coil looks and sounds 
identical to the active setting but has a hidden aluminum plate blocking actual stimulation. The 
MagVenture TMS device holds a blinded key code that is kept by the individual that holds the blind. During 
the rTMS setup, the operator is instructed to flip the coil to correspond with the key code, but the operator 
is not able to discern the active versus sham stimulation. 
 
For additional blinding of the operator: 
- The participant wears a mouth-guard to prevent potential teeth grinding and/or audible noises from the 
sound of his/her mouth moving from active stimulation. 
- Participants will wear headphones that generate the sound of the TMS machine as well as earmuffs to 
mask the actual noise of the TMS machine. 
- The operator will apply lidocaine numbing gel before sessions 1, 3, 5, 7 and 9 to the scalp where the TMS 
coil is being placed to alleviate active stimulation discomfort. 
- The operator will not touch the surface of the coil, as one side may be hotter than the other; knowing 
which side is hotter or colder can potentially unblind him/her. 

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- The operator will hang a blinding sheet/cloth over the side of the TMS coil to act as a barrier between 
him/her and the participant. This prevents the operator from being able to see if there are facial muscle 
movements, which could indicate active stimulation.  
This protocol has been used to successfully blind participants in our recent RCT. 
 
The blinded randomization code will be kept in the individual case report form (CRF), and the key linking 
the code to the participants condition will be kept separately in an encrypted file, stored outside of the 
lab and able to be accessed only by a person who has no direct or indirect interaction with participants or 
data collection. The blind will be maintained until the completion of the study and data-lock is achieved, 
after which planned unblinding will take place. 
 
Unplanned unblinding will only take place in the unlikely events that either: a) the independent DSMB 
requests unblinding for concerns over adverse events that are more serious / frequent than expected, or; 
b) on an individual basis should knowing the randomized condition for an individual participant result in 
improved clinical decision making in an emergency setting. In the case of unplanned unblinding, both the 
Stanford IRB and the Program Officer assigned to the project at NIMH will be informed. 
 
We do not anticipate unintentional unblinding; however, in the event a member of the study team 
becomes unblinded, we will track this event in the CRF, and all study-team members know to not unblind 
other study-team members. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
The study intervention is procedural in nature and, accordingly, study adherence will be directly observed. 
There are pre-specified places within each participant's CRF where notes to file can be logged, and we 
plan on documenting any missed aiTBS / MRI sessions in this location. In our experience with other 
investigations using aiTBS, retention is high and missed sessions are low. We subsequently do not expect 
to have many instances of non-adherence. 
 
6.5 
CONCOMITANT THERAPY 
 
Participants will be required to continue all psychotropic medications throughout the study period, as 
they were at the time of screening. Any ongoing psychotherapy that is in a maintenance phase (i.e., not 
skills training) may be continued, but no new psychotherapy may be initiated during the course of the 
study. 
 
To ensure adequate sleep each evening prior to TMS intervention (a safety requirement), certain sleep 
medications (e.g., zolpidem, zaleplon, eszopiclone, quetiapine) may be prescribed by the PD or study MD 
immediately prior to or during the course of TMS. These medications may be administered up to the night 
prior to the stimulation session (until midnight), but not during the morning of the sessions or at any time 
during the intervention day. The use of alternative hypnotics or the short term use of anxiolytic 
medications (e.g., hydroxyzine, propranolol) during an intervention day requires prior approval from the 
PD or study MD.  
 
As per clinical standard of care with rTMS, participants are encouraged to bring OTC acetaminophen or 
ibuprofen for prophylactic use if they are concerned about the potential emergence of adverse events 

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that are commonly experienced with rTMS. Such use would be considered as standard of care. Short-term 
treatments for other headaches, mild aches/pains, or seasonal allergies will be allowed during the study 
provided the medications utilized have no established psychotropic effects that might confound 
interpretation of study outcome measures. These medications may include non-sedating, over-the-
counter analgesics or antihistamines.  
 
6.5.1  
RESCUE MEDICINE  
 
No rescue medications will be used. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Discontinuation from aiTBS does not mean discontinuation from the study, and remaining study 
procedures will be completed as indicated by the study protocol. If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be documented as an adverse event (AE), according to the AE protocol. 
 
Discontinuation from aiTBS can be classified as temporary or permanent depending on the timing in which 
it occurs. If the participant has not completed visit 3 as defined in the Section 1.3, Schedule of Activities 
(SoA), they may qualify for temporary study discontinuation. Temporary discontinuation may result from 
any COVID-19 related reason or other qualifying reason. This may be, but is not limited to, temporary 
study discontinuation while a participant quarantines or receives COVID-19 care. After receiving health 
clearance, they may resume the study at visit 2 if they continue to meet study criteria.  
 
If aiTBS discontinuation occurs after the completion of visit 3, as defined in Section 1.3 SoA, or if a 
participant chooses to discontinue the study intervention, this will be classified as a permanent study 
discontinuation.  
 
The data to be collected at the time of permanent study intervention discontinuation will include (if 
possible) the following: 
 
● A final MRI scan (if not yet completed). 
● Questionnaires about mood and well being. 
● Questions about any adverse events or health problems since the last visit. 
 
Subjects may be withdrawn from the study by the Protocol Director if a subject: 
  
● Experiences a seizure  
● Is non-adherent with study procedures 
● The randomization code is broken for the subject 
 

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The Protocol Director may also withdraw a subject if he/she believes that for safety reasons it is in the 
best interest of the subject to be withdrawn. 
  
Discontinuation information [e.g., date and the reason(s) for discontinuation] will be recorded in the 
subject’s CRF (i.e., Study Completion Form) and relevant forms on REDCap. 
   
As this is a mechanistic study, subjects withdrawn from the study may be replaced if withdrawal occurs 
any time prior to study completion. Should a participant fail to return for required visits or drop out of the 
study, effort will be made to determine why. This information will subsequently be recorded on the 
subject’s CRF and relevant forms on REDCap. 
  
Subjects will be encouraged to remain adherent 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 informed consent process and reinforced throughout the study through regular screening for 
issues with compliance. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
● Pregnancy. 
● Significant study intervention non-compliance.  
● If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant. 
● Disease progression which requires discontinuation of the study intervention. 
● If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation. 
● Participant unable to receive aiTBS for the entire 5 days.  
● If an incidental finding is discovered upon imaging that either the study staff (physicians) and/or 
CNI assigned radiologist deems unsafe or requires immediate medical followup. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the REDCap 
eCRF. Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced. Subjects who sign the informed consent form and are randomized and 
receive the study intervention and subsequently withdraw or are withdrawn or discontinued from the 
study before completing all required MRI scans as defined in the SoA, may be replaced.  
 
Subjects may withdraw voluntarily from the study at any time. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for one scheduled visit and is 
unable to be contacted by the study staff.  
 
We will take the following actions if a participant fails to return for a required study visit: 

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● We will attempt to contact the participant and reschedule the missed visit within 24 hours and 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
● Before a participant is deemed lost to follow-up, the investigator or his designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls or emails and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). We will record these contact attempts in the participant’s designated REDCap eCRF.  
● Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with the primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
 
8.1 
EFFICACY ASSESSMENTS  
 
Screening process:  
 
Participants will be recruited through the Stanford Brain Stimulation Lab online recruitment pipeline 
(online portal for referrals) and the Stanford Depression Research Clinic (Dr. Williams is a member). 
Potential participants will then be invited to consent to and participate in screening with a study team 
member (over zoom) for further assessment of eligibility. Screening and enrollment info can be pulled 
from the REDCap study database. Screening and enrollment info will include consent dates, subject IDs, 
and outcomes . When a remote consent is conducted, electronic signature of consent will be obtained via 
Adobe Sign. 
 
Our target population is rTMS-naïve participants with major depression and moderate-high treatment-
resistance (on MSM). In-depth screening will include demographics information; psychiatric and medical 
history; current and past medications with adequacy of trials assessed by the Antidepressant Treatment 
History Form (ATHF) Current/Lifetime208; psychiatric diagnoses via the Overview/History section of the 
Structured Clinical Interview for DSM-5 (SCID) and the Mini-International Neuropsychiatric Interview for 
DSM-5 (MINI v.7.0.2); borderline personality disorder diagnostic module from SCID for DSM-5 (if a 
participant meets the screening threshold on the self-reported prescreening questions); the Montgomery-
Asberg Depression Rating Scale-Self Report (MADRS-S), and the Montgomery-Asberg Depression Rating 
Scale-Clinician Rated (MADRS-CR); suicidal ideation and behavior with the Modified Scale for Suicidal 
Ideation (MSSI) and the Columbia-Suicide Screening Rating Scale (C-SSRS); acute mood state with the 
Immediate Mood Scaler (IMS209-12); manic symptoms will be screened for with the Young Mania Rating 
Scale (YMRS); severe insomnia will be screened for with the Pittsburgh Sleep Quality Index (PSQI). 
Participants will also be asked specifically about any contraindications to receiving rTMS such as metal in 
or near the head using the TMS Adult Safety Screen (TASS); any significant neurologic disease, including 
dementia, Parkinson's or Huntington's disease, brain tumor, seizure disorder, subdural hematoma, 
multiple sclerosis, or history of significant head trauma; previous exposure to any rTMS approach; history 
of dementia or cognitive impairment; active suicidal ideation or a suicide attempt within the past one 
year; and whether they are receiving or planning to receive any other investigational interventions during 
this study. A motor threshold (MT) will be obtained (at Visit 2 - In-person Screening 2/Baseline as a 
screening measure) to confirm it does not exceed the threshold for study eligibility. Screening will be 
performed by a consistent group of qualified study staff who have been trained and certified by the lab’s 
Psychological Director to ensure fidelity to assessment procedures.  

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Screening (Visit 1 - Remote Screening) must be completed within 3 months of formal study enrollment 
and baseline assessment (Visit 2 - In-person Screening 2 / Baseline), otherwise screening will need to be 
repeated prior to moving forward with enrollment and baseline assessment. Visit 2  In-person Screening 
2/Baseline is separated from the screening visit (Visit 1 - Remote Screening) to allow initial remote 
screening and to confirm stability of symptoms (stability is defined as a change in MADRS-S score < 30% 
from screening). Accordingly, a potential subject still may be considered a screen failure even if they 
participate in Visit 2. Screen failures are defined as participants who sign the screening ICF and/or the 
study ICF and complete some or all of the Visit 1 and/or Visit 2 visit(s) but are not subsequently enrolled 
in 
the 
study 
due 
to 
not 
meeting 
study 
entry 
criteria.  
 
Subjects who have provided screening data for another study in Stanford University’s Brain Stimulation 
Laboratory (BSL) may have their screening data used for this study. Additionally, screening data used in 
this study may be used in another study in BSL. The purpose of this is to reduce unnecessary burden to 
the subject. The discretion of which screening data is accepted is up to the discretion of the investigator. 
Data will be manually re-entered within BSL’s RedCap system from the previous study into the new study. 
 
Please refer to the Schedule of Activities in Section 1.3 of the MOP understand the screening measures 
required to confirm study eligibility that occur at the In-person Screening 2 / Baseline (Visit 2) 
 
Efficacy assessments related to primary and secondary objectives:  
  
● Radiographic or other imaging assessments: All participants will undergo magnetic resonance 
imaging (MRI) evaluations at: baseline (morning prior to first TMS session) and each subsequent 
morning throughout the five-day TMS course (visits 3-8). MRI acquisitions will include T1-
weighted structural and resting state functional magnetic resonance imaging sequences. 
Participants will be instructed to keep their eyes open and concentrate on a fixation cross for the 
duration of the resting state fMRI scan and to lie as still as possible. The fixation cross will be 
presented via a projector system and visualized through a mirror on the head coil. Subjects will 
confirm verbally during setup that the fixation cross is centered within their visual field, which can 
be adjusted via the head coil mirror angle. The image quality of the baseline scan will be evaluated 
for quality assurance, it is important that these are assessed, as they are the bases for our 
personalized targeting generation, as well as subsequent determination of a dose-response curve. 
We anticipate little to no group differences in functional connectivity between the active and 
sham groups at the time of baseline acquisition due to random allocation; however, this will be 
confirmed statistically post study completion. Following the establishment of fMRI baseline, we  
hypothesize that we will observe functional connectivity changes  that are linearly correlated with 
the effects of the 5-day active TMS intervention. 
● Administration of questionnaires or other instruments: The clinical active versus sham aiTBS-
induced effect will be tested using either the standard (72-hour) version or a 24-hour version of 
the MADRS-S depending on time point (clinical improvement) and IMS-12 (acute mood state). On 
the morning after the 5th day of stimulation (visit 8), participants will receive the IMS-12, 
MADRS-S and YMRS at the same visit as their MRI scan. 
 
●     Additional optional blood draw study: 
  

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An additional optional procedure consisting of three blood draws will be available to participants 
in this trial. These blood draws will occur on the In-person Screening 2/Baseline (Visit 2), the next 
day 
(Visit 
8), 
and 
one-month 
follow 
up 
visit 
(Visit 
9).  
 
This procedure aims to establish how peripheral levels of the mitochondrial metabolite acetyl-L-
carnitine (LAC) are predictive of the anti-suicidal response to accelerated intermittent theta burst 
stimulation (aiTBS) repetitive transcranial stimulation (rTMS) in patients with treatment resistent 
depression. Recent evidence suggests that peripheral LAC levels may be a biomarker of 
depression210. No studies to date have investigated the influence of antidepressant rTMS 
treatments and peripheral LAC levels. The relationship between baseline levels of LAC and 
response to rTMS are unknown. Further, the effects of rTMS on peripheral levels of LAC is also 
unknown. This additional study seeks to investigate these questions. Blood will be drawn by a 
certified phlebotomist at the time points noted above. A total of 30 mL of blood will be collected 
for each blood draw (10 mL in a heparinized tube and 20 mL in EDTA tubes). Additionally, 
Childhood Trauma Questionnaire (CTQ) and Family Interview for Genetic Studies (FIGS) 
assessments will be administered during the baseline evaluation to those who consent for this 
optional study.  Additional biomarkers of depression may also be assayed by our group or our 
collaborators at NYU and/or University of Antwerp. A portion of the de-identified plasma samples 
will be sent to our collaborators at NYU and/or University of Antwerp for analysis. Another portion 
of the de-identified plasma samples will be stored at Stanford along with buffy coat samples for 
subsequent analyses of depression biomarkers including telomere length. 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
All patients will undergo a clinical study visit with the study psychiatrist (or their designee) as part of the 
assessment for suitability in the study. This visit will include assessment of current psychiatric symptoms, 
psychiatric history (including past diagnoses, hospitalization, suicide attempts, past medication trials), 
current medical concerns [if any], past medical history, current medications, allergies, family psychiatric 
history, and social history. A mental status exam will be performed. If assessed by clinical judgment to be 
needed, vital signs and certain studies (e.g., ECG, basic labs) will be obtained. Follow up clinical study visits 
will be performed as needed. 
   
● Emergency Escalation 
o A study MD is always available and is the first point of contact in the case of an emergency.  
o In the event of a significant safety concern or medical emergency, staff will call emergency 
medical services (911 from a cell phone or 9-911 for University Police from a campus 
phone) 
or 
the 
study 
MD. 
 
● Radiographic or other imaging assessments. Participants will be screened for MRI 
contraindications prior to enrollment in the study (at the screening visit). The Stanford CNI MRI 
safety form will be completed by the participant prior to each imaging session to confirm no 
changes in medical history occurred relevant to MRI contraindications. This safety screening  tool 
includes questions regarding occupational/hobby risks (metal workers), surgical procedures 

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involving implants and devices, as well as questions about tattoos and piercings. The investigator 
or qualified study staff will review MRI risks and the MRI safety form in detail when signing the 
study informed consent and before each imaging session. Finally, a hand-held metal detector will 
be used to confirm the participant has removed all metal from their person (hair clips, jewelry, 
etc). If an incidental finding is discovered upon imaging that either the study staff (physicians) 
and/or CNI assigned radiologist deems unsafe or requires immediate medical followup, the 
participant will be alerted to the need for appropriate clinical follow up according to the protocol 
that has been created by the Stanford Center for Cognitive and Neurobiological Imaging (CNI) 
(https://cni.stanford.edu/wiki/Operations#Incidental_Findings). 
o MRI Safety Screening Form: This is a participant self-report instrument. Participants will 
fill out a MRI Safety Screening Form to determine if the participant is safe to receive an 
MRI. We will utilize this screening tool to make sure that the participant has no 
contraindications for MRI that would exclude the participant from participating. 
 
● TMS safety:  
o Transcranial Magnetic Stimulation Adult Safety Screen (TASS)1: This is a participant self-
report instrument. Participants will fill out a TASS questionnaire to determine risk of 
seizure related to rTMS. Any identified seizure risk will disqualify the participant. This 
assessment is utilized in order to minimize the risk of seizure induction with rTMS. 
o As part of the clinical study visit, the study psychiatrist (or their designee) will review the 
participant’s medical history to assess for any contraindications to receiving TMS. 
o Seizure monitoring: Treaters will be monitoring subjects for the potential development of 
seizures by continuous visual inspection during the course of each stimulation session 
(especially the more subtle signs and symptoms of frontal lobe seizures) and are trained 
in first responder management in the event of a seizure. In the event of a seizure or other 
medical emergency, EMS would be called for further support and management and to 
transport the participant to our local Emergency Department, which is located minutes 
away on the Stanford campus.  
o TMS adverse event monitoring: AEs will be monitored continuously by designated study 
staff, recorded in applicable subject-specific and study wide REDCap eCRFs, and reported 
to the Stanford IRB annually. Research staff will be trained to attend to signs of AEs and 
to report any potential unrelated or unexpected AE immediately to the PD or study 
psychiatrists. Follow-up of any AEs/SAEs will be performed as described in 8.3.4. 
 
● Depression/Psychiatric Assessments:  
 
● Young Mania Rating Scale (YMRS): This is an 11-item clinician-administered scale used to 
measure symptoms of mania. Each item is scored from 0-4 with scores of 4 indicating the 
presence of more severe mania. Participants who are currently experiencing a manic 
episode will not be enrolled in the study. This scale will be used to monitor symptoms of 
mania each day they receive aiTBS to make sure manic symptoms have not arisen during 
study enrollment. If patients develop hypomanic/manic symptoms (defined as YMRS ≥ 
12), no further stimulation will be administered and the patient's clinician will be notified. 
● Item 9 on the Montgomery and Åsberg Depression Rating Scale - Self Report (MADRS-S - 
item 9): The 9-item self-report version of the MADRS has an overall score range from 0 to 
27 with higher scores corresponding to higher levels of depression. We will use item 9 
(‘Zest for Life’) as a safety measure in regards to suicide risk. A score of 3 on that item will 
trigger a consultation with the study psychiatrist or their designee which will include an 

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MSSI to further assess suicide risk and determine whether it is safe for the participant to 
continue in the study and whether any further intervention is indicated to maintain the 
participant’s safety. 
● CTQ and FIGS assessments will be given to those participants who consent for the optional 
blood draw study. CTQ responses will determine any correlation between LAC levels, 
aiTBS response, and childhood trauma. FIGS responses will be used to determine any 
correlation between LAC levels, aiTBS response, and family history of mental illness.  
● All participants will receive a weekly phone call check-in from a CRC between Visits 8 and 
9 for support and to ensure continuity. If any safety concerns are identified, the study MD 
will be alerted for further assessment and management, if indicated. 
● CTQ and FIGS assessments will be given to those participants who consent for the optional 
blood draw study. CTQ responses will determine any correlation between LAC levels, 
aiTBS response, and childhood trauma. FIGS responses will be used to determine any 
correlation between LAC levels, aiTBS response, and family history of mental illness. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
 
An adverse event (AE) 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 stimulation 
with a TMS device or an MRI scan. The event need not be causally related to the TMS device or the MRI 
scan in order to be considered an AE. 
An AE includes, but is not limited to: 
● Any adverse finding including a sign, symptom, abnormal assessment (laboratory test 
value, vital signs, electrocardiogram finding, etc.), or any combination of these. 
● Any clinically significant worsening of a pre-existing condition; 
● An AE that has been associated with a preexisting condition is a clinical condition 
(including a condition being treated) that is diagnosed before an informed consent form 
is signed and is documented as part of the subject’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 
an intervention-emergent AE (IEAE). 
An AE is considered to be intervention-emergent 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 subject’s medical history, or [2] it was present 
at the start of the active phase of the study or as part of the subject’s medical history, but the severity or 
frequency increased during the active phase. The active phase of the study begins at Visit 3. 
For this study, the intervention follow-up period for adverse events is defined as 30 days following the 
last day of study intervention. 
Follow up will be documented in the subject’s study file. 
 

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8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
A Serious Adverse Event (SAE) is defined as an AE that: 
● Results in death 
○ 
Is life threatening 
■ 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 
● Requires inpatient hospitalization or prolongation of an existing hospitalization 
○ 
Admission to or prolongation of an existing partial hospitalization program (PHP) 
or intensive outpatient program (IOP), both of which are outpatient programs, 
are not included in this definition 
○ 
Hospitalization is defined only as an actual admission 
○ 
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 
a total knee replacement due to a preexisting condition of osteoarthritis of the 
knee that has not worsened during the study) 
● Results in a substantial disruption of a person's ability to conduct normal life functions, 
i.e., the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the patient's body function/structure, physical 
activities and/or quality of life 
● Necessitates medical or surgical intervention to preclude such impairment 
● Results in a congenital anomaly or birth defect 
  
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. 
  
 
An adverse event of special interest is a device-specific adverse event designated by the PD for 
transmission in the same time frame as an SAE, even if it does not meet serious reporting criteria. See 
section 8.3.8 for further details. 
  
If there is any doubt whether the information constitutes an SAE, the PD will review the event and make 
a determination. 
  
 
 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1  
SEVERITY OF EVENT 
 

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All AEs will be assessed by the study clinician using the  grading system defined below and recorded on 
designated REDCap subject-specific and study-wide AE logs.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
 
8.3.3.2  
RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below.  
Causal relationship options and definitions are as follows: 
·    
Definitely related: Event can be fully attributable to administration of the TMS stimulation 
or the MRI device. 
·    
Probably related: Event is most likely to be explained by administration of the TMS 
stimulation or MRI device, rather than the subject’s clinical state or other agents/therapies. 
·    
Possibly related: Event is as likely explained by administration of the TMS stimulation or 
MRI device, as by the subject’s clinical state or other agents/therapies. 
·    
Probably not related: Event is most likely to be explained by the subject’s clinical state or 
other agents/therapies, rather than the TMS stimulation or MRI device. 
·    
Definitely not related: Event can be fully explained by the subject’s clinical state or other 
agents/therapies, rather than the TMS stimulation or MRI device. 
 
When assessing the relationship between an investigational product/protocol and an AE, the following 
parameters are considered: 
  
·    
Temporal relationship between the TMS device/protocol and the AE 
·    
Biologic plausibility of relationship 
·    
Subjects’ underlying clinical state or concomitant agents/therapies 
·    
Where applicable, whether the AE abates on discontinuation of the TMS device or MRI 
device (de-challenge) 
·    
Where applicable, whether the AE reappears on repeat exposure to the TMS device or 
MRI device (re-challenge) 
SAEs that are not TMS/MRI device-related may nevertheless be considered by the Protocol Director or 
the IMC to be related to the conduct of the study, i.e., to a subject's participation in the study. 
 

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8.3.3.3  
EXPECTEDNESS  
 
 
 
In Table 3 above, there is a list of common, expected AEs87. Worsening of any symptoms of depression or 
related to depression also is an expected AE, as could be the case for any clinical trial of a novel therapy, 
particularly when there is a sham control condition as in our case. Furthermore, any iTBS study has a risk 
of mania and hypomania as an expected AE. The study psychiatrist, in accordance with the listed risks on 
the study ICF, will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent 
with 
the 
risk 
information 
previously 
described 
for 
the 
study 
intervention. 
 
Additional expected potential AEs associated with the intervention and other study procedures include: 
● Seizure 
● Induction of mania 
● Mild pain at site of stimulation 
● Anxiety 
● Panic 
● Symptoms of claustrophobia (feeling fearful, sweating, chills, dizziness, nausea, dry mouth, high 
heart rate, and high blood pressure) 
● Rash, itching, redness, irritation, pain, swelling, and blistering conditions 
8.3.4  
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 

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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate electronic case report form (eCRF). Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs occurring while on study must be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution or until medical stability as judged by the PD or his designee. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Study psychiatrist will record all reportable events with start dates occurring any time after the first study 
intervention until 30 days following the last day of study intervention. At each study visit, study staff will 
inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization. 
 
 
 
AEs will be systematically screened for at the start and end of every visit beginning at the active phase of 
the study (Visit 3). They will be screened for via the following standardized questions that will be asked by 
research staff:  
● Have you had any difficulty with the study interventions?  
● Have you had any problems or other things bothering you since our last visit?  
● Has anything bothered you enough to...  
○ 
...prevent you from doing anything you had planned? 
○ 
...take a prescription or over-the-counter medication or supplement?  
○ 
...see a medical professional? 
○ 
...modify the treatment of a pre-existing medical condition? 
● Have you been admitted to a hospital or seen in an emergency / urgent care clinic? 
 
Any positive response(s) to the above questions will be documented electronically and further 
investigated as appropriate. Any documented AE will be asked about at each subsequent AE assessment 
until it resolves or through the time frame specified above. If an unexpected AE occurs, or if a common 
AE occurs with severity greater than that expected, the participant will be further evaluated by a member 
of the study team with formal medical training. 
 
In addition, although the risk of TMS-induced mania is low211, it will be monitored using the YMRS scale 
as a solicited event. The scale will be administered at the end of each stimulation day.  
 
8.3.5  
ADVERSE EVENT REPORTING  

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AEs will be monitored continuously by designated study staff, recorded in applicable subject-specific and 
study wide REDCap eCRFs, and reported to the Stanford IRB annually.  
 
Research staff will be trained to attend to signs of AEs and to report any potential unrelated or unexpected 
AE immediately to the PD. If AEs occur, appropriate medical and/or psychiatric care will be facilitated for 
the research participant, and recorded in the appropriate electronic AE logs on REDCap. As per Stanford 
IRB requirements, AEs will be reported to the IRB annually. The NIMH Program Officer will be informed of 
any actions taken by the IRB as a result of any AEs within 7 business days of notification by the IRB (e.g. 
study modifications imposed by the IRB). 
 
All subjects will have telephone and email contact information to reach the Protocol Director and the 
Stanford IRB, in case of any distress or adverse response to rTMS or other components of the study. 
 
All AEs and SAEs will be recorded on the subject-specific and study wide eCRFs, which will be provided to 
the DSMB on a bi-annual basis. Signs and symptoms will be recorded using standard medical terminology. 
  
The following AE information will 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 TMS device; action 
taken; and outcome. 
 
 
8.3.6  
SERIOUS ADVERSE EVENT REPORTING  
 
The PD or his designee will immediately report to the sponsor any serious adverse event (SAE), whether 
or not considered study intervention related, including those listed in the protocol or investigator 
brochure, and must include an assessment of whether there is a reasonable possibility that the study 
intervention caused the event. Study endpoints that are SAEs  (e.g., all-cause mortality) must be reported 
in accordance with the protocol unless there is evidence suggesting a causal relationship between the 
study intervention and the event. In that case, the investigator will immediately report the event to the 
sponsor. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems either the event 
is chronic or the participant is stable. Other supporting documentation of the event may be requested by 
the study sponsor and should be provided as soon as possible. 
 
In case of SAEs, the study investigator will complete an Unanticipated Serious Adverse Event  Form and 
submit to the study sponsor and to the reviewing Institutional Review Board (IRB) as soon as possible, but 
in no event later than 10 working days after the investigator first learns of the effect.  The study sponsor 
will conduct an evaluation of an unanticipated adverse device effect and will report the results of such 
evaluation to the Food and Drug Administration (FDA) and to all reviewing IRBs and participating 
investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter, the 

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sponsor will submit such additional reports concerning the event as FDA requests. The Investigator will 
provide all relevant documentation pertaining to an SAE (e.g., additional laboratory tests, consultation 
reports, discharge summaries, postmortem reports, etc.) to the DSMB and NIMH in a timely manner. 
Reports relative to the subject’s subsequent course will be submitted to the DSMB and NIMH until the 
event has subsided or, in case of permanent impairment, until the condition stabilizes.  
 
Designated study staff will be responsible for ensuring that unanticipated problems are reported to the 
IRB in compliance with their requirements for reporting serious and unexpected adverse events. 
Reporting will be conducted in compliance with guidelines specified by the Stanford University Research 
Compliance Office. 
 
8.3.7  
REPORTING EVENTS TO PARTICIPANTS  
 
At enrollment, participants will be asked whether or not they would like to be informed about study 
outcomes. We will compile a list of those participants who would like to know about outcomes, and 
following study completion they will be individually emailed a copy of the study’s primary outcome paper 
using individual, encrypted email.    
 
We will closely monitor AE’s on a continuous basis and will involve the independent DSMB in assessing 
whether any AE is unexpected or more severe than expected (at a rate greater than what would be 
expected by chance). Should we identify any AE that meets one of those two criteria or should we have 
any unexpected SAE’s, we will notify currently enrolled participants and change our consent to include 
the pertinent information. 
 
Incidental findings are likely to occur in one of two categories including clinical diagnostic findings and 
radiographic abnormalities. Should a pertinent clinical diagnostic finding (for instance an interview highly 
suggestive of occult bipolar disorder), we will inform the participant’s psychiatrist. Should an incidental 
radiographic abnormality be detected during MRI, we will send the imaging to Stanford neuroradiology 
(as further described in 8.2).  
 
8.3.8  
EVENTS OF SPECIAL INTEREST  
 
An adverse event of special interest is a device-specific adverse event designated by the PD for 
transmission in the same time frame as an SAE, even if it does not meet serious reporting criteria. For this 
protocol, seizure should be reported as an adverse event of special interest. 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. 
Other reportable information that does not meet the definition of an SAE but is reportable to NIMH and 
the DSMB with the timeliness of an SAE includes: 
·    
Seizure 
·    
Pregnancy occurring during the study period in which the subject was exposed to the TMS 
device; 
·    
Overdose (e.g., a dose higher than that prescribed by a healthcare professional for clinical 
reasons) with or without AEs; 
·    
Abuse (e.g., use for non-clinical reasons) with or without an AE; 

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·    
Inadvertent or accidental exposure with or without an AE; 
·    
Device malfunction that would likely result in death, serious injury or other significant 
adverse event. 
 
8.3.9  
REPORTING OF PREGNANCY  
 
We will not include pregnant women in this study. If the participant is of childbearing potential and not 
already pregnant, the participant must agree to use adequate contraception (hormonal / barrier method 
of birth control or abstinence) prior to study and for the duration of the study participation. During the 
screening phase of this study, participants of childbearing potential will be administered a pregnancy test; 
a negative pregnancy test will be required to confirm eligibility for study participation and will be 
completed prior to their receiving any rTMS stimulation. If a participant becomes pregnant or suspects 
she is pregnant while participating in the aiTBS stimulation week of the study, she should inform the 
research staff immediately via in-person meeting, telephone call, or email. If a participant reports 
pregnancy occurring during the study period in which the participant was exposed to the rTMS 
stimulation, research staff will stop rTMS stimulation and then notify the Protocol Director. 
 
8.4  
UNANTICIPATED PROBLEMS 
 
8.4.1  
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, any serious adverse effect on health 
or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)). 
 
 
8.4.2  
UNANTICIPATED PROBLEM REPORTING  
 

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The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PD’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) and/or result in unexpected deaths or life-threatening 
experiences related to the research will be reported to the IRB and to the Data Safety Monitoring 
Board (DSMB) within 10  days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the DSMB  within 30 days of the investigator becoming aware of 
the event and subsequently reported to the IRB  within 10 working days from receiving 
assessment from the DSMB.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 30 days of the IRB’s receipt of the report of the 
problem from the investigator. 
 
An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse 
device effect occurring during an investigation as soon as possible, but in no event later than 10 working 
days after the investigator first learns of the effect (21 CFR 812.150(a)(1)). A sponsor who conducts an 
evaluation of an unanticipated adverse device effect under 812.46(b) shall report the results of such 
evaluation to the Food and Drug Administration (FDA) and to all reviewing IRB's and participating 
investigators within 10 working days after the sponsor first receives notice of the effect. Thereafter the 
sponsor shall submit such additional reports concerning the effect as FDA requests (21 CFR 812.150(b)(1)).    
 
 
8.4.3  
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Should an unanticipated problem occur (such as identifying an AE that is more common or severe than 
expected, or a data breach of any sort), the investigators will inform those participants that have been 
affected of both the problem and any proposed solution. Should the unanticipated problem have the 
potential to affect future participants it will be added to the consent document.    
 
9  
STATISTICAL CONSIDERATIONS  
 
9.1  
STATISTICAL HYPOTHESES 
 
● Primary Mechanistic Endpoint:  
 

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We hypothesize that the reduction in resting-state functional connectivity between the subgenual 
anterior cingulate cortex and the default mode network from baseline through intervention day 5 will be 
significantly greater for participants receiving active as compared to sham aiTBS.  
 
● Secondary Mechanistic Endpoints: 
 
(a) We hypothesize that there will be a significantly greater association between the change in depression 
symptoms (as measured by the MADRS-S) and the change in resting-state functional connectivity 
between the subgenual anterior cingulate cortex and the default mode network from baseline to after 
intervention day 5 for participants receiving active as compared to sham aiTBS.  
 
(b) We hypothesize that there will be a significantly greater association between acute mood state (as 
measured by the IMS-12) and the change in resting-state functional connectivity between the 
subgenual anterior cingulate cortex and the default mode network from baseline to after intervention 
day 5 for participants receiving active as compared to sham aiTBS. 
 
9.2  
SAMPLE SIZE DETERMINATION 
 
Sample size justification (power analysis): 
Key Hypothesis of the study: A significant reduction in functional connectivity between sgACC and DMN. 
We hypothesize that the reduction in functional connectivity between the subgenual cingulate cortex and 
the default mode network from baseline to after intervention day 5 will be significantly greater for 
participants receiving active compared to sham aiTBS. Several past studies have found no significant 
changes in functional connectivity with sham rTMS targeted to DLPFC136,212. Using preliminary data from 
our open-label study of aiTBS for treatment of severe depression, there was an effect size of 1-1.47 
(depending on DMN node) for change in connectivity between sgACC and DMN150.  One potential 
approach for determining the power calculation would be that considering we will have 10 unique 
comparisons with each day’s data be compared to every other day over 5 days, and that we will be 
comparing across 4 DMN nodes and 2 sgACC nodes, our target alpha needs to be 0.05/(10*4*2) = 
0.000625. Thus, for an effect size of 1, alpha of 0.000625, and a power of 0.80, and powering for an 
independent-measures t-test, 40 participants will be required for each arm. Regarding our secondary 
mechanistic endpoints, we have previously found a significant correlation between change in FC between 
sgACC and DMN in participants receiving open-lab aiTBS, Pearson r = 0.51. For a point biserial model, a 
two-tailed 2 test, and a power target of 0.80, 25 participants will be required for each group.  
 
Our recruitment goals are based on our primary mechanistic endpoint. Considering a ~25% attrition rate 
(combined participants lost to followup and unusable or missing scans), we plan to recruit 50 participants 
in each arm, as this is larger than the 18 per arm that is required to power for a significant reduction in 
IMS-12, and large enough to provide sufficient power for our secondary mechanistic endpoints. Given 
that there are ~1,000 new depressed patients at Stanford per year, >75% are TMS-naïve, there are many 
more than 100 patients per year that meet inclusion criteria. 
 
9.3  
POPULATIONS FOR ANALYSES 
 
This protocol is designed to test the mechanistic hypothesis that aiTBS reduces functional connectivity 
between sgACC and DMN. Thus, these mechanistic analyses will include only a Per-Protocol Analysis 
Dataset. The Per-Protocol Analysis Dataset defines a subset of the participants who complied with the 
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intervention according to the underlying scientific model (e.g., participants who took at least 80% of study 
intervention for 80% of the days within the maintenance period). 
 
9.4  
STATISTICAL ANALYSES 
 
 
9.4.1  
GENERAL APPROACH 
 
Descriptive Statistics: Categorical data will be presented as percentages. Continuous data will be 
presented as means with standard deviations. 
 
Inferential tests: Statistical significance will be set at p<0.05, two-tailed.  
 
Covariates: Baseline demographic and clinical measures will be compared across intervention groups 
using standard statistical methods (i.e., categorical variables compared using Pearson chi square test of 
independence; continuous variables compared using univariate ANOVAs). Characteristics that display 
imbalance at the baseline measure or an association with the dependent variable will be assessed for 
inclusion as covariates in the final models. 
 
Assumption checks: Continuous data will be analyzed using standard linear mixed-effects modeling in line 
with intent to treat analysis principles. If residuals of the standard linear models are non-normally 
distributed (Shapiro-Wilk), then data will be analyzed with generalized linear mixed models with 
Satterthwaite approximation of degrees of freedom and robust estimation of coefficients to handle 
violations of model assumptions. Autoregressive covariance structure will be used for all analyses except 
for cases in which the models fail to converge or converge on non-real solutions. In these cases, alternate 
covariance structures will be explored until the models converge on real solutions. All post-hoc pairwise 
comparisons will be Bonferroni-corrected for multiple comparisons. 
 
General approach considerations: Primary analysis models will be reported both unadjusted and adjusted 
for significant clinical covariates. All statistical analysis will be conducted using SAS/STAT version 9.4 (SAS 
Institute Inc. 2015. SAS® 9.4 Statements: Reference, Fourth Edition. Cary, NC: SAS Institute Inc.). All 
statistical analyses will be overseen by our biostatistician Dr. Booil Jo, an associate professor in the 
Stanford department of psychiatry and behavioral sciences - Center for Interdisciplinary Brain Sciences 
Research. Dr. Jo holds a PhD in Applied Statistics from UCLA and is a leading expert in statistical analysis 
of mental health research.    
 
9.4.2  
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Our primary hypothesis is that participants receiving per-protocol active aiTBS will demonstrate a 
significant attenuation of resting-state functional connectivity (FC) between subgenual anterior cingulate 
cortex (sgACC) and default mode network (DMN) compared to per-protocol sham intervention. 
 
We will use fMRI to measure resting-state FC between sgACC & DMN. Participants will be treated for 5 
consecutive days with 10 sessions per day of active or sham aiTBS. Participants have a baseline MRI scan 
prior to each day of aiTBS intervention as well as the day following the completion of intervention. After 
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time between the sgACC and DMN regions of interest. All correlation coefficients will then be transformed 
into Fisher's Z score for further analysis. 
 
Baseline demographic and clinical measures will be compared across intervention groups using standard 
statistical methods (i.e., categorical variables compared using Pearson chi square test of independence; 
continuous variables compared using univariate ANOVAs). Characteristics that display imbalance at the 
baseline measure or association with the dependent variable will be assessed for inclusion as covariates 
in the final models. Differences in effects as a function of gender will be considered for all analyses.  
 
FC data being a continuous variable, will be analyzed using standard linear mixed-effects modeling, with 
time and intervention group (active vs. sham) set as fixed factors. Time (throughout the intervention) will 
be set as the within-subject, repeated measure. The effects of intervention group, time, and their 
interaction will be included in the model. If residuals of the standard linear models are non-normally 
distributed (Shapiro-Wilk), then data will be analyzed with generalized linear mixed models with 
Satterthwaite approximation of degrees of freedom and robust estimation of coefficients to handle 
violations of model assumptions. Autoregressive covariance structure will be used unless the model fails 
to converge or displays variance inflation. In these cases, alternate covariance structures will be explored 
until the models converge on real solutions. All post-hoc pairwise comparisons will be corrected for 
multiple comparisons.  
 
The null hypothesis (i.e. no difference in change in FC between active and sham intervention groups) will 
be rejected if the intervention group x time interaction has a p-value < 0.05. Data will be presented as 
least-squares means with standard errors. 
 
 
9.4.3  
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Our secondary hypotheses are: 
 
(a) We hypothesize that there will be a significantly greater association between the change in depression 
symptoms (as measured by the MADRS-S) and the change in resting-state functional connectivity 
between the subgenual anterior cingulate cortex and the default mode network from baseline to after 
intervention day 5 for participants receiving active as compared to sham aiTBS.  
 
(b) We hypothesize that there will be a significantly greater association between acute mood state (as 
measured by the IMS-12) and the change in resting-state functional connectivity between the 
subgenual anterior cingulate cortex and the default mode network from baseline to after intervention 
day 5 for participants receiving active as compared to sham aiTBS. 
 
 
We will use fMRI to measure resting-state FC between sgACC & DMN. Participants will be treated for 5 
consecutive days with 10 sessions per day of active or sham aiTBS. Participants have a baseline MRI scan 
prior to each day of aiTBS intervention as well as the day following the completion of intervention. After 
standard preprocessing of fMRI data, we will calculate FC as the correlation of the activity pattern across 
time between the sgACC and DMN regions of interest. All correlation coefficients will then be transformed 
into Fisher's Z score for further analysis.  
 

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MADRS-S will be collected at baseline, the end of each intervention day, and the day following 
intervention. IMS-12 will be collected at baseline, on the morning of each intervention day, and the day 
following intervention. 
 
Normality in change in both assessments and change in FC from baseline to post-intervention will be 
assessed via Shapiro-Wilk. Appropriate correlational analysis (Pearson or Spearman) will be used to 
quantify the association between change in FC and change in each assessment for each treatment group. 
Correlation coefficients will be compared statistically by performing Fisher’s R-to-Z transformation and 
the difference between the two Z-scores will be tested for statistical significance using a two-tailed Z-test 
with an alpha level of 0.05 (p<0.05). The null hypothesis, i.e. no difference in the association between 
change in FC and change in each assessment between groups, will be rejected if the Z-test has a p-value 
< 0.05. 
 
9.4.4  
SAFETY ANALYSES 
 
We will inquire about AE’s at each visit as described above in the Safety and Other Assessment section 
above (section 8.2). AE’s will initially be inquired about by clinical research coordinators and may then be 
assessed by study physicians during the same visit. The study physician in charge of assessing a given AE 
will provide a thorough description of the event in the participant’s CRF and the AE will be followed up at 
each visit (or more frequently if needed) until it has completely resolved or until 30 days from the 
participant’s last study visit. The study physician will specifically report on start date, stop date, severity, 
relationship, expectedness, outcome, and duration, as well as whether or not the AE meets criteria for a 
SAE. AE’s will be coded based upon Medical Dictionary for Regulatory Activities (MedDRA) criteria, coded 
only once per participant (e.g. should a participant have a headache at each visit only a single headache 
AE will be coded), and compiled continuously for DSMB and progress reports. AE’s will specifically be 
presented in table format based on System Organ Class, and grouped based on severity, relationship, and 
expectedness. Adverse events leading to premature discontinuation from the study intervention and 
serious intervention-emergent AE’s, should they occur, will be presented separately in regulatory reports 
and final publications in table format. Once data lock and unblinding has occurred, safety data will be 
compared between active and sham aiTBS using chi-squared tests (or Fisher's exact test if indicated). 
 
9.4.5  
BASELINE DESCRIPTIVE STATISTICS 
 
Demographic data will be summarized for sham and active intervention groups separately using standard 
descriptive statistics. For continuous measures (i.e. age and years of education), means and standard 
deviations will be calculated, and any group differences will be identified using univariate ANOVAs. 
Categorical measures (i.e. sex and race/ethnicity) will be quantified by counts and percentages, and any 
group differences will be detected using Chi-squared tests. Characteristics that display imbalance at the 
baseline measure or an association with the dependent variable will be assessed for inclusion as covariates 
in the final models. 
 
9.4.6  
PLANNED INTERIM ANALYSES  
 
Because of the anticipated low level of adverse events of aiTBS given our recently completed smaller RCT, 
interim analysis of data, protocol and  adverse events is not anticipated to be necessary.  Serious adverse 
events will be reviewed on a monthly basis, unless a more urgent review is requested. As described in 
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due to aiTBS, would the PD be charged with breaking the study mask. This study will be stopped prior to 
its completion if: [1] the intervention is associated with adverse effects that call into question the safety 
of the intervention; [2] difficulty in study recruitment or retention will significantly impact the ability to 
evaluate the study endpoints; [3] any new information becomes available during the study that 
necessitates stopping the study; or [4] other situations occur that might warrant stopping the study. 
 
 
9.4.7  
SUB-GROUP ANALYSES 
We are recruiting 100 participants of all gender, ethnic, and racial backgrounds. We will assess the role of 
gender in our analyses to determine the potential utility of additional follow-up projects that focus on any 
discovered gender-based observations. However, it may not be feasible to run sub-group analyses in this 
study because of potentially insufficient sub-group sample sizes. 
9.4.8  
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
All participant data will be directly exported from REDCap. The exported data will be listed in a long 
format, such that each row (i.e. observation) represents a specific time point for each subject. The 
individual variables collected will be represented by columns (i.e. measures). For reproducibility, data will 
be exported and tabulated using either the R or Python programming language. 
 
9.4.9  
EXPLORATORY ANALYSES 
Two additional analyses will be applied to exploring the intervention effect-related FC features in the 
whole brain: the brain networks’ organization and the multivariate FC patterns. 
The brain is thought to organize in the way that brain regions could work together to maximize the ability 
to respond to cognitive demands while minimizing the wiring cost. Accordingly, brain regions are found 
to be closely correlated within brain networks, but for the regions across brain networks the correlations 
are relatively weaker or even anti-correlated213. We will calculate brain network segregation214 to explore 
the relationship between the organization of brain networks and intervention effect. We will use Power’s 
parcellation215 and extract data from: somatosensory-motor, default-mode, frontoparietal, ventral 
attention, dorsal attention, cinguloopercular and salience networks. In order to calculate the brain 
network segregation, the mean within network correlation (Rwithin) will be calculated by averaging the 
FCs for regions within each network, and the mean between network (Rbetween) correlation will be 
calculated by averaging the FCs for regions from two different networks. Only positive correlations will be 
used in these calculations. And then the brain network segregation (BNS) will be calculated as: (Rwithin - 
Rbetween) / Rwithin 216. BNS will then be compared between baseline and post-intervention to find the 
intervention related BNS, and then the group differences will also be tested. Linear regression models will 
be used to test the relationship between BNS and both depression scores and acute mood states. 
We also will use TDA-based Mapper analysis (Saggar et al 2018; 2022) to investigate how brain state 
transitions (at rest) evolve in patients with depression undergoing accelerated iTBS intervention. By 
constructing high-dimensional manifolds of neuroimaging data and visualizing their topological structures 
as graphs, we aim to identify patterns of brain state changes associated with treatment. Additionally, we 

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will characterize the dose-response relationship of iTBS by analyzing how dosage (over the course of 
treatment) influences these state transitions, providing insights into individualized treatment 
optimization. 
To understand the physiological mechanisms underlying the stimulation effects, we will employ the 
reduced Wong-Wang (RWW) neural mass model to simulate whole-brain dynamics. This modeling 
approach will complement our empirical analyses by providing mechanistic insights into how aiTBS 
influences brain network dynamics. The RWW model will be implemented by modeling each brain region 
as a neural mass unit described by the RWW equations. Structural connectivity data from diffusion MRI 
will inform the coupling between regions, and model parameters will be calibrated using resting-state 
fMRI data from baseline measurements. Stimulation effects will be modeled as external input to the 
targeted regions, with both direct stimulation effects and network-wide propagation being simulated. 
statistical analysis of model outputs will be compared with empirical fMRI data using Pearson correlation 
between simulated and observed functional connectivity patterns, root mean square error between 
model predictions and actual measurements, and analysis of dynamic functional connectivity states and 
their temporal evolution. For parameter optimization, we will employ Bayesian optimization to identify 
model parameters that best reproduce the observed changes in sgACC-DMN connectivity, network-wide 
reorganization patterns, and individual variation in treatment response. This approach will allow us to 
systematically explore the parameter space while accounting for the complex interactions between 
different model components. A crucial component of our analysis will focus on evaluating changes in 
model parameters, particularly the excitation/inhibition (E/I) balance across brain regions. We will 
quantify how aiTBS modulates the E/I balance by analyzing changes in local coupling parameters and 
synaptic gains before and after intervention. Statistical comparisons of these parameters between active 
and sham conditions will be performed using mixed-effects models with appropriate corrections for 
multiple comparisons. Additionally, we will examine the relationship between E/I balance changes and 
clinical outcomes to identify potential biomarkers of treatment response. 
This modeling framework will provide insights into the causal chain from stimulation to observed clinical 
effects, individual variation in treatment response, and optimal stimulation parameters for maximizing 
therapeutic impact. The analysis will integrate with our primary and secondary endpoints by providing 
mechanistic explanations for observed changes in functional connectivity and clinical outcomes, while 
offering a deeper understanding of how aiTBS modulates neural dynamics through changes in local circuit 
properties and E/I balance. 
10.  
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1  
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1  
INFORMED CONSENT PROCESS 
 
 

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10.1.1.1  CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. The following consent materials are submitted with this 
protocol: 
 
Two signed consent forms will be obtained from each participant: (1) Screening consent form and (2) 
Study consent form. These consent forms will be administered electronically using Adobe Sign.  
 
10.1.1.2  CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be IRB-approved and 
the participant will be asked to read and review the document. The study investigator or his designee will 
explain the research study to the participant and answer any questions that may arise in a private setting. 
A verbal explanation will be provided in English of the purposes, procedures, and potential risks of the 
study and of their rights as research participants. Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. Participants will be informed that 
participation is voluntary and that they may withdraw from the study at any time, without prejudice. A 
copy of the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the date), and the 
form signed, before the participant undergoes any study-specific procedures. The rights and welfare of 
the participants will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in this study. 
Consenting Processes: There will be two consent forms: one consent for screening procedures, and the 
other for study and enrollment procedures. For the first consent process, the clinical research coordinator 
(CRC) will screen the participant’s eligibility for enrollment in the study. The study PD or psychiatrist or 
their designee will consent the participants for the second phase of the consenting process, which involves 
discussing the risks of the rTMS procedure and MRI scanning. The participant will be consented in the 
sequence that has been defined by our protocol. 
Education and Informed Consent Process: Consent forms will be Institutional Review Board (IRB)-
approved, and the participant will be asked to read and review the document. The participant will sign 
the informed consent document prior to any procedures being done specifically for the study. The 
signature will be electronically obtained as described above. The consent process will start with an 
introductory paragraph that describes the study. This statement will be followed by a description of the 
purpose of the research. The participant will be informed that this is a double blind study and they have 
a 50% chance of receiving active stimulation and that their participation is voluntary. Next, the duration 
of study involvement and the procedures involved will be described.  
The participant will be notified of the discomforts and risks along with the potential benefits. The 
participant will receive a Statement of Confidentiality. The participant will be notified as to the costs for 
participation (none) as well as the compensation for participation. The participant will be made aware of 
the research funding source. The participant will be given information regarding the fact that their 
participation is voluntary. The rights and welfare of the participants will be protected by emphasizing to 

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them that the quality of their medical care will not be adversely affected if they decline to participate in 
this study. The participant will be made aware of their  alternative options. The participant will then be 
given the contact information for questions or concerns. The participant will have the opportunity to 
carefully review the written consent form and ask questions prior to signing. The participants will have 
the opportunity to discuss the study with their family or surrogates or think about it prior to agreeing to 
participate. The participant will sign the informed consent document prior to any procedures being done 
specifically for the study. All participants will be provided a copy of their signed consent forms. 
Finally, after reading the experimental subjects’ bill of rights, the participant will be asked for their 
signature in order to consent and give permission to be in the research study. To ensure the participant 
has capacity to consent, as part of this process the study psychiatrist or their designee will complete a 
Capacity to Consent form. 
Plan for Review of Consent Document: The signed consent document will be confirmed by the PD,  study 
psychiatrist, or their designee (which includes regulatory staff). 
Documentation of Signed Consent: The  screening and enrollment logs will be utilized to record the 
consent and screening of all subjects and the outcome of each screening. These logs will provide a 
comprehensive list of all subjects who were screened for eligibility and all participants who enrolled into 
the study. This information will be maintained inREDCap. All subjects who were consented and screened 
on site will be included in these logs, including screen failures.   
10.1.2  
STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, and funding agency.  If the 
study is prematurely terminated or suspended, the Protocol Director (PD) will promptly inform study 
participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the 
termination or suspension. Study participants will be contacted, as applicable, and be informed of changes 
to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
● Determination of unexpected, significant, or unacceptable risk to participants 
● Insufficient compliance to protocol requirements 
● Data that are not sufficiently complete and/or evaluable 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3  
CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their interventions. This confidentiality is extended to cover clinical information 
relating to participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the PI and/or sponsor.  
 

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All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), or regulatory agencies may inspect all documents and records required to be 
maintained by the investigator, as specified and approved by Stanford’s IRB.  
 
The study participant’s contact information will be securely stored at the clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be securely transmitted to and stored within either Stanford REDCap or Stanford Medicine Box. This will 
not include the participant’s contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data entry and study 
data management systems used by Stanford research staff will be secured and password protected. At 
the end of the study, all study data will be archived on either Stanford REDCap or Stanford Medicine Box. 
 
Certificate of Confidentiality 
 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
National Institutes of Health (NIH).  This certificate protects identifiable research information from forced 
disclosure. It allows the investigator and others who have access to research records to refuse to disclose 
identifying information on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and institutions from 
being compelled to disclose information that would identify research participants, Certificates of 
Confidentiality help achieve the research objectives and promote participation in studies by helping 
assure confidentiality and privacy to participants. 
 
Information about study subjects 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 subject authorization informing the subject of the following: 
● What protected health information (PHI) will be collected from subjects in this study  
● Who will have access to that information and why 
● Who will use or disclose that information  
● The rights of a research subject to revoke their authorization for use of their PHI. 
  
In the event that a subject revokes authorization to collect or use PHI, the Protocol Director, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization. For 
subjects who 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 subject is alive) at the end of 
their scheduled study period. Subject confidentiality is strictly held in trust by the investigators and the 
study staff.  This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to any study information relating to subjects. 
  

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The study protocol, documentation, data, and all other information generated will be held in strict 
confidence.  No information concerning the study, or the data will be released to any unauthorized third 
party without prior written approval of the Protocol Director. 
 
Any data, specimens, forms, reports, and other records that leave the Stanford study site will be identified 
only by a participant identification number (Participant ID, PID) to maintain confidentiality. All records will 
be kept in a locked file cabinet. All computer entry and networking programs will be done using PIDs only. 
Information will not be released without written permission of the participant, except as necessary for 
monitoring by the IRB and OHRP. 
 
10.1.4  
FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be stored and analyzed on Flywheel, a  fully HIPAA and GDPR compliant 
platform for medical images. Permission to transmit data to Flywheel will be included in the informed 
consent, and imaging data will be automatically uploaded to the platform after acquisition. Only lab 
members with 2-factor authentication will have access privileges. After the study is completed, the de-
identified  data will continue to be stored on Flywheel in perpetuity for potential use by other researchers, 
including those outside of the study.  
 
When the study is completed, access to study data will be provided through the Flywheel Medical Imaging 
Platform and Data Repository. Or alternatively the data can be exported and shared in an encrypted 
format to be shared. 
 
10.1.5  
KEY ROLES AND STUDY GOVERNANCE 
 
Principal 
Investigator 
Protocol 
Director 
Study Psychiatrists 
Study Psychologist 
Neuro-Imaging 
Lead 
Nolan 
Williams, MD 
David 
Spiegel, MD 
Greg Sahlem, MD and  
Ian Kratter, MD, PhD 
Thomas Knightly, MD 
Chris Austelle, M 
Bora Kim, MD 
Flint Espil, PhD 
Manish Saggar, 
PhD 
Stanford 
University 
Stanford 
University 
Stanford University  
Stanford University 
Stanford 
University 
401 Quarry 
Road 
Mail Code 
5719 
Stanford, CA 
94305 
401 Quarry 
Road 
Mail Code 
5719 
Stanford, CA 
94305 
401 Quarry Road 
Mail Code 5723 
Stanford, CA 94305 
401 Quarry Road 
Mail Code 5719 
Stanford, CA 94305 
401 Quarry Road 
Mail Code 5719 
Stanford, CA 
94305 
nolanw@stan
ford.edu 
dspiegel@sta
nford.edu 
gsahlem@stanford.edu 
ikratter@stanford.edu 
thomas.knightly@stanfo
rd.edu 
espil@stanford.edu 
saggar@stanford.
edu 

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austelle@stanford.edu 
borakim2@stanford.edu 
 
 
 
 
 
10.1.6  
SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) composed of 
individuals with the appropriate expertise in study relevant subjects including treatment-resistant 
depression, TMS, and statistics. Members of the DSMB should be independent from the study conduct 
and free of conflict of interest, or measures should be in place to minimize perceived conflict of interest.  
The DSMB will meet at least biannually to assess safety and efficacy data on each arm of the study. The 
DSMB will operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to assess will 
be clearly defined. The DSMB will provide its input to NIMH. 
 
There are three DSMB members:  
 
1. Charles Nemeroff: Dr. Charles Nemeroff is Chair and Professor with the Department of Psychiatry 
and Behavioral Sciences at Dell Medical School at the University of Texas at Austin. He also directs 
the Institute for Early Life Adversity Research within the Department of Psychiatry and Behavioral 
Sciences as part of the Mulva Clinic for the Neurosciences. Prior to joining Dell Med, Dr. Nemeroff 
was chair of the Department of Psychiatry and Behavioral Sciences and clinical director of the 
Center on Aging at the University of Miami Miller School of Medicine in Miami, Florida. He 
received his medical degree and doctorate degrees in neurobiology from the University of North 
Carolina (UNC) School of Medicine. After psychiatry residency training at UNC and Duke 
University, he held faculty positions at Duke University Medical Center and at Emory University 
School of Medicine before relocating to the University of Miami in 2009. He has served as 
president of the American College of Psychiatrists (ACP) and the American College of 
Neuropsychopharmacology (ACNP), and he sits on the Scientific Advisory Board and board of 
directors of the American Foundation for Suicide Prevention (AFSP) and the Anxiety and 
Depression Association of America (ADAA). 
 
2. Ian Cook: Dr. Ian Cook holds the Joanne and George Miller and Family Endowed Chair in 
Depression Research and is a Professor of Psychiatry and Biobehavioral Sciences at the David 
Geffen School of Medicine and a Research Scientist at the Semel Institute for Neuroscience and 
Human Behavior. Dr. Cook received his Bachelor’s degree with high honors from Princeton 
University and his medical degree from the Yale University School of Medicine. He completed his 
psychiatry residency training at UCLA's Neuropsychiatric Institute, where he also was an NIMH-
funded research fellow. Dr. Cook served on the Executive Committee on Practice Guidelines of 
the American Psychiatric Association, and he guided the electronic dissemination of their 
evidence-based guidelines in psychiatry.  
 
3. Rita Popat: Dr. Popat is a Clinical Associate Professor in the Department of Epidemiology and 
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Parkinson's disease and amyotrophic lateral sclerosis, specifically evaluating the genetic and 
environmental contributions to these neurodegenerative disorders. She is also interested in 
studying the relation of cognition, estradiol exposure (endogenous and exogenous), and genetic 
factors. At Stanford she additionally co-directs the MS program in Clinical Research & 
Epidemiology and is a member of the steering committee for the Stanford Medicine Teaching and 
Mentoring Academy.  
 
10.1.7  
CLINICAL MONITORING 
 
Safety oversight of this study will be under the direction of a Data and Safety Monitoring Board (DSMB), 
as detailed in section 10.1.6. Dr. David Spiegel will serve as the study medical monitor. We will hold 
internal weekly meetings to review significant changes study recruitment, enrollment numbers,  AE/SAEs, 
and overall study progress. All participant safety data will be captured in eCRFs. Study psychiatrists will 
review participant eCRFs periodically to ensure adequate clinical monitoring. 
 
 
10.1.8  
QUALITY ASSURANCE AND QUALITY CONTROL 
 
We will perform internal quality management of study conduct, data collection, documentation and 
completion, per Quality Management SOP.. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical study is 
conducted and data are generated and biological specimens are collected, documented (recorded), and 
reported in compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related source data/documents and reports 
for the purpose of monitoring and auditing by the sponsor and inspection by local and regulatory 
authorities. 
 
Staff Training:  
● rTMS Training: Every TMS operator on this study will be trained in basic knowledge of 
brain physiology, basic mechanisms of TMS, the potential risks of the rTMS procedure, 
and the physiological changes induced by rTMS182. All trainings will be led by the PD, study 
psychiatrists, or trained TMS operator.  This training will be stored in REDCap. In order to 
operate the rTMS device, all operators must have approval from a trained TMS operator.  
 
● MT Training: The PD, study psychiatrists, or trained TMS operator will train all TMS 
operators and relevant study personnel to acquire proper motor thresholds for TMS 
intervention via visual observation and neuronavigated mapping combined with an 
automated threshold-quantification technique named PEST (Parameter Estimation by 
Sequential Testing). Training will include determination of MT via visual observation and 
neuronavigated mapping combined with the PEST technique. In order to acquire MT using 
the TMS coil, all operators must have approval from a trained and certified TMS operator.     
 

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● MRI Scanning: Study personnel who perform MRI scanning will have to receive 
appropriate MRI training from the Stanford Center for Neurobiological Imaging (CNI) in 
accordance with their protocols (https://cni.stanford.edu/wiki/MR_Protocols), as all MRI 
scans will be conducted in their facility.  
 
Ongoing quality control will include regular data verification and protocol compliance checks to be 
performed by the senior research staff and the research team (designated study staff). An ongoing review 
of study procedures will be done to ensure that the privacy of participants and confidentiality of data are 
not violated. There will also be adequate provisions for monitoring the collected data to ensure the safety 
of participants and to maintain the confidentiality of the research data. The CRC will be responsible for 
addressing quality assurance issues (correcting procedures that are not in compliance with protocol) and 
quality control issues (correcting errors in data entry). 
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, subjects’ 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, subject 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. 
Following written standard operating procedures, this monitor will verify that this clinical study is 
conducted, and data are generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements. 
10.1.9  
DATA HANDLING AND RECORD KEEPING  
 
 
10.1.9.1  DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical study staff at the site under the supervision of the site 
investigator. A dedicated data manager will oversee the collection and organization of study data, and the 
investigator will ensure the accuracy, completeness, legibility, and timeliness of the data reported. 
All study data, except for medical images, blood specimens, and select consent forms, will be stored in an 
electronic data capture (EDC) system called REDCap.  Study data stored on REDCap will include CRFs as 
well additional clinical data such as adverse events (AEs), current medications, TMS session parameters.  
Medical images will be stored on Flywheel (see section 10.1.4). Documentation of the blood draws will be 
extracted from EPIC and will be filed accordingly in REDCap. 
To ensure the protection and confidentiality of patient information, we will have two REDCap databases. 
One database will contain any PHI collected during the study and will be accessible to only the PD, the lab 
data manager, and the clinical coordinators collecting and entering this data. A separate database will 
contain all non-PHI data collected during the study. Subjects in this database will be identified using only 
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Edit checks, electronic queries, and audit trails are built into REDCap to ensure accurate and complete 
data collection and security.  In addition, pdf copies of the case files will be created for each subject where 
completed CRFs will be securely stored..  
The REDCap database will be centralized on a dedicated file server located on a secure rack in the Stanford 
University Forsythe Hall data center. The data center is maintained by Stanford University IT Services and 
includes secured entry, 24/7 monitoring, environmental control systems, fire detection and suppression, 
and an Uninterruptible Power Supply (UPS) for protection against power anomalies. A Backup and 
Recovery Service (BaRS) is available. The file server is only accessible through the Stanford University 
network (SUNET), however off campus access to the file server through SUNET is sometimes necessary 
and a secure connection is available through the Stanford Virtual Private Network (VPN) service. This file 
server has been utilized in the past to store databases for previous studies and also used the VPN service 
without incident. All raw data forms received will be promptly stamped, entered or scanned, and filed in 
a locked filing cabinet. No information will be released to persons other than the patient without 
permission. Confidentiality is assured. Results of all studies are published in a manner that does not reveal 
the identity of individual subjects. 
The database and web servers will be secured through controlled physical access. For security reasons, 
and in compliance with regulatory guidelines, remote access to the EDC system is only granted to users 
who complete 2-factor authentication by providing a correct username and password as well as confirm 
their identity using a physical device. Access codes are non-transferrable. Personnel who have not 
undergone training will not access the study eCRF until appropriate training is completed and 
documented. The eCRF data elements do not reside on the user’s workstation; they are securely 
transmitted to a database as forms are completed or updated. Protocol-specified source documents (e.g. 
hospital discharge summaries, operative/procedural reports) will be retrieved as necessary. Copies of all 
study-related documentation will be retained within the central laboratory. Case files will be located in a 
secured area at the study site. All completed CRFs will be de-identified and subjects will be referred to 
using only their assigned study subject identifier and initials. Information stored in the source documents 
will be safeguarded according to institutional guidelines. 
Access to the database will be restricted and only the database manager can view and update the 
complete database. Research assistants will be able to modify parts of the database to enter data or 
make necessary corrections to the data. Access to specific parts of the database can be granted to other 
project members with permission obtained through the Protocol Director. All personnel will be required 
to successfully complete HIPAA and CITI group 7 training. Access to the database on the file server is 
monitored and controlled through SUNET and separate SUNET IDs and passwords are required. Secure 
email alternatives will be used to safely communicate information or send data between project 
members. Stanford IT Services provides a Secure Email service, which is very easy and seamless to use. 
To achieve email encryption, only the word “SECURE:'' needs to be added to the subject line in an email 
message. Stanford School of Medicine Information Resources and Technology (IRT) group also provides 
MedSecureSend (MSS) service for large files up to 20GB. Secure Email is only available to project 
members and collaborators with SUNET IDs. For collaborators outside of campus, a MedSecureSend 
email message can include an option to invite a recipient to create a MedSecure account before the 
content of the email can be opened or read. 
 
Participants who agree to have their blood drawn will have their blood spun down, and the plasma will 
be aliquoted and stored in a -80 degree Celsius freezer. Labels will have no personal identifiers. A 
portion of these plasma samples may be shipped on dry ice to our collaborators at New York University 
and/or University of Antwerp. The remaining portion will be stored at Stanford. Buffy coat will also be 

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collected and stored at Stanford. Some or all of these samples may be sent outside of Stanford for 
analysis. 
 
10.1.9.2  STUDY RECORDS RETENTION  
 
In accordance with NIH grant policy, all electronic and paper records for this study will be maintained for 
at least three years from when the annual Federal Financial Report (FFR) is submitted to the NIH. 
Permission to destroy any records after this time is at the discretion of the principal investigator and the 
department or laboratory. 
 
10.1.10  PROTOCOL DEVIATIONS  
 
A protocol deviation is defined as any noncompliance with the clinical study protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) 
requirements. In general protocol deviations are not allowed, except as stipulated below. We will 
continually monitor for instances of protocol deviation. Should a deviation occur we will record the 
deviation in a pre-designated subject-specific Protocol Deviation CRF and report the reason and nature of 
the deviation to both the Stanford IRB and the Data Safety Monitoring Board (DSMB)  responsible for this 
study. All documentation will be reported depending on the type of deviation (see below for time-frames 
of reporting). Protocol deviations that constitute unanticipated problems involving risks will be promptly 
reported to the Stanford IRB. 
A protocol deviation that constitutes an unanticipated problem involving risks to subjects or to others will 
be reported promptly to the IRB, as follows:  
1. Emergency deviations:  When a deviation occurs in an emergency situation, such as when a deviation 
from the protocol is required to protect the life or physical well-being of a participant.  The Stanford IRB 
will be notified as soon as possible and no later than 10 days after the PD has been informed of the 
emergency situation. The PD or his designee will submit a report to the Stanford IRB.  
2. Major, non-emergent deviations without prior approval:  A planned deviation that is non-emergent and 
represents a major change in the protocol as approved by the Stanford IRB. The Stanford IRB must approve 
the request before the proposed change is implemented.  The PD or co-investigators must submit non-
emergent deviations to the IRB for review. If a major, non-emergent deviation occurs without prior IRB 
approval the event is considered non-compliance. Non-compliance will be reported to the IRB promptly. 
The PD or co-investigator’s failure to report promptly any major, non-emergent deviation for which the 
PD did not obtain prior approval is itself an incident of non-compliance. 
  
3. Protocol deviations that are only minor or administrative: At Stanford, minor or administrative protocol 
deviations are defined as those, which do not affect the scientific soundness of the research plan or the 
rights, safety, or welfare of human subjects. If a protocol deviation occurs which meets this definition, the 
deviation will be reported to the Stanford IRB at the time the continuing review application is submitted. 
Examples of minor or administrative deviations could include: follow up visits that occurred outside the 
protocol required time frame because of the participant’s schedule, or blood samples obtained at times 
close to but not precisely at the time points specified in the protocol. 
 
The above practices are consistent with ICH GCP:  
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
5.1 Quality Assurance and Quality Control, section 5.1.1  

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5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
10.1.11  PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this study will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals.  Data from this study may be requested from other researchers 5 years after the completion of 
the primary endpoint by contacting  the PI.  
 
We will adhere to the NIH Grants Policy on Availability of Research Results: Publications, Intellectual 
Property Rights, and Sharing Biomedical Research Resources. Specifically, transfers of research materials 
out of the laboratory to other researchers will be made under terms no more restrictive than in the Simple 
Letter Agreement for the Transfer of Materials or the Uniform Biological Materials Transfer Agreement 
(UBMTA) and made without reach-through requirements. Should any intellectual property arise that may 
be patentable, Stanford will ensure that the related technology (materials and final research data) remains 
widely available in a timely fashion to the research community in compliance with policies and regulations 
governing research awards from the NIH. 
 
After the outcome data have been published, the data will be made available to individuals or institutions 
who have received IRB approval to conduct secondary data analyses on the dataset. The final dataset will 
include data on mood, effects of psychological and neuromodulatory intervention on mood and fMRI 
neuroimaging of regional brain activity, functional connectivity, and structure. 
 
Thus, we will make the data and associated documentation available to users only under a data sharing 
agreement that provides for: (1) a commitment to using the data only for research purposes and not to 
identify any individual participant; (2) a commitment to securing the data using appropriate computer 
protection technology; and (3) a commitment to destroying or returning the data after analyses are 
completed. The datasets will be put on a computer disk (CD) that is encrypted. Once verification of IRB 
approval is obtained, we will send the encryption code and CD in separate mailings to the investigator(s). 
All storage and sharing of data will be in accordance with Stanford IRB policy and approval, and HIPAA 
guidelines. By requesting IRB approval, we will be able to track recipients of the data, the type of data 
analyses proposed, and subsequent research findings. This data will be compiled in our database and may 
be of interest to NIH as well as lend itself to subsequent secondary data analyses that are important to 
the fields of emotion regulation, CNS neurophysiology, fMRI, and depression treatment. 
 
10.1.12  CONFLICT OF INTEREST POLICY 
 

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The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this study will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 
that is appropriate to their participation in the design and conduct of this study.  The study leadership in 
conjunction with the NIMH has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
 
10.2  
ADDITIONAL CONSIDERATIONS 
 
N/A 
 
10.3  
ABBREVIATIONS 
 
ACC 
Anterior Cingulate Cortex 
AE 
Adverse Event 
aiTBS 
Accelerated Intermittent Theta-Burst Stimulation 
ATHF 
Antidepressant Treatment History Form 
BaRS 
Backup Recovery Service 
BNS 
Brain Network Segregation 
BPD 
Borderline Personality Disorder 
BOLD 
Blood-oxygen-level-dependent 
CAC 
Clinical assessment committee 
CEN 
Central Executive Network 
CFR 
Code of Federal Regulations 
CITI 
Collaborative Institutional Training Initiative 
CNI 
Stanford Center for Cognitive and Neurobiological Imaging 
CNS 
Central Nervous System 
COVID-19 
Coronavirus Disease 2019 
CRC 
Clinical Research Coordinator 
CRF 
Case Report Form 
cTBS 
Continuous Theta Burst Stimulation 

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CTQ 
Childhood Trauma Questionnaire 
DMN 
Default Mode Network 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders- version 5 
EC 
Ethics Committee or Effective Connectivity 
ECG 
Electrocardiography 
ER 
Emotion Regulation 
eCRF 
Electronic Case Report Form 
ECT 
Electroconvulsive Therapy 
EDC 
Electronic Data Capture 
EDTA 
ethylenediaminetetraacetic acid 
eIRB 
Electronic IRB 
FC 
Functional Connectivity 
fcMRI 
Functional Connectivity Magnetic Resonance Imaging 
FDA 
Food and Drug Administration 
FIGS 
Family Interview for Genetic Studies 
fMRI 
Functional Magnetic Resonance Imaging 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
IC 
Institute or Centre 
ID 
Identification 
IDE 
Investigational Device Exemption 
IEAE 
Intervention-emergent AE 
IMC 
Independent Monitoring Committee 
IMS 
Immediate Mood Scaler 
IND 
Investigational New Drug 
IQ 
Intelligence Quotient  
IRB 
Institutional Review Board 

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IRT 
Resources and Technology group 
ISI 
Intersession Interval 
ISTS 
International Society for Transcranial Stimulation 
iTBS 
Intermittent Theta-Burst Stimulation 
ITT 
Intent to Treat 
LAC 
Acetyl-L-carnitine 
L-DLPFC 
Left Dorsolateral Prefrontal Cortex 
LTD 
Long-term Depression 
LTP 
Long-term Potentiation 
MADRS-CR 
Montgomery-Asberg Depression Rating Scale-clinician rated 
MADRS-S 
Montgomery-Asberg Depression Rating Scale- Self Report 
MC 
Motor Cortex 
MDD 
Major Depressive Disorder 
MI 
Myocardial Infarction 
MINI 
MINI International Neuropsychiatric Interview 
MRI 
Magnetic Resonance Imaging 
MSM 
Maudsley Staging Method 
MSSI 
Modified Scale for Suicidal Ideation 
MSS 
MedSendSecure 
MT 
Motor Threshold 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NHC 
Normal Healthy Control 
NSR 
Nonsignificant Risk 
OHRP 
Office for Human Research Protections 
PD 
Protocol Director 
PEST 
Parameter Estimation by Sequential Testing 

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PHI 
Protected Health INformation 
PI 
Principal Investigator 
PID 
Participant identification number 
QC 
Quality Control 
REDCap 
Research Electronic Data Capture 
rMT 
Resting Motor Threshold 
RS 
Resting-State 
RS FC 
Resting-State Functional Connectivity 
rTMS 
Repetitive Transcranial Magnetic Stimulation 
SAE 
Serious Adverse Event 
SCC 
Subcallosal Cingulate 
SCID 
Structured Clinical Interview for DSM-5 
sgACC 
Subgenual Anterior Cingulate Cortex 
SoA 
Schedule of Activities 
SN 
Salience Network 
SUNet 
Stanford University Network 
TASS 
TMS Safety form 
TBS 
Theta-Burst Stimulation 
TMS 
Transcranial Magnetic Stimulation 
TRD 
Treatment Resistant Depression 
UPS 
Uninterruptible Power Supply 
UP 
Unanticipated Problem 
US 
United States 
vlPFC 
Ventrolateral Prefrontal Cortex 
VPN 
Virtual Private Network 
YMRS 
Young Mania Rating Scale 
 
 
 

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10.4  
PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.1 
11JAN2021 
- 
changed 'SAINT' to 'aiTBS' 
- 
addition of severe BPD as 
an exclusion criterion 
- 
addition of BPD diagnostic 
module (if indicated) to 
screening visit 
- 
update to statistical design 
to include random blocks of 
2, 4, 6  
- 
update of personnel 
- 
addition of data quality 
check log 
- 
MRI training certification 
process updated 
 
Changes made as per DSMB 
suggestions and clarify study 
workflow. 
2.0 
05OCT2021 
-        Soterix Neuronavigation 
System replaced with Localite 
TMS Navigator 
-        MagPro XP 120V Edition 
replaced with MagPro X100 
-        Standard MADRS-S replaces 
24-hour version of MADRS-S 
for visit 3, baseline, and 1-
month assessments 
-        Clearly state that MSSI will be 
performed at screening and 
then will be included as part 
of a clinical consult with PI or 
study psychiatrist if triggered 
by a score of 3 on item 9 of 
the MADRS-S (‘Zest for life’ 
item) 
-        David Spiegel, MD, added as 
protocol director under ‘Key 
Roles and Study Governance’ 
section. 
-        Two new exclusion criteria 
added related to maximum 
treatment dose and stability 
of symptoms 
-        Justification for newly added 
exclusion criterion related to 
stimulation dose added 
Changes made as per DSMB 
suggestions, study updates, and 
to clarify study workflow 

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-        DSMB to meet at least 
triannually 
-        Motor threshold may be 
checked as part of screening 
visit. 
-        SoA updated to include mSSI 
at screening, baseline, and as 
part of a clinical consult if 
triggered by a score of 3 on 
item 9 of the MADRS-S (‘Zest 
for life’ item) 
-        SoA updated to include PSQI 
at screening and baseline. 
-        Updated language regarding 
use of OTC medications, 
timing of dosing of any 
hypnotic medications, and use 
of any anxiolytic medications. 
-        Updated language on 
definition of a screen failure. 
-        Clarified informed consent 
process 
-        Study responsibilities 
supervised by protocol 
director (PD) 
-        Use of EMG for measurement 
of MT removed 
-        Lidocaine application 
schedule modified 
 
3.0 
04FEB2022 
       
-‘Urine Analysis’ broken into ‘Urine 
Drug Screen’ and ‘Urine Pregnancy 
Test 
- Urine Drug Screen added to Visits 
3-8 
-Addition of C-SSRS to screening 
visit - Update of SOE to include 
FIGS, CTQ, and blood draw if 
participant opts into optional 
substudy 
- Removed minimum HAM-D score 
as an inclusion criterion 
- Changed recent suicide attempt 
exclusion criterion to past one year 
(instead of past 90 days) 
- Modified definition of ‘recent use’ 
of a rapid-acting antidepressant in 
an exclusion criterion 
- Update of lifestyle considerations 
General update 

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to increase accuracy 
- Added clarifying details related to 
the definition of screen failure and 
the process of rescreening. 
- Study responsibilities supervised 
by protocol director (PD) 
- Removed line related to AE follow 
up that is redundant to section 
8.3.1. 
- Addition of a weekly phone call by 
CRC for check in between Visits 8 
and 9 
- Addition of optional blood draw 
and questionnaires added 
- Addition of C-SSRS to screening 
instruments 
- Addition of Adobe Sign for remote 
consent electronic signatures 
- Clarified time period for AE 
assessment. 
- Updated definition of SAE to 
enhance clarity. 
- Removed lines related to SAE 
reporting timeline that are 
redundant to section 8.3.6 
- Removed lines related to 
expected AEs that are redundant to 
section 8.3.3.3 
- Added table (previously in section 
8.3.4) and expanded discussion of 
expected 
- AEs Removed table (moved to 
section 8.3.3.3) 
- Clarified time period of AE 
assessment, time period for 
following of an AE, and AE 
screening process 
- Removed line related to period of 
AE assessment that is redundant to 
section 8.3.4 
- Storage of blood specimens 
specified 
3.0 
25FEB2022 
- 
Optional blood draws 
- 
Adobe Sign Consenting 
- 
Removed HAMD and 
update to eligibility criteria 
and lifestyle considerations 
General update 

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3.1 
20APR2022 
- 
Clarified language and 
timepoints for optional 
blood draws 
- 
Clarified blood specimens 
are not saved in REDCap 
- 
Added specimen 
processing, storage, 
shipping, and labeling 
language 
- 
Added terms to 
abbreviations list 
 
3.2 
09SEP2022 
- 
Allow screening data in 
REDCap to be shared 
between BSL studies 
General update 
3.2 
31MAR2023 
- 
Added Spanish recruitment 
material 
General update 
3.3 
19May2023 
- 
Clarified side effects 
associated with Lidocaine 
and MRIs 
Clarification 
3.3 
19May2023 
- 
Listing of study 
psychiatrists 
Update 
3.4 
30Nov2023 
Removed Box eCRF backup 
language  
Update 
3.4 
30Nov2023 
Added University of Antwerp as a 
collaborator who may receive 
samples. 
Update 
3.4 
30Nov2023 
Updated total blood draw volume 
to 30 mL.  
Update 
3.4 
30Nov2023 
Updates to amendment history 
Update 
3.4 
30Nov2023 
Added a timetable for eligibility 
criteria 
Clarification 
3.4 
30Nov2023 
Removed outdated video language 
Clarification 
 
 
 

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11   
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APPENDICES