Transcranial Near Infrared Radiation and Cerebral Blood Flow in Depression
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: NYU Langone Health

 
 
Official Title: 
Transcranial Near Infrared Radiation and Cerebral Blood Flow in 
Depression (TRIADE)   
NCT Number: 
NCT04366258 
Study Number: 
20-00217 
Document Type:  
Study Protocol and Statistical Analysis Plan 
Date of the 
Document: 
 
• 
November 16, 2021 
 
 

Study number: i20-00217 
 
Page i 
Version: 2.3, 4 NOV 2021 
 
 
 
 
 
 
 
 
 
 
Tool Revision History: 
 
Version Number 
Version Date 
Summary of Revisions Made 
1.0 
12 FEB 2020 
Original version 
1.1 
3 MAR 2020 
IRB edits incorporated 
1.2 
27 MAY 2020 
Insertion of remote activities where possible 
1.3 
22 SEP 2020 
Change of blinding, option to omit thermometry 
1.4 
17 NOV 2020 
Option to omit bloodwork  
2.0 
11 DEC 2020 
Option to modify high dose parameters for tolerability and 
blind preservation. 
2.1 
19 MAR 2021 
Option for neurologist to review scan; change review from all 
scans to one scan per subject. Broaden antidepressant type 
permitted on study from SSRIs and SNRIs to SSRIs, SNRIs, 
and Wellbutrin (bupropion). Change of high dose parameters 
for tolerability and blind preservation. 
2.2 
3 MAY 2021 
Addition of CGI to follow-up visit; addition of neuronavigation 
to MGH imaging protocol during experimental visits 
2.3 
4 NOV 2021 
1. Increase number of study enrollment and screening to 
62 participants; 
2. Addition to study exclusion criteria to exclude 
participants with seizure disorders requiring treatment in 
the last 5 years.  
 
 

Study number: i20-00217 
 
Page ii 
Version: 2.3, 4 NOV 2021 
 
 
TRANSCRANIAL NEAR INFRARED RADIATION AND CEREBRAL BLOOD FLOW IN 
DEPRESION (TRIADE) 
 
Principal Investigator: 
 
Dan Iosifescu, MD, MSc 
Department of Psychiatry 
New York University School of Medicine 
One Park Ave, 8th Floor 
New York, NY 10016 
dan.iosifescu@nyulangone.org 
646-754-5156 
Additional Investigators: 
 
Paolo Cassano, MD, PhD 
Department of Psychiatry 
Massachusetts General Hospital 
1 Bowdoin Sq. 6th Floor 
Boston MA 02114 
Phone: 617-726-6421 
PCASSANO@mgh.harvard.edu 
 
Jacek Dmochowski, Ph.D. 
Department of Biomedical Engineering 
The City College of the City University of New York 
160 Convent Avenue 
Steinman Hall, 460 
New York, NY 10031 
(212) 650-8626  
jdmochowski@ccny.cuny.edu 
 
Eva Petkova, Ph.D. 
Department of Child and Adolescent Psychiatry  
New York University School of Medicine 
Eva.Petkova@nyulangone.org 
 
Katherine A. Collins, MSW, PhD 
Clinical Research Division 
Nathan Kline Institute for Psychiatric Research 
140 Old Orangeburg Rd., Bldg 35 
Orangeburg, NY 10962 
845-398-6580 
Kate.Collins@NKI.rfmh.org 
 
Umit Tural. M.D. 
Nathan Kline Institute for Psychiatric Research 
140 Old Orangeburg Rd., Bldg 35 
Orangeburg, NY 10962 
845-398-6573 
Umit.Tural@nki.rfmh.org 
NYULMC Study Number: 
i20-00217  
Funding Sponsor:  
National Institute of Health 
IND/IDE Number:  
N/A 
Regulatory Sponsor:  
N/A 
Study Product: 
LightForce® EXPi Deep Tissue Laser TherapyTM System, 
Transcranial PhotoBioModulation-1000 (tPBM-2.0) 
Study Product Provider:  
LiteCure 
ClinicalTrials.gov Number     NCT04366258 
 

Study number: i20-00217 
 
Page iii 
Version: 2.3, 4 NOV 2021 
 
 
Statement of Compliance 
 
This study will be conducted in accordance with the Code of Federal Regulations on the Protection of 
Human Subjects (45 CFR Part 46), 21 CFR Parts 50, 56, 312, and 812 as applicable, any other applicable 
US government research regulations, and institutional research policies and procedures. The International 
Conference on Harmonisation (“ICH”) Guideline for Good Clinical Practice (“GCP”) (sometimes referred to 
as “ICH-GCP” or “E6”) will be applied only to the extent that it is compatible with FDA and DHHS regulations. 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the sponsor and documented approval from the Institutional Review Board 
(IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
 

Study number: i20-00217 
 
Page iv 
Version: 2.3, 4 NOV 2021 
 
 
Table of Contents 
 
STATEMENT OF COMPLIANCE ................................................................................................................ III 
LIST OF ABBREVIATIONS........................................................................................................................ VII 
PROTOCOL SUMMARY .............................................................................................................................. 1 
SCHEMATIC OF STUDY DESIGN ............................................................................................................... 2 
1 
KEY ROLES ......................................................................................................................................... 3 
2 
INTRODUCTION, BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................... 4 
2.1 
BACKGROUND INFORMATION AND RELEVANT LITERATURE ................................................................ 4 
2.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL AGENT ............ ERROR! BOOKMARK NOT DEFINED. 
2.3 
PRECLINICAL DATA ........................................................................................................................ 8 
t-PBM Effects on Animal Models of Depression: Multiple pre-clinical studies support the efficacy of t-
PBM, in single or repeated administration, on animal models of depression such as the forced swim 
test24,27,90,98, tail suspension test27,90, mild chronic stress26,28, or the reserpine-induced depression24. 
In several of these studies the antidepressant effects were associated with biological effects related 
to mitochondrial stimulation, such as increased ATP biosynthesis and mitochondrial complex IV 
expression and activity in the prefrontal cortex (PFC)27 and increased hippocampal neurogenesis98.8 
2.4 
CLINICAL DATA TO DATE................................................................................................................. 8 
2.5 
DOSE RATIONALE ........................................................................................................................... 9 
2.6 
RATIONALE .................................................................................................................................. 10 
2.7 
POTENTIAL RISKS & BENEFITS ...................................................................................................... 11 
2.7.1 
Known Potential Risks ........................................................................................................... 11 
2.7.2 
Known Potential Benefits ...................................................................................................... 12 
3 
OBJECTIVES AND PURPOSE ......................................................................................................... 13 
3.1 
PRIMARY OBJECTIVE .................................................................................................................... 13 
3.2 
SECONDARY OBJECTIVE ............................................................................................................... 13 
3.3 
EXPLORATORY OBJECTIVES ......................................................................................................... 13 
3.4 
DESCRIPTION OF STUDY DESIGN .................................................................................................. 13 
3.5 
STUDY ENDPOINTS....................................................................................................................... 13 
3.5.1 
Primary Study Endpoints ....................................................................................................... 13 
3.5.2 
Secondary Study Endpoints .................................................................................................. 13 
3.5.3 
Exploratory Endpoints ........................................................................................................... 13 
4 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................................. 14 
4.1 
INCLUSION AND EXCLUSION CRITERIA ........................................................................................... 14 
4.2 
VULNERABLE SUBJECTS ............................................................................................................... 16 
4.3 
STRATEGIES FOR RECRUITMENT AND RETENTION .......................................................................... 16 
4.4 
DURATION OF STUDY PARTICIPATION ............................................................................................ 19 
4.5 
TOTAL NUMBER OF PARTICIPANTS AND SITES ................................................................................ 19 
4.6 
PARTICIPANT WITHDRAWAL OR TERMINATION ................................................................................ 20 
4.6.1 
Reasons for Withdrawal or Termination ................................................................................ 20 
4.6.2 
Handling of Participant Withdrawals or Termination ............................................................. 20 
4.7 
PREMATURE TERMINATION OR SUSPENSION OF STUDY .................................................................. 21 
5 
STUDY AGENT (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE ETC.) AND/OR PROCEDURAL 
INTERVENTION ......................................................................................................................................... 21 
5.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .............................................................................. 21 
5.1.1 
Acquisition ............................................................................................................................. 23 
5.1.2 
Product Storage and Stability ................................................................................................ 23 
5.1.3 
Dosing and Administration .................................................................................................... 23 
5.1.4 
Duration of Therapy ............................................................................................................... 23 
5.1.5 
Device Specific Considerations ............................................... Error! Bookmark not defined. 

Study number: i20-00217 
 
Page v 
Version: 2.3, 4 NOV 2021 
 
 
5.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ............................................................................. 23 
6 
STUDY PROCEDURES AND SCHEDULE ....................................................................................... 23 
6.1 
STUDY PROCEDURES/EVALUATIONS ............................................................................................. 23 
6.1.1 
Study Specific Procedures versus Standard Clinical Care ................................................... 23 
6.2 
STUDY SCHEDULE ........................................................................................................................ 23 
6.2.1 
Screening Phase ................................................................................................................... 23 
6.2.2 
Clinical Laboratory Evaluations ............................................................................................. 24 
6.2.3 
Experimental Phase .............................................................................................................. 24 
6.2.4 
Follow-up Phase .................................................................................................................... 25 
6.2.5 
Withdrawal/Early Termination Visit........................................................................................ 26 
6.2.6 
Unscheduled Visit .................................................................................................................. 26 
6.3 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................................... 26 
6.4 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES ........................................................ 26 
6.5 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................... 26 
6.6 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ............................................................. 26 
6.7 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE ........................................................ 26 
7 
ASSESSMENT OF SAFETY ............................................................................................................. 26 
7.1 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 26 
7.1.1 
Definition of Adverse Events (AE) ......................................................................................... 26 
7.1.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 27 
7.1.3 
Definition of Unanticipated Problems (UP) ............................................................................ 27 
7.2 
CLASSIFICATION OF AN ADVERSE EVENT ....................................................................................... 27 
7.2.1 
Severity of Event ................................................................................................................... 27 
7.2.2 
Relationship to Study Agent .................................................................................................. 28 
7.2.3 
Expectedness ........................................................................................................................ 28 
7.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................................... 28 
7.4 
REPORTING PROCEDURES – NOTIFYING THE IRB .......................................................................... 29 
7.4.1 
Adverse Event Reporting ...................................................................................................... 29 
7.4.2 
Serious Adverse Event Reporting ......................................................................................... 29 
7.4.3 
Unanticipated Problem Reporting ......................................................................................... 30 
7.4.4 
Reporting of Pregnancy ......................................................................................................... 30 
7.5 
REPORTING PROCEDURES – NOTIFYING THE STUDY SPONSOR ...................................................... 30 
7.6 
PARTICIPATING INVESTIGATORS .................................................................................................... 31 
7.7 
STUDY HALTING RULES ................................................................................................................ 31 
7.8 
SAFETY OVERSIGHT ..................................................................................................................... 31 
8 
CLINICAL MONITORING .................................................................................................................. 33 
9 
STATISTICAL CONSIDERATIONS .................................................................................................. 33 
9.1 
STATISTICAL HYPOTHESES ........................................................................................................... 33 
9.2 
ANALYSIS DATASETS .................................................................................................................... 33 
9.3 
DESCRIPTION OF STATISTICAL METHODS ...................................................................................... 33 
9.3.1 
General Approach ................................................................................................................. 33 
9.3.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................................ 34 
9.3.3 
Analysis of the Secondary Endpoint(s) ................................................................................. 34 
9.3.4 
Safety Analyses ..................................................................................................................... 34 
9.3.5 
Exploratory Analyses ............................................................................................................. 34 
9.4 
SAMPLE SIZE ............................................................................................................................... 35 
9.5 
MEASURES TO MINIMIZE BIAS ....................................................................................................... 35 
9.5.1 
Enrollment/Randomization/Blinding Procedures ................................................................... 35 
9.5.2 
Evaluation of Success of Blinding ......................................................................................... 35 
9.5.3 
Breaking the Study Blind/Participant Code ............................. Error! Bookmark not defined. 
10 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 35 
11 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................................... 36 

Study number: i20-00217 
 
Page vi 
Version: 2.3, 4 NOV 2021 
 
 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................. 36 
12.1 
ETHICAL STANDARD ..................................................................................................................... 36 
12.2 
INSTITUTIONAL REVIEW BOARD ..................................................................................................... 36 
12.3 
INFORMED CONSENT PROCESS .................................................................................................... 36 
12.3.1 
Consent/Assent and Other Informational Documents Provided to Participants ............... 36 
12.3.2 
Consent Procedures and Documentation ......................................................................... 36 
12.4 
POSTING OF CLINICAL TRIAL CONSENT FORM ................................................................................ 37 
12.5 
PARTICIPANT AND DATA CONFIDENTIALITY .................................................................................... 37 
12.5.1 
Research Use of Stored Human Samples, Specimens, or Data ...................................... 38 
13 
DATA HANDLING AND RECORD KEEPING. .................................................................................. 38 
13.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES .............................................................. 38 
13.2 
STUDY RECORDS RETENTION ....................................................................................................... 38 
13.3 
PROTOCOL DEVIATIONS ............................................................................................................... 39 
13.4 
PUBLICATION AND DATA SHARING POLICY ..................................................................................... 39 
14 
STUDY FINANCES ............................................................................................................................ 40 
14.1 
FUNDING SOURCE ........................................................................................................................ 40 
14.2 
COSTS TO THE PARTICIPANT ......................................................................................................... 40 
14.3 
PARTICIPANT REIMBURSEMENTS OR PAYMENTS ............................................................................ 40 
15 
STUDY ADMINISTRATION ............................................................................................................... 40 
15.1 
STUDY LEADERSHIP ..................................................................................................................... 40 
16 
CONFLICT OF INTEREST POLICY .................................................................................................. 40 
17 
REFERENCES ................................................................................................................................... 41 
18 
SCHEDULE OF EVENTS .................................................................................................................. 47 
 
 

Study number: i20-00217 
 
Page vii 
Version: 2.3, 4 NOV 2021 
 
 
 
List of Abbreviations 
 
 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
AVM 
Arteriovenous Malformation 
BDNF 
Brain Derived Neurotrophic Factor 
BOLD 
Blood Oxygen Level Dependent 
CBF 
Cerebral Blood Flow 
CCO 
Cytochrome c oxidase 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIMU 
Conflict of Interest Management Unit 
cm 
Centimeter(s) 
CNS 
Central Nervous System 
CREF 
Clinical Research Evaluation Facility 
CRF 
Case Report Form 
CUNY 
City University of New York 
CW 
Continuous Wave 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
dLPFC 
Dorsolateral Prefrontal Cortex 
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
ECT 
Electroconvulsive Therapy 
EEG 
Electroencephalogram 
ES 
Effect Size 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act (of 2007) 
fMRI 
functional Magnetic Resonance Imaging 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practices 

Study number: i20-00217 
 
Page viii 
Version: 2.3, 4 NOV 2021 
 
 
GSK-3β 
Glycogen Synthase Kinase 3 Beta 
HAMD-17 
Hamilton Depression Rating Scale, 17-item version 
HCTZ 
Hydrochlorothiazide 
HIPAA 
Health Insurance Portability and Accountability Act 
IC 
Informed Consent 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IL-1β 
Interleukin 1 Beta 
IL-6 
Interleukin 6 
IL-8 
Interleukin 8 
iNOS 
Inducible Nitric Oxide Synthase 
IRB 
Institutional Review Board 
LED 
Light Emitting Diodes 
MDD 
Major Depressive Disorder 
MDSG 
Mood Disorders Support Group 
MFG 
Medial Frontal Gyrus 
MGH 
Massachusetts General Hospital 
MGH DCRP 
Massachusetts General Hospital Depression and Clinical Research Program 
MPE 
Maximum Permissible Exposure 
mPFC 
medial Prefrontal Cortex 
MR 
Magnetic Resonance 
MRI 
Magnetic Resonance Imaging 
mW 
Milliwatt 
N 
Number (typically refers to participants) 
NAMI 
National Alliance on Mental Illness 
nm 
Nanometer(s) 
NF-κB 
Nuclear Factor κB 
NIH 
National Institutes of Health 
NIH IC 
National Institutes of Health Institute/Center 
NIMH 
National Institute of Mental Health 
NIR 
Near-infrared Radiation 
NKI 
Nathan Kline Institute 
NO 
Nitric Oxide 
NSMHA 
North Suffolk Mental Health Association 
NYU 
New York University 
NYUMC 
New York University Medical Center 

Study number: i20-00217 
 
Page ix 
Version: 2.3, 4 NOV 2021 
 
 
OPD 
Outpatient Psychiatry Department 
OPRD 
Outpatient Research Department 
PBM 
Photobiomodulation 
PET 
Positron Emission Tomography 
PFC 
Prefrontal Cortex 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PW 
Pulsed Wave 
QC 
Quality Control 
RCT 
Randomized Controlled Trial 
RNA 
Ribonucleic Acid 
ROI 
Region of Interest 
ROS 
Reactive Oxygen Species 
RF 
Report Form 
rTMS 
repetitive Transcranial Magnetic Stimulation 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical and Analytical Plan 
SC 
Steering Committee 
SCID 
Structured Clinical Interview for DSM Disorders 
SD 
Standard Deviation 
SFG 
Superior Frontal Gyrus 
SNRI 
Serotonin-Norepinephrine Reuptake Inhibitor 
SOP 
Standard Operating Procedure 
SPECT 
Single Proton Emission Computerized Tomography 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TBI 
Traumatic Brain Injury 
tDCS 
Transcranial Direct Current Stimulation 
TNF- α 
Tumor Necrosis Factor alpha 
TSH 
Thyroid Stimulating Hormone 
t-PBM 
transcranial Photobiomodulation 
UP 
Unanticipated Problem 
VNS 
Vagal Nerve Stimulation 
VRP 
Volunteer Recruitment Pool 
WBC 
White Blood Cells 
 

Study number:  
 
Page 1 
Version: 
 
 
Protocol Summary 
Title 
Transcranial Near Infrared Radiation and Cerebral Blood Flow in Depression  
Short Title 
TRIADE 
Brief Summary 
This study will compare the effect of three t-PBM doses (high, middle, and 
low irradiance) to sham t-PBM on PFC CBF as assessed with fMRI (BOLD) in 
this multi-center, phase I, single-blind, dose-ranging, controlled, crossover 
study of 30 subjects with MDD. All eligible participants will undergo four 
sessions of t-PBM during fMRI so that they experience irradiances of 50, 300 
and ≥700 mW/cm2 as well as sham. The order of dose administration will be 
randomized and t-PBM will be administered with the LightForce® EXPi Deep 
Tissue Laser TherapyTM System, Transcranial PhotoBioModulation-1000 
(tPBM-2.0). 
Phase 
I 
Objectives 
Primary: To identify the t-PBM irradiance dose (50, 300, or ≥700 mW/cm2) with 
the largest impact on PFC CBF in MDD. 
Secondary: To compare the safety and tolerability of three t-PBM irradiance 
doses. 
Methodology 
Single-blind, dose-ranging, controlled, crossover study. 
Endpoint 
Primary: t-PBM effects on BOLD signal.  
Secondary: t-PBM effects on the frequency and severity of adverse events 
and side effects.  
Study Duration 
24 months 
Participant Duration 
6-12 weeks 
Duration of IP 
administration 
4 sessions 
Population 
30 men and women ages 18-65 with MDD 
Study Sites 
NYUSOM, NKI, MGH 
Number of participants 
30 
Description of Study 
Agent/Procedure 
Transcranial photobiomodulator, delivers laser-generated NIR to forehead. 
Reference Therapy 
Sham 
Key Procedures 
4 Sessions of t-PBM during MR scanning 
Statistical Analysis 
For each subject at each t-PBM dose we will model the BOLD signal at 
specified ROIs as a function of dose (considered a categorical variable with 4 
levels) using mixed effects models, including random subject intercepts to 
account for the potentially correlated measures on the same subject.   
 
 
 

Study number: i20-00217 
 
Page 2 
Version: 2.3, 4 NOV 2021 
 
 
Schematic of Study Design 
 
 
N=30: Obtain informed consent. Screen potential subjects by inclusion and exclusion 
criteria; obtain history, document. All screen procedures to be done remotely if possible. 
Scanning/tPBM Dose A 
Track adverse events, side effects, potential confounds, depression severity and 
anxiety severity. 
Scanning/tPBM Dose C 
Track adverse events, side effects, potential confounds, depression severity and 
anxiety severity. 
Visit 1  
Screen 
Visit 2 
Visit 3 
Visit 4 
Follow-
Up 
Scanning/tPBM Dose B 
Track adverse events, side effects, potential confounds, depression severity and 
anxiety severity. 
Scanning/tPBM Dose D 
Track adverse events, side effects, potential confounds, depression severity and 
anxiety severity. 
Track adverse events, side effects, potential confounds, depression severity and 
anxiety severity. 
Order of 
Doses 
Randomized 

Study number: i20-00217 
 
Page 3 
Version: 2.3, 4 NOV 2021 
 
 
 
 
1 Key Roles 
Principal Investigator, NYSOM and NKI 
Dan Iosifescu, MD, MSc,  
Associate Professor of Psychiatry 
NYUSOM 
Director, Clinical Research Department, Nathan Kline Institute for Psychiatric Research 
One Park Ave, 8th Floor 
New York NY 10016 
646-754-5156 
 
Director, Clinical Research Division 
NKI 
140 Old Orangeburg Rd., Bldg 35 
Orangeburg, NY 10962 
845-398-6580 
 
Principal Investigator, MGH  
Paolo Cassano, MD, PhD,  
Assistant Professor of Psychiatry, Harvard Medical School 
Director of Photobiomodulation and Investigator at the Center for Anxiety and Traumatic Stress Disorders 
MGH 
1 Bowdoin Sq. 6th Floor 
Boston MA 02114 
Phone: 617-726-6421 
PCASSANO@mgh.harvard.edu 
 
Statistician 
Eva Petkova, Ph.D. 
Department of Child and Adolescent Psychiatry  
NYUSOM 
Eva.Petkova@nyulangone.org 
 
Program Officer 
David McMullen, M.D. 
Program Chief, Neuromodulation and Neurostimulation Program 
6001 Executive Boulevard, Room 7129, MSC 9632 
301-451-0180 
David.mcmullen@nih.gov 
 
Data Manager 
Umit Tural. M.D. 
NKI 
140 Old Orangeburg Rd., Bldg 35 
Orangeburg, NY 10962 
845-398-6573 
Umit.Tural@nki.rfmh.org 
 
Data Coordinating Center 
Innovative Clinical Research Solutions (ICRS)  
NKI 
140 Old Orangeburg Rd., Bldg 35 
 

Study number: i20-00217 
 
Page 4 
Version: 2.3, 4 NOV 2021 
 
 
Industry Partner 
LiteCure LLC 
101 Lukens Dr, Suite A 
New Castle, DE 18720. 
 
2 Introduction, Background Information and Scientific Rationale 
 
2.1 Background Information and Relevant Literature 
 
2.1.1 Problem: Unmet Need for Accessible, Scalable, and Effective Treatments for Depression 
Twenty-one million Americans (~10%) suffered from a depressive episode over the past year1. Major 
depressive disorder (MDD) is the third leading cause of global disability2; the global cost of mental illness 
is expected to more than double by 2030, with depressive disorders at the forefront3. Sadly, 43% of primary 
care patients experiencing a six-month depressive episode remain untreated, with most preferring self-
management4 over professional help and/or prescription medications5,6. Factors limiting the adoption of 
firstline interventions for MDD include burdensome side effects of medications7,8 and the time commitment 
for psychotherapies9. Somatic therapies such as electroconvulsive therapy (ECT), repetitive transcranial 
magnetic stimulation (rTMS) and vagus nerve stimulation (VNS) are approved for treatment resistant 
MDD10; however, they are unsuitable to become first line treatments, since they require in-office 
administration, and sometimes anesthesia and/or surgical procedures10. In contrast, the use of wellness 
devices is especially popular, since nearly 25% of Americans own a wearable device11. A new generation 
of at-home devices for MDD that are safe, well-tolerated, inexpensive and easy to use, would 
represent a valuable firstline intervention, both accessible and scalable. 
 
2.1.2 Potential Solution: Transcranial Photobiomodulation (t-PBM)  
Transcranial photobiomodulation (t-PBM) is a novel neuromodulation based on non-retinal exposure to 
light at specific wavelengths.  As summarized below, a substantial body of literature proves that transcranial 
photobiomodulation (t-PBM) with near-infrared (NIR) light penetrates deeply into the cerebral cortex12-14, 
modulates cortical excitability15,16 and improves cerebral perfusion17-19 and oxygenation20. Its safety was 
demonstrated in 1,410 acute stroke patients21-23,102. Antidepressant effects of t-PBM have been reported in 
both animal models24-28 and human studies29-34. In a double-blind clinical trial (n=21), our team 
demonstrated the antidepressant effect of adjunct t-PBM NIR delivered to the prefrontal cortex (PFC) over 
8 weeks35.  Devices capable of administering t-PBM are already FDA- approved and can be manufactured 
with basic and relatively inexpensive lasers or light emitting diodes (LEDs). Due to its low cost, excellent 
safety profile, and ease of administration, PBM has the potential to become widely accessible. However, 
despite its clear advantages, no consensus exists on the optimal dose irradiance of t-PBM for MDD.  
 
2.1.3 t-PBM Penetration: NIR undergoes exponential decay of the photon flux as it travels through tissues. 
Nevertheless, a small but significant fraction of the light delivered to the scalp reaches the cortex. 
Depending on parameters used, the distribution of the therapeutic dose (sufficient energy deposition for 
therapeutic effects) might vary from only the most superficial cortex to the whole cortical width, always in 
proximity of the light source51. While therapeutic NIR penetration varies based on wavelength13,14, light 
source (LED versus laser)12, pulsing52 and intensity12,13, a 2% to 3% penetration rate of NIR is attainable at 
target prefrontal cortex regions. This corresponds to an NIR penetration of about 2 cm of intervening skin, 
skull, meninges, cerebrospinal fluid and brain. The magnitude of NIR fluence (energy density, J/cm2) to the 
skin surface –necessary to reach target areas of the brain therapeutically– is both safe and well tolerated. 
It is feasible to attain an NIR fluence on the human brain equivalent to the fluence inducing neurological 
benefits in animal models53.  
 
2.1.4 t-PBM Effects on Cerebral Blood Flow (CBF): In vivo t-PBM has robust and immediate effects on 
CBF. In rats, t-PBM at 660 nm with a LED device (9 mW/cm2) was associated with increased oxygen 
consumption in the frontal cortex95, while in mice NIR (808 nm) t-PBM with laser (1.6 W/cm2) resulted in 
30% increased CBF96.  In healthy humans, t-PBM with a 3.4W laser (1064 nm) led to increased 

Study number: i20-00217 
 
Page 5 
Version: 2.3, 4 NOV 2021 
 
 
concentration of oxygenated hemoglobin20, while in elderly women t-PBM with a 0.2W LED (627 nm) 
increased blood flow in the middle cerebral and basilar arteries19. In chronic traumatic brain injury (TBI) 
patients, t-PBM with a 3.3W LED device (629 and 850nm) increased CBF (measured by SPECT)36. Our 
own preliminary data (Section 2.4) show immediate increase in CBF [measured as blood-oxygenation-level 
dependent (BOLD) signal on fMRI] in healthy volunteers exposed to 808 nm laser NIR. Therefore, changes 
in CBF during t-PBM administration, measured as changes in BOLD fMRI signal, is an excellent target 
engagement biomarker. Secondarily, t-PBM also has a modulatory effect on cortical excitability, reducing 
motor evoked potentials elicited by TMS15 and may result in increased functional connectivity in the default 
mode network97. 
 
2.1.5 t-PBM Cellular Mechanisms: The NIR delivered through t-PBM is absorbed by a mitochondrial 
enzyme and chromophore, cytochrome c oxidase (CCO), and is only minimally dissipated as thermal 
energy53,54. The peak absorption of light energy by CCO occurs at four different wavelengths; one of these 
peaks is 812–846 nm55, overlapping with the wavelengths with best brain penetration described above. 
 
Depression is associated with hypometabolism in specific brain areas56-59 and mitochondrial dysfunction60-
64. Results in cellular and animal models indicate that PBM can enhance mitochondrial activity. NIR delivers 
energy to the CCO and stimulates the mitochondrial respiratory chain leading to increased ATP 
production54,65,66. In addition, NIR can improve mitochondrial activity by promoting the dissociation of nitric 
oxide (NO) from the CCO releasing the binding site for oxygen and restoring oxidative phosphorylation53. 
The released NO may also act as a local vasodilator67. A study on isolated mitochondria also reported 
increased RNA and protein synthesis after irradiation with a low-level laser (632.8 nm)68. 
 
Animal research suggests that PBM might also exert, via its impact on mitochondria, beneficial effects on 
several other pathophysiological mechanisms implicated in MDD, such as oxidative stress69-73, 
neuroinflammation74-78, and deficits in neuroplasticity and brain derived neurotrophic factor (BDNF)79-81, and 
default mode network connectivity97. NIR can induce short bursts of reactive oxygen species (ROS) leading 
to the activation of antioxidant mechanisms and the activation of the transcription factor nuclear factor κB 
(NF-κB), resulting in decreased overexpression of the inducible form of nitric oxide synthase (iNOS) and 
reduction of oxidative stress67,82,83. In animal models, NIR light (600 to 1000 nm) reduced neuroinflammation 
by decreasing proinflammatory cytokines such as IL-6, TNF-α, IL-1β, and IL-884-86, and decreasing the 
infiltration of macrophages, activated microglia and T lymphocytes to the CNS86.  In animal studies PBM 
also stimulates neurogenesis and neuroprotective mechanisms in models of neuronal injury, possibly 
mediated by increased BDNF and by inhibition of GSK-3β and pro-apoptotic molecules67,87-94.  
 
2.1.6 t-PBM Safety and Tolerability: The safety of one session of t-PBM was evaluated in three large 
RCTs with a pooled sample of 1,410 subjects with stroke21,22,100. No significant difference in the rate of 
adverse effects were observed between the group receiving laser NIR (808 nm; 5W) or sham. No serious 
adverse events were found in our review of the literature33. Two open studies using 1 and 6 sessions of t-
PBM reported no treatment-emergent side-effects29,30. A clinical trial with 16 t-PBM sessions reported an 
increased number of mild side-effects in the active treatment group, the most frequent being insomnia, 
“seeing vivid colors”, “an ashtray-like taste”, and irritable mood35. Other potential risks relate to inappropriate 
administration and will be mitigated by the safety procedures. The risk of thermal injury from t-PBM 
delivered with the parameters used in the studies we reviewed is considered minimal and limited to the 
skin. In ten individuals treated for TBI with 10-15W lasers –a much higher power than what is used in t-
PBM– the skin temperature increased to no more than 30°C with rapid cooling after removal of the NIR 
light. Clinically, patients reported slight skin warming, but no discomfort101.  Laser devices have a potential 
risk of retinal lesions when used improperly; this is mitigated with appropriate safety eye gear and 
procedures.     
 
2.1.7 t-PBM Effects on Depression: Multiple pre-clinical studies support the efficacy of t-PBM, in single 
or repeated administration, on animal models of depression such as the forced swim test24,27,90,98, tail 
suspension test27,90, mild chronic stress26,28, or the reserpine-induced depression24. In several of these 
studies the antidepressant effects were associated with biological effects related to mitochondrial 
stimulation, such as increased ATP biosynthesis and mitochondrial complex IV expression and activity in 
the prefrontal cortex (PFC)27 and increased hippocampal neurogenesis98.  All clinical studies using t-PBM 

Study number: i20-00217 
 
Page 6 
Version: 2.3, 4 NOV 2021 
 
 
for MDD reported in the literature aimed to modulate the forebrain, consistently with the dysfunction of the 
prefrontal cortex associated with MDD99.  In pilot studies with open designs, NIR was associated with an 
antidepressant response after a single29 or repeated (6) administrations30. Our recent RCT showed t-PBM 
was more efficacious than sham in 21 MDD subjects receiving bilateral t-PBM at 823 nm or sham directed 
on dorsolateral PFC (dlPFC, EEG sites F3 and F4) twice-a-week for 8 weeks35. Another study suggested 
that t-PBM paired with a cognitive therapy may be effective in depression34. All these studies measured 
acute, short term effects; only a case report describes persistence of effects over 9 months of repeated 
administration in a subject with MDD32. 
 
2.1.8 Scales and Measures: The following clinician-administered scales and patient-reported measures 
will be utilized in the study. 
 
• 
(M.I.N.I)40 – The M.I.N.I. is a short structured diagnostic interview, developed jointly by 
psychiatrists and clinicians in the United States and Europe, for DSM and ICD psychiatric 
disorders. With an administration time of approximately 15 minutes, it is designed to meet the 
need for a short but accurate structured psychiatric interview for clinical trials. According to 
researchers at the National Institute of Mental Health's (NIMH) Division of Clinical and Treatment 
Research, the M.I.N.I. is a fully validated and more time-efficient alternative to the Structured 
Clinical Interview for DSM Disorders (SCID). 
 
• 
Inventory of Depressive Symptomatology(IDS)41 – This is a 30-item clinician-rated inventory 
of depressive symptoms such as sleep, depressed mood, appetite, concentration, suicidal 
ideation, interest, energy, psychomotor retardation or agitation.  
 
• 
Montreal Cognitive Assessment (MoCA)42–This is a 10-item rapid screening instrument for 
mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, 
executive functions, memory, language, visuoconstructional skills, conceptual thinking, 
calculations, and orientation. This measure will be used to assess entry criteria. 
 
• 
The Massachusetts General Hospital (MGH) Antidepressant Treatment Response 
Questionnaire (ATRQ)43 – This scale is used to determine treatment resistance in major 
depressive disorder (MDD). The ATRQ examines the efficacy (improvement from 0% [not 
improved at all] to 100% [completely improved]), and adequacy (adequate duration and dose) 
of any antidepressant treatment in a step-by-step procedure. 
 
• 
New Immigrant Survey-Skin Color Scale (NIS-SCS)44 – The scale is an 11-point scale, 
ranging from zero to 10, with zero representing albinism, or the total absence of color, and 10 
representing the darkest possible skin.  The ten shades of skin color corresponding to the 
points 1 to 10 on the Massey and Martin Skin Color Scale are depicted in a chart, with each 
point represented by a hand, of identical form, but differing in color. The respondent never sees 
the chart. We gather this data for use as a potential covariate in analyses as skin color can 
affect absorption of NIR. 
 
• 
Systematic Assessment for Treatment Emergent Events (SAFTEE)45 – The SAFTEE is a 
commonly used instrument originally developed by NIMH and adapted into a self-report 
instrument. The version of the scale that we plan to use is the same used by the multi-center, 
NIMH-sponsored CO-MED trial, and it examines in a systematic fashion all possible treatment-
emergent side effects and probes specific adverse symptoms, including suicidal thoughts and 
behaviors, and self-injurious behavior. 
 
• 
Columbia Suicide Severity Rating Scale (C-SSRS)110 – An instrument endorsed by the FDA 
for clinical trials. This instrument systematically tracks suicidal ideation and behavior (e.g., 
suicide attempts, wish to die, thoughts of suicide, plan and intent). 
 

Study number: i20-00217 
 
Page 7 
Version: 2.3, 4 NOV 2021 
 
 
• 
Clinical Global Impressions – Severity and Improvement (CGI-S, CGI-I) – These two 
instruments are scored 1-7 by the clinician based on assessment of the subject's overall 
clinical status. They measure, based on history and scores on other instruments: (a) 
depressive severity (CGI-S) and (b) clinical improvement (CGI-I). 
 
• 
The Potential Confounders Questionnaire (PCQ) –This questionnaire solicits information 
about sleep, presence of jet lag, diet change, and the intake of over-the-counter drugs, 
prescription medications, caffeine, alcohol, nicotine, marijuana, and other street drugs.  
 
• 
The Perceptions of Blinding Questionnaire (PBQ) –The Perceptions of Blinding 
Questionnaire (PBQ) – The PBQ is a self-report questionnaire to determine the degree to 
which the participant believes s/he is receiving the treatment or the sham. 
 
• 
Positive and Negative Affect Schedule (PANAS)46 –This 20 item scale measures positive 
affect (e.g., excited, inspired) and negative affect (e.g., upset, afraid). Each item is rated on a 
five-point Likert Scale, ranging from 1 = Very Slightly or Not at all, to 5 = Extremely. 
 
• 
Montgomery-Åsberg Depression Rating Scale (MADRS)47 –This 10-item clinician-rated 
instrument measures depression severity. It will be administered with a structured interview 
guide. The time frame for this scale is the past 7 days  
 
• 
Symptoms of Depression Questionnaire (SDQ)48 – This is a comprehensive measure of 
depression that includes the assessment of symptoms in the anxiety–depression spectrum. It 
assesses irritability, anger attacks, and anxiety symptoms together with the commonly 
considered symptoms of depression. Analysis of the factor structure of the SDQ identified 5 
subscales, including one in the anxiety–depression spectrum, with adequate internal 
consistency and concurrent validity. 
 
• 
Anxiety Symptoms Questionnaire (ASQ)49 – This, is a 17-item self-report questionnaire 
measuring the frequency and intensity of 17 symptoms of anxiety, including nervousness, 
worrying, irritability, trouble relaxing, insomnia, lack of energy, difficulty concentrating, somatic 
symptoms, and impairment in functioning due to anxiety.  
 
• 
Adverse Events Form- The Adverse Events Form captures any adverse event (serious or 
otherwise) specifically related to the application of the t-PBM.  
 
• 
Concomitant medications and therapies form – This form records all ongoing medications, 
as well as other therapies targeting depression, and will be completed at every study visit, 
including the screening visit, as a safety-monitoring tool. 
 
• 
Quality of Life in Neurological Disorders, Cognitive Section (Neuro-QoL)50 - The cognitive 
section of the Neuro-QoL is an 8 item self-rated measure of both executive function and 
general concerns. It measures perceived difficulties in cognitive abilities (e.g., memory, 
attention, and decision making) or in the application of such abilities to everyday tasks (e.g., 
planning, organizing, calculating, remembering, and learning). 
 
• 
Quality of Life, Enjoyment, and Satisfaction Questionnaire (Q-LES-Q)111- Assesses 
subjective quality of life (i.e. physical health, subjective feelings, leisure activities and social 
relationships).   
 
• 
MRI Safety Checklist- Identifies risk factors that may make MRI participation unsafe. 
 
• 
The t-PBM Self-Report Questionnaire (TSRQ) – An open-ended questionnaire focusing on 
potential inconveniences and discomforts from the t-PBM.  

Study number: i20-00217 
 
Page 8 
Version: 2.3, 4 NOV 2021 
 
 
2.2 Preclinical Data 
t-PBM Effects on Animal Models of Depression: Multiple pre-clinical studies support the efficacy of t-PBM, 
in single or repeated administration, on animal models of depression such as the forced swim test24,27,90,98, 
tail suspension test27,90, mild chronic stress26,28, or the reserpine-induced depression24. In several of these 
studies the antidepressant effects were associated with biological effects related to mitochondrial 
stimulation, such as increased ATP biosynthesis and mitochondrial complex IV expression and activity in 
the prefrontal cortex (PFC)27 and increased hippocampal neurogenesis98. 
 
t-PBM NIR with laser devices have good penetration. NIR (808 nm) was detected 4 cm below the skin in 
unfixed cadaver brains (n = 8) with a 5-W laser; the penetration at 808 nm (NIR) wavelength was superior 
to the 940 (NIR) and 660 nm (red) light14. Also, a 15-W laser produced a 2.9% penetration of NIR (810 nm) 
at 3 cm from skin surface of recently slaughtered sheep heads12. Moreover, pulsed wave (PW) delivery 
might allow higher penetration than continuous wave (CW), by increasing peak irradiance and by lowering 
skin warming, which would limit light exposure52. The penetration for LED devices has been more 
variable12,13, which supports our decision to use lasers for this application. 
 
2.3 Clinical Data to Date 
Evidence of Efficacy in Depression: All clinical studies using t-PBM for MDD reported in the literature aimed 
to modulate the forebrain, consistently with the dysfunction of the PFC associated with MDD99. Dr. Cassano 
conducted a proof of concept, prospective trial on the safety and efficacy of adjunct t-PBM NIR (810nm) 
delivered to PFC, twice a week for 3 weeks in subjects with MDD, demonstrating the feasibility and safety 
of t-PBM in this population. In this investigation, mean HAM-D17 scores decreased from 19.8 ± 4.4 (SD) to 
13 ± 5.35 (SD) after 
treatment 
(p=0.004). 
Patients 
tolerated 
the 
treatment well without 
any 
serious 
adverse 
events. 
Our 
recently 
published RCT showed t-
PBM 
was 
more 
efficacious than sham in 
21 
MDD 
subjects 
receiving bilateral t-PBM 
at 823 nm or sham 
directed on dorsolateral 
PFC (dlPFC) (EEG sites 
F3 and F4) twice-a-week 
for 8 weeks35. Completer 
analyses 
showed 
a 
significantly 
greater 
decrease of depression 
scores per the HAMD-17 
in 
the 
NIR-mode 
compared to sham [NIR 
(n=6) 
-15.7±4.41 
vs. 
sham (n=7) -6.1±7.86; 
p=.031)]. Further, t-PBM 
was well tolerated, with 
no 
serious 
adverse 
events. The effect size 
was 
large 
(Cohen’s 
d=1.5) 
and 
reached 
significance with an n=13 

Study number: i20-00217 
 
Page 9 
Version: 2.3, 4 NOV 2021 
 
 
(Figure 1). Another randomized, controlled study suggested that t-PBM paired with a cognitive therapy may 
be effective in depression34. All these studies measured acute, short term effects; only a case report 
describes persistence of effects over 9 months of repeated administration in a subject with MDD and 
anxiety32. 
 
Impact: These data support the eventual clinical utility of t-PBM and highlight the importance of determining 
optimal parameters, as proposed in this application. 
 
Preliminary data on t-PBM effect on Cerebral Blood Flow (measured with fMRI-BOLD): We have collected 
data from n=20 subjects undergoing tPBM during resting state fMRI 103.  To disambiguate the effects of 
CBF from those of blood oxygenation, we employed a multi-echo MR sequence104.  Subjects’ brain activity 
in the form of the BOLD signal was acquired continuously for 30 minutes, with tPBM applied for 10 minutes 
beginning at minute 11.   Stimulation was delivered with a laser (808 nm), with an intensity of 318 mW/cm2 
and a spot size of 1 cm2 to the right forehead (standard EEG electrode location “Fp2”).  Whole-brain voxel-
wise statistical Chow tests105 were conducted separately at each echo of the group-averaged BOLD in 
order to detect significant changes during and after t-PBM, relative to the pre-stimulation baseline period. 
 
During t-PBM, we found a significant modulation of early-echo (13 ms) BOLD in a cluster of 214 voxels in 
the right medial frontal gyrus (MFG), 24 mm from the site of light incidence (Figure 2). A cluster of 154 
voxels in the right MFG, 22.4 mm from incidence, was also found at echo 2 (34 ms). Four smaller clusters 
were detected at echo 3 (56 ms), including one in the right superior frontal gyrus (SFG), 22.5 mm from 
incidence. Interestingly, we found that t-PBM produced an effect on the early-echo BOLD that outlasted the 
stimulation.  A cluster of 218 significant voxels centered in the MFG was found at a distance of 28.7 mm 
from incidence. The presence of significant BOLD effects at all echos, including the early-echo which is 
insensitive to blood oxygenation, suggests that CBF was increased during and after t-PBM.   
 
Impact: Thus, we are in a position to employ quantitative changes in fMRI-BOLD as a biomarker for target 
engagement during t-PBM.  
 
Evidence of t-PBM Safety and Tolerability: The safety of one session of t-PBM was evaluated in three 
large RCTs with a pooled sample of 1,410 subjects with stroke21,22,100. No significant difference in the rate 
of adverse effects were observed between the group receiving laser NIR (808 nm; 5W) or sham. No serious 
adverse events were found in our review of the literature33. Two open studies using 1 and 6 sessions of t-
PBM reported no treatment-emergent side-effects29,30. A clinical trial with 16 sessions reported an increased 
number of mild side-effects in the active treatment group, the most frequent being insomnia, “seeing vivid 
colors”, “an ashtray-like taste”, and irritable mood35. Other potential risks relate to inappropriate 
administration and will be mitigated by the safety procedures such as the use of protective eye wear.The 
risk of thermal injury from PBM delivered with the parameters used in the studies we reviewed is considered 
minimal and limited to the skin. In ten individuals treated for TBI with 10-15W lasers –a much higher power 
than what is used in t-PBM– the skin temperature increased to no more than 30°C with rapid cooling after 
removal of the NIR light. Clinically, patients reported slight skin warming, but no discomfort101.  Inherent to 
the use of any laser device is the potential risk of retinal lesions resulting from improper use of the laser 
and from the shedding of the light beams straight through lens and from their convergence on the macula; 
this is mitigated with appropriate safety eyewear and procedures. 
2.4 Dose Rationale  
As depicted in Table 1, all t-PBM sessions will incorporate: 1. laser light with 2. a wavelength of 808nm, 
corresponding to the absorption peak of the primary photoreceptor cytochrome-C oxidase 3.  and target 
bilaterally the dlPFC (standard EEG electrode sites F4, F3). The total area of exposure, as a result, will also 
remain constant at 24cm2 (12 cm2 bilaterally). 
 
The irradiance will vary across three experimental doses (50, 300, and ≥700 mW/cm2) therefore also 
impacting the exposure time, fluence, and total energy. The low and medium doses will both be 
administered in continuous wave mode; the high dose will be administered in pulsed wave mode 
(≥700mW/cm2). . 

Study number: i20-00217 
 
Page 10 
Version: 2.3, 4 NOV 2021 
 
 
 
Rationale for Constant t-PBM parameters: We will use a laser source of NIR since, in contrast to LED 
devices, lasers on optic fibers are MRI-compatible and can more easily produce high irradiation (e.g. 700 
mW/cm2). The 808 nm NIR wavelength is at the absorption peak of the primary photoacceptor cytochrome-
C oxidase55, has optimal penetration through the skull12,14, and proven effects on CBF (BOLD signal)103 and 
on mood30,35..  We chose to broadly irradiate and engage the PFC, since: 1) the aforementioned areas are 
all involved in emotion-regulation processes99; 2) abnormalities in CBF, which are well-documented in MDD 
patients, involve broadly PFC38,39,41.   
 
Rationale for Irradiance Doses: t-PBM at irradiance doses of 50 mW/cm2 had significant effects on 
mood29,30 and cognition108; t-PBM at 300 mW/cm2 have been associated with changes in CBF103 and on 
cognition107,109, while irradiance doses of 700 mW/cm2 have been effective in depression30 and in large 
studies in stroke21,22,100.  All three doses have been safely used in adults.  Therefore, the three irradiance 
doses proposed (50, 300, and ≥700 mW/cm2) cover the full spectrum of doses in the literature, enabling 
us to determine the optimal dose for target engagement 
 
Rationale for Wave Form Selection: We will use continuous wave (CW) NIR for the low and medium 
doses, which is supported by a preponderance of current data..  
 
We will use a pulse wave for the high dose because pulsing can prevent skin warming and discomfort 
thus facilitating enrollment and retention and safeguarding the integrity of the single blind.  Safety data 
from three previously referenced stroke RCTs including 1,410 participants21, 22, 100 offer ample evidence 
that a 700 mW/cm2 continuous wave dose is safe, However, testing during the development of our study-
specific device suggests that some participants may experience it as “hot” and/or unpleasant and be able 
to distinguish it from the sham and lower doses. Offering the pulsed high dose instead allows us to 
expose participants to a similar peak irradiance while lowering the average irradiance, thus reducing the 
likelihood of inducing skin warming or discomfort. 
 
 
 
Table 1. t-PBM Parameters Across 4 Sessions 
 
Dose 
Parameters 
 
High 
Middle  
Low  
Sham 
Peak Irradiance 
(mW/cm2) 
 
833 
300 
50 
0 
Average Irradiance 
(mW/cm2) 
 
275 
300 
50 
0 
Time Irradiation (s) 
 
600 
333 
1200 
0 
Average 
Fluence 
(J/cm2) 
 
165 
100 
60 
0 
Total energy (kJ/ cm2) 
 
2.0 
2.4 
1.4 
0 
Wave Mode 
 
Pulsed 
Continuous 
Continuous 
N/A 
NIR source 
 
Laser 
Laser 
Laser 
N/A 
Wavelength 
 
808nm 
808nm 
808nm 
N/A 
 
 
 
 
 
 
Area of exposure 
 
24cm2 
24cm2 
24cm2 
N/A 
Anatomical targets 
 
F4, F3 
F4, F3 
F4, F3 
F4, F3 
2.5 Rationale 
 
Why test t-PBM parameters with BOLD fMRI 
A novel or innovative therapy would not be clinically justified unless it adds significant value in terms of 
risk/benefit.  The limitations of current treatments in MDD are well-documented [Section 2.1.1]. Preliminary 
data suggests t-PBM targeting the PFC could be a novel treatment strategy in MDD [Section 2.2.1 and 

Study number: i20-00217 
 
Page 11 
Version: 2.3, 4 NOV 2021 
 
 
2.2.2]. However, the t-PBM parameters that would maximize its neural impact and therefore its 
antidepressant potential are not known.  Therefore, this study will apply a novel measurement of changes 
in BOLD fMRI signal as a marker of changes in CBF in the search for optimal t-PBM parameters, with the 
long-term goal of transforming clinical practice for patients with MDD.  Proof of engagement of CBF 
on PFC would support future clinical testing of this low-cost, time-efficient, accessible and user-friendly 
intervention in MDD subjects. 
 
We considered alternative 
measures of CBF, including 
near-infrared spectroscopy 
(which is associated with 
much 
poorer 
spatial 
resolution and can only 
evaluate CBF changes in 
the superficial cortex in 
adults), 
or 
PET/SPECT 
(where changes in CBF over 
a short period of time would 
be difficult to quantify, and 
repeated 
weekly 
administrations would be 
limited by the total dose of 
radiation). We believe the 
method we propose offers 
the 
best 
balance 
of 
accuracy, spatial resolution 
and repeatability. In our 
preliminary data, we found a 
strong effect at echo 1 
(Cohen’s d = 1.54, when 
comparing the echo 1 BOLD 
immediately 
before 
light 
onset with the BOLD 200 
seconds after onset, (Fig.3). 
  
The project is innovative because (1) it tests t-PBM with near-infrared light, an innovative technology with 
a well-established safety profile, and (2) it uses changes in CBF, as measured with changes in BOLD fMRI 
signal, as a state-of-the-art target engagement biomarker.  
 
2.6 Potential Risks & Benefits 
2.6.1 Known Potential Risks 
General:  By agreeing to participate in this study, subjects temporarily forgo the opportunity to receive 
regular psychiatric care in the community. For patients with major depressive disorder resistant to 
medications, alternative options would include ECT, VNS, rTMS, and additional augmentation strategies 
(psychotherapies, atypical antipsychotics, lithium, T3). The alternatives to this research are clearly 
explained to all patients, and treatment strategies that are generally used for these patients are discussed. 
Subjects are informed that t-PBM is not FDA approved for any psychiatric disorder and would therefore not 
be recommended for use after the study. 
 
Screening and Evaluation:  The risks and discomforts of the screening evaluations include discomfort or 
distress responding to potentially sensitive questions regarding mental illness and drug use. Research 
interviews are interrupted if individuals become distressed or object to answering questions. 
 
 
Fig. 3:  Time series of BOLD changes after t-PBM was applied to 
the right forehead 10 min. into a 30-min. BOLD scan103.  The 
duration of stimulation was 10 min. (grey area).  The colored time 
series indicate the subject-averaged BOLD (shown here in a ROI 
corresponding to the right medial frontal gyrus, MFG) at echos 1 (blue, 
13 ms), 2 (red, 34 ms), and 3 (orange, 55 ms).  A rapid increase in the 
BOLD was observed shortly after stimulation onset, while a second 
peak emerged later in the 10 min. stimulation window. 
The picture can't be displayed.

Study number: i20-00217 
 
Page 12 
Version: 2.3, 4 NOV 2021 
 
 
Delay in Initiation of New, or Changes in Ongoing, Antidepressant Treatment: While this study is not testing 
t-PBM as a treatment for depression, an antidepressant effect of t-PBM is possible. Any delay in receiving 
t-PBM (while screening procedures are completed) might be considered as a delay in treatment from a 
patient perspective. We will emphasize that the study is not geared to test a treatment but instead the 
impact on cerebral blood flow of t-PBM. 
Further, study participation requires stable antidepressant treatment. It is therefore possible that the 
participant’s condition could worsen and lead to increased disturbances in mood, anxiety, sleep, appetite, 
energy and cognition. This could result in work loss, loss of social function, and possibly increased risk of 
suicide. However, the risk should be minimized as there are several safety precautions in place and 
participants will have frequent contact with study clinicians. 
 
Risks of Clinical Decompensation: If a patient has worsened to such a degree that further participation 
would put him or her at risk, then he or she will be discontinued from the study. In such cases, the patient 
is immediately transferred to standard clinical treatment and exited from the research.  At any point during 
the study, patients are told to immediately inform their study psychiatrist if they develop worsening of 
depression or anxiety, symptoms of mania or psychosis, or active suicidal plans.   
 
Risks of t-PBM: The study laser device emits light with a longer wavelength than the human eye can see. 
The staff will be provided training on basic safety procedures relative to the use of the device. The staff 
administering the t-PBM will be careful not to operate the laser unless it is in direct contact with the subject’s 
skin. Protective eyewear is required since the device is a laser. Failure of laser device, resulting in the 
cessation of investigative therapy can cause no adverse event to our knowledge. Delivery of the infrared 
laser energy to an inappropriate site, such as directly over the open eye, would pose risk to the subject, 
such as blindness. Based on previous observations with similar laser devices, application of the laser may 
result in mild thermal sensation of warmth during use. The temperature of the skin is however kept well 
below the level for thermal damage. Based on human clinical trial experience to date and on sale of t-PBM 
devices for their intended use (e.g. Omnilux New-U), each adverse event listed below has been reported 
by less than 0.1% of all subjects and users: erythema, pain, discomfort, warmth, headache or other 
reactions at the application site. In our research experience, t-PBM devices could produce insomnia, 
irritability and fleeting illusions. The modality of administration for the t-PBM with the study laser device is 
analogous to the protocols used in our feasibility studies. The dose of light delivered by the study device is 
analogous to our feasibility studies and to published studies on t-PBM.  No serious adverse events occurred 
during our feasibility trials.     
 
The MGH and NKI sites have extensive experience in transcranial photobiomodulation. The MGH Wellman 
Center of Photomedicine conducted the first open study on t-PBM in subject with clinically-significant mood 
symptoms. At the MGH DCRP, Dr. Cassano has conducted two studies on t-PBM in subjects with clinically-
significant mood symptoms, also in collaboration with Dr. Iosifescu (NKI/ NYU).  
 
Risks of MR: The risks associated with the MRI procedure are minimal. Subjects who have non-MRI 
compatible metal implants, cardiac pacemakers, and potential pregnancy will be excluded. Some patients 
experience claustrophobia (fear of being in a closed space) while inside the machine. In these cases, the 
examination will be terminated immediately, and the participant will be rapidly removed from the scanner. 
2.6.2 Known Potential Benefits 
All study participants receive without cost an extensive psychiatric and medical evaluation. No other direct 
benefits result from study participation. The possible benefits to the patient (remission or improvement of 
mood and anxiety symptoms) and to others (development of new treatments with sound target engagement 
of the brain) are reasonable in relation to the risks of this study. The intervention itself with tPBM may 
potentially provide relief of mood and anxiety symptoms, at a level equal to antidepressant medication. 

Study number: i20-00217 
 
Page 13 
Version: 2.3, 4 NOV 2021 
 
 
3 Objectives and Purpose 
3.1 Primary Objective 
Our primary objective is to identify the t-PBM irradiance dose (50, 300, or ≥700 mW/cm2) with the largest 
impact on PFC CBF in MDD. 
3.2 Secondary Objective 
Our secondary objective is to compare the safety and tolerability of three t-PBM irradiance doses. 
3.3 Exploratory Objectives 
Our exploratory objectives are to compare the effects of three t-PBM doses on depression symptom 
severity, anxiety symptom severity, and quality of life. 
3.4 Description of Study Design 
We will compare the effect of three t-PBM doses (high, middle, and low irradiance) to sham t-PBM on 
PFC CBF as assessed with fMRI (BOLD) in this multi-center, phase I, single-blind, dose-ranging, 
crossover study of 30 subjects with MDD. All eligible participants will undergo four sessions of t-PBM 
during fMRI so that they experience irradiances of 50, 300 and ≥700 mW/cm2 as well as sham. The order 
of dose administration will be randomized and t-PBM will be administered with the LightForce® EXPi 
Deep Tissue Laser TherapyTM System, Transcranial PhotoBioModulation-1000 (tPBM-2.0). 
3.5 Study Endpoints 
3.5.1 Primary Study Endpoints 
The primary endpoint will be t-PBM effects on BOLD signal.  
 
The specificity of t-PBM effects on BOLD signal increases will be assessed by testing three irradiance 
doses covering a wide range (50, 300 and ≥700 mW/cm2) versus sham. If a reliable effect on BOLD 
(compared to sham, the BOLD increase at the optimal dose will have an effect size of Cohen’s d≥0.5)  is 
seen with PBM, the study validate BOLD fMRI as a robust biomarker of target engagement for t-PBM and 
act as a “go” signal. In contrast, if none of the t-PBM doses yield reliable BOLD increases, this will fail the 
putative mechanism (no go). 
 
Rationale for the effect size (E.S.) threshold: We have previously observed large effect size changes in 
BOLD (Cohen’s d=0.6) after a single administration of t-PBM (at 318 mW/cm2)103.  In our clinical pilot 
study, significant, large effect size improvements in depressive symptoms were reported in MDD after 8 
weeks (Cohen’s d=1.5, n=21)35. Given these preliminary results, we will use as threshold for the Go/No-
Go decision an effect of t-PBM on BOLD at one dose (but not all doses, vs. sham) of magnitude Cohen’s 
d > 0.5 (at least medium size). 
3.5.2 Secondary Study Endpoints 
The secondary endpoints will be t-PBM effects on brain temperature, suicidal ideation/behavior, and the 
frequency and severity of adverse events and side effects occurring at the time of each t-PBM session 
and between each t-PBM session and the subsequent study visit. Brain temperature will be assessed 
with MR; suicidal ideation/behavior with the C-SSRS. Adverse events will be tracked with the adverse 
events log; side effects, with the SAFTEE and TSRQ. 
3.5.3 Exploratory Endpoints 
The exploratory end points include the total scores of the following scales as assessed at the study visit 
subsequent to each t-PBM session: MADRS, SDQ, ASQ, Q-LES-Q-SF, and NeuroQoL. 

Study number: i20-00217 
 
Page 14 
Version: 2.3, 4 NOV 2021 
 
 
4 Study Enrollment and Withdrawal 
4.1 Inclusion and Exclusion Criteria 
Inclusion Criteria: 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Participants must be able to give written informed consent and follow study procedures. 
 
2. Participants must be 18-65 years of age.  
Rationale: The lower age limit for participation is 18 years old, due to diagnostic uncertainty in children 
and adolescents with MDD, as well as differences in response to antidepressants in this population. 
The enrollment of subjects older than 65 years might introduce a confound, as comorbid 
cerebrovascular and degenerative pathology is more frequent and might confound the impairment 
associated with depressive symptoms. Because even subject younger than 65 are at risk of 
cerebrovascular and degenerative pathology, additional provisions are adopted to exclude subjects 
with significant cognitive decline.  
 
3. Participants must have major depressive disorder; all the following conditions need to be met to 
ensure presence of significant depression symptoms:  
a) Meeting diagnostic criteria for Major Depressive Disorder (MDD) in the past two weeks,  
 
at the DSM-5 Mini-International Neuropsychiatric Interview (MINI) 
b) Inventory for Depressive Symptomatology Clinician-rated (IDS-C) total score ≥23 at 
 
screening  
c) Depression symptoms are the primary target of treatment or treatment-seeking.  
 
4. Women of child-bearing potential must agree to use adequate contraception (e.g. oral contraceptives, 
intrauterine device, double barrier methods, or total abstinence from intercourse). Rationale: Although 
t-PBM would be unlikely to have an effect on pregnancy and fetal development, the risks to a fetus 
are unknown; also, depression in pregnant women likely has a different biological and hormonal 
etiology. 
 
5. Participants taking medications or psychotherapy approved for the treatment of major depressive 
disorder will need to be stable for at least 8 weeks prior to screen. Rationale: Other treatments initiated 
close to the study intervention could potentially confound the effect of t-PBM on BOLD-MR signal.     
 
6. Participants must be able to fit comfortably in the study scanner while wearing the study device. 
Rationale: We wish to avoid enrolling subjects who will not be able to complete the study because 
they find the device or scannertoo uncomfortable. 
 
 
Exclusion Criteria:  
An individual who meets any of the following criteria will be excluded from participation in this study: 
 
1. Unwilling or unable to comply with study requirements 
 
2. Patients judged to be at serious and imminent suicidal (C-SSRS≥4) or homicide risk, or currently in 
crisis such that inpatient hospitalization or other crisis management should take priority. Rationale: 
Suicidal thoughts are prospectively assessed at each visit throughout the study with the C-SSRS 
scale. Given that the t-PBM intervention is not an approved treatment for major depressive disorder 
and that the current study is not designed to test treatment-response in a population of major 
depressive disorder, and given the inclusion of sham, we considered that subjects with severe suicide 
risk would be better served outside the study frame.   
 
3. History of any or psychotic or bipolar disorder Rationale: The aforementioned disorders require the 
use of specific medications (e.g. antipsychotic medications and mood stabilizers), allowing these 
disorders would likely increase the heterogeneity of the sample and thus obscure findings.  

Study number: i20-00217 
 
Page 15 
Version: 2.3, 4 NOV 2021 
 
 
 
4. Met diagnostic criteria for an alcohol or substance use disorder, post-traumatic stress disorder, 
obsessive-compulsive disorder, anorexia nervosa, or bulimia nervosa within the preceding 12 months 
Rationale: We adopt a broader exclusion criterion within the past 12 months to disallow participation 
by individuals suffering from disorders that would likely increase the heterogeneity of the sample.  
 
5. History of dementia, traumatic brain injury (TBI), or neurological disorders affecting the brain, 
including any history of stroke or seizure disorders requiring treatment in the last 5 years (even if 
controlled with medications).  Rationale: The aforementioned are common, could contribute to the 
individual’s current impairment and may be associated with a different pattern of CBF response to t-
PBM. 
 
6. Cognitive impairment significant as determined by the Montreal Cognitive Assessment (MOCA) <22 
or MOCA-Blind <19. Rationale: We will exclude subjects with significant cognitive decline, which could 
be a clinical indicator of potential underlying pathology. 
 
7. History of antisocial personality disorder, or any clinically significant personality trait that would, in the 
investigator’s judgment, preclude safe study participation or impair ability to remain adherent with the 
treatment protocol. 
 
8. History of significant treatment non-adherence or situations where the subjects are unlikely to adhere 
to treatment, in the opinion of the investigator. Rationale: In our pilot studies, subjects were very 
motivated and good retention rates were demonstrated. However, the study schedule with four, 
weekly t-PBM-MR sessions requires adequate commitment from study subjects. 
 
9. Pregnant (as confirmed by pregnancy test at screen) or nursing. Rationale: The medical risk of using 
t-PBM during pregnancy and breast-feeding is unknown. 
 
10. Currently undergoing device-based treatment for depression or taking medications for depression 
other than SSRIs,SNRIs, or Wellbutrin (bupropion). Rationale: We wish to minimize the biological 
heterogeneity of the sample (with respect to effects of t-PBM on CBF). 
 
11. Treatment resistance with failure to respond to more than two adequate treatments with FDA-
approved antidepressant medications during current episode of major depressive disorder. Rationale: 
A wide spectrum of treatment resistance would likely increase the biological heterogeneity of the 
sample (with respect to effects of t-PBM on CBF). 
 
12. History of ECT in the last 12 months; lifetime history of VNS; lifetime treatment resistance to any FDA-
approved device-based treatment for major depressive disorder (such as ECT, TMS, VNS); device-
based interventions for depression will need to be discontinued at least 8 weeks prior to screen. 
Rationale: We will not allow ECT in the recent past in order to reduce confounding cognitive side 
effects.  Patients previously implanted with VNS, or having failed treatment with ECT or TMS would 
represent a treatment refractory population which would increase heterogeneity and reduce the 
chance to detect an efficacy signal. 
 
13. Serious, unstable medical illnesses including hepatic, renal, gastroenterologic, respiratory, 
cardiovascular, endocrinologic, neurologic, immunologic, hematologic disease; defined as any 
medical illness which is not well-controlled with standard-of-care medications (e.g., insulin for 
diabetes mellitus, HCTZ for hypertension) Rationale:  Although t-PBM appears to be well-tolerated 
and safe, in subjects with unstable medical illnesses the CBF (and its response to t-PBM) may be 
altered secondary to their physical illness. 
 
14. Clinically significant abnormal findings of laboratory parameters including urine toxicology screen for 
drugs of abuse or at physical examination. 
 

Study number: i20-00217 
 
Page 16 
Version: 2.3, 4 NOV 2021 
 
 
15. Clinical or laboratory evidence of uncontrolled hypothyroidism; if maintained on thyroid medication 
must be euthyroid for at least 1 month before screening. Rationale: Hypothyroidism is sometimes 
associated with depression-like symptoms which would confound the diagnosis and severity ratings. 
 
16. Past intolerance or hypersensivity to t-PBM. 
 
17. Significant skin conditions (i.e., hemangioma, scleroderma, psoriasis, rash, open wound or tattoo) on 
the subject’s scalp that are found in the area of the procedure sites. Rationale: These conditions 
would impede the penetration of the near-infrared (NIR) light. 
 
18. Any use of light-activated drugs (photodynamic therapy) within 14 days prior to study enrollment. 
Rationale:  The NIR light would interfere with pre-existing treatments. 
 
19. Any type of implants in the head, whose functioning might be affected by t-PBM (e.g. stent, clipped 
aneurysm, embolized AVM, implantable shunt – Hakim valve). Rationale: The NIR light could, by 
increasing cerebral blood flow, induce the dislodgement of existing implants.  
 
20. Failure to meet standard MRI safety requirements (e.g. claustrophobia, non-removable piercings, 
implanted medical devices, other non-removable metals) as determined by the MRI Safety Checklist. 
 
4.2 Vulnerable Subjects 
We will not enroll vulnerable subjects. Further, we will enroll only individuals who are: 1)  fluent in English 
because some of the instruments used in this study have not been translated and validated in other 
languages; and 2) and literate, as illiterate subjects may not be able to validly complete some of the 
assessments.  
 
We may enroll NYU students and/or employees. However, we will not enroll any students or employees 
who are under the direct supervision or oversight of study team members. 
4.3 Strategies for Recruitment and Retention 
We intend to enroll 30 subjects over 24 months. We believe that our combined track record of recruitment 
in previous MDD research (see below) and our existing referral sources described below show the feasibility 
of recruiting sufficient numbers of MDD patients for this study. 
 
This trial will recruit patients at two independent sites: 1) NYU and Nathan Kline Institute (NKI), acting as a 
single site with two locations in the greater New York City area, and 2) Massachusetts General Hospital 
(MGH), in Boston. MA. The two sites (NYU/NKI and MGH) will each be responsible for enrolling 50% of the 
total sample.  We anticipate completing the R61 within 22 months, with fMRI data analyzed on a rolling 
basis. 
 
At NYU, participants will be enrolled by the Mood Disorders Research Program, led by Dr. Dan Iosifescu, 
which has an excellent track record of recruitment in studies involving the assessment and treatment of 
subjects with MDD. Participants with MDD will primarily be recruited from the NYU Langone Medical Center 
(NYUMC) Outpatient Psychiatry Department and from the NYU Bellevue Hospital, as well as from an 
extensive network of community partners, supplemented with local advertising and recruitment outreach 
efforts. We have strong relationships with the NYU Langone OPD, where currently 500 MDD patients 
receive on-going treatment and approximately 300 new bipolar disorder patients are evaluated every 
year.  NYU Bellevue Hospital, with 330 inpatient mental health beds, has ≥ 200 admissions of MDD patients 
per year. We will have periodic meetings with the Psychiatry staff at NYU Langone and at Bellevue Hospital 
to facilitate referrals to our study.  We are also able to recruit through our relationship with NYU-affiliated 
community psychiatric clinics in Manhattan and Brooklyn, and with NYU Langone Brooklyn (formerly 
Lutheran Hospital in Brooklyn), where we have traditionally received referrals from clinicians and from 
posting NYU IRB-approved advertisements. To further increase our potential enrollment for this study Dr. 
Iosifescu has established relationships with the Mood Disorders Support Group of New York (MSDG/NY), 

Study number: i20-00217 
 
Page 17 
Version: 2.3, 4 NOV 2021 
 
 
an association which provides peer support and education to several hundred of patients with mood 
disorders in NYC every year.  MDSG/NY sees 2-4 new patients or family members in one of the two weekly 
support groups (2/3 of these patients or family members have an MDD diagnosis). We estimate 104 
newcomers to MDSG/NY per year, 50 with an MDD diagnosis. 
 
At NKI, participants will be recruited by the Clinical Research Division (director: Dan Iosifescu), which 
coordinates all outpatient recruitment for clinical trials.  Participants for the proposed study will be recruited 
from the NKI Volunteer Recruitment Pool (VRP), a core NKI institutional resource maintained by the 
Outpatient Research Department (OPRD), a component of the Clinical Research Department. 
Approximately 1,550 individuals (patients and community controls) have been enrolled in the VRP and have 
undergone formal diagnostic characterization with the Structured Clinical Interview for DSM Disorders 
(SCID).  The VRP maintains close research relationships with outpatient psychiatric aftercare centers 
throughout the Rockland County area. In addition, we have close relationships with private clinical practices 
in the area and with patient-support organizations (such as NAMI), which will provide additional referrals. 
 
At MGH, The MGH Depression Clinical and Research Program (DCRP) is a nationally and internationally 
recognized center in mood disorders research. The DCRP at MGH is part of Partners Health Care (an 
integrated Hospital System in Boston, which includes MGH; www.partners.org). Taken together, we have 
access to over 9,000 patients with MDD (Source: Partners Research Patient Data Registry [RPDR]). The 
DCRP has a successful track record of clinical studies of treatments for all phases of MDD. A query of the 
Research Patient Database of Partners Healthcare System (of which MGH is a founder) performed on 
10/27/18 reveals 17,089 subjects with “ever” a diagnosis of MDD (mean age = 43, 4043 females, 57%) 
currently followed in the Partners clinics.  
 
For the recruitment at MGH, we will use the following strategies:  1. Advertisements (see below). 2.MGH’s 
RSVP for Health database. This database can be used to send out postings to volunteers who expressed 
interest in research. 3. Most of the participants in our feasibility study (ELATED-2 and ELATED-3) were 
from our general MGH DCRP advertising (e.g. radio and public transportation). The MGH DCRP program 
has a large volume of studies, however typically only limited device-based interventions are offered. This 
helps recruitment, as in our tPBM studies, since from the flow of people attracted by general advertising 
there is a fixed portion that is not interested in traditional interventions (e.g. medication and psychotherapy). 
We will potentiate this referral source as we will conduct specific advertising for our study; 4. MGH and 
MGH-affiliated clinics (Charlestown, Chelsea, Revere, MA) will constitute an additional source of referral; 
5. Online posting (e.g., Craigslist) has been effective for our most recent MGH studies on tPBM. In both 
ELATED-2 and -3, we received 1-2 calls per week from Craigslist. 6. Electronic letters can be delivered 
within the Partners HealthCare System to inform clinicians in the greater Boston metropolitan area about 
the study. 7. Dr. Cassano (study PI) has also worked for the past 10 years as an attending psychiatrist at 
North Suffolk Mental Health Association (NSMHA) and has a network of collaborators who are favorably 
inclined towards clinical research. 
 
All sites will provide local clinicians with IRB-approved materials that provide patients with the necessary 
information on how to contact the study investigators should they be interested in potential participation. 
Referring clinicians do not discuss the specific details of the study but inform their patients that this clinical 
trial is recruiting participants with mood symptoms. 
 
At all sites, an additional source of referrals will be self-referral through media advertisement, and through 
internet postings on medical and mental health-related web sites. All advertisements will be approved by 
the IRB. 
 
Interested individuals who contact the research clinic by phone are informed that the information they give 
over the phone is written down and discussed by the research team. They are advised that if they do not 
enroll in research, the information will be destroyed, and that if they do enroll, the information becomes part 
of their research chart, which is destroyed after seven years. An initial IRB-approved phone screening will 
be completed after they give verbal authorization.  
 

Study number: i20-00217 
 
Page 18 
Version: 2.3, 4 NOV 2021 
 
 
On the phone screen, we have included sensitive questions related to mental illness and drug use in order 
to establish a general baseline of eligibility for the study over the phone before we invite potential 
participants to our site. Because this investigational device is being investigated for its use in MDD, we 
want to make sure that we only bring in individuals with MDD. That is, we do not want to invite people who 
meet exclusionary criteria to come all the way to our offices if they will be an instant screen fail. The same 
logic applies to asking about recreational drug use: we ask about drug use because our study includes 
multiple urine toxicity tests (including the screen visit), and recreational drug use would show on these tests 
and subsequently make the participant ineligible. Before starting the phone screening interview, we obtain 
verbal consent (we outline the scope of the interview, that it includes some personal questions related to 
mental illness and drug use which are necessary to establish eligibility, and that the subject can choose to 
not answer specific questions). We then ask the subject to confirm they are willing to proceed. For subjects 
who screen fail, the phone screen material will be shredded at the end of the day, to maintain confidentiality. 
In order to avoid duplicate screens, the names of subjects who failed the phone screen will be kept in a 
database hosted on secure HIPAA-compliant servers at each study site, but no confidential information will 
be recorded in the database (only exclusion criterion # relevant). For subjects who pass the phone screen 
and are scheduled for an in-person screen visit, we save the phone screen to our secure HIPAA-compliant 
server for use during the in-person screen visit. 
 
If an individual meets initial enrollment criterion and is interested in participating, a face-to-face interview is 
conducted with a study investigator. The PI or his designees obtain written voluntary informed consent from 
all participants prior to any study procedure. The initial consent form describes the nature of the procedures 
and time requirements, potential risks, the confidentiality of information, and the rights of research 
participants. Following signing the initial informed consent document, medical and psychiatric screening 
procedures are undertaken to confirm eligibility. Participants are given a copy of the consent form to review 
at their leisure, and ample time is given for questions by the prospective study participant (and family 
member, if applicable). The original signed Consent Forms are kept in a research binder.  The Consent 
Form makes it explicit that the protocol involves return visits at specified times.  In particular, the consent 
form indicates that the nature of intervention is determined by the protocol, and that the study is a 
randomized investigation to evaluate the impact of tPBM on cerebral blood flow. Patients are informed that 
if their clinical condition deteriorates during the study, they may be hospitalized. The consent procedure is 
viewed as a process rather than a single event, and patients are encouraged to discuss the study with the 
research team at any time.  Informed consent procedures, other study procedures and tPBM occur at the 
MGH, NKI and NYU sites. 
 
The consent process also includes documentation of permission to obtain previous medical records, 
including contact with previous physicians, pharmacies, and family members.  A release of information is 
obtained for review of any available historical and clinical data, permitting the research team to use, create, 
or disclose his or her PHI for research purposes. If the individual decides not to participate in this study, a 
staff member provides reasonable and timely assistance in obtaining an alternative referral, if so desired. 
The decision not to participate does not affect eligibility to participate in future studies, to receive treatment 
at MGH-, NKI- or NYU-affiliated hospitals, or to receive treatment on a private basis from a referring 
clinician.  Patients are also given the opportunity to withdraw from the study prior to analysis of their data. 
 
Inclusion of Women: 
We will enroll eligible subjects regardless of gender. We will aim to enroll women and men, according to 
the natural prevalence of major depressive disorder (which affects larger number of women) so that we can 
test whether the transcranial photobiomodulation (tPBM) has the same or a different impact on cerebral 
blood flow across gender. In a recent study in photobiomodulation at the Massachusetts General Hospital 
(MGH) (2016P001490), the Depression and Clinical Research Program (DCRP), jointly with other 
programs, recruited 54 subjects with a range of severity of depression symptoms. Approximately 70% of 
this sample was female.  Similarly, consistent with the prevalence of MDD in the general population, 
approximately 55% of participants recruited at NKI and at NYU in MDD studies have been females. 
Consequently, we anticipate our study sample to be approximately 60% women.  
 
Inclusion of Minorities:  

Study number: i20-00217 
 
Page 19 
Version: 2.3, 4 NOV 2021 
 
 
 
MGH: In the present study, we hope to oversample the percentage of minorities that we recruit in order to 
test the effects tPBM on cerebral blood flow across different races and ethnicities. The MGH DCRP has 
been successful in the past at recruiting a diverse participation population. In a recent NIH-sponsored study 
at MGH (1R01MH101486), of the 316 subjects recruited at MGH, approximately 3% were black or African 
American,12% were Asian, 3% were more than one race, and 10% were Hispanic or Latino. 
 
We intend to target a minority participation rate similar to the past studies. As a result, we plan to recruit a 
diverse study population that is approximately 20% Hispanic or Latino, 7% black or African American, 13% 
Asian. 
 
In order to ensure the recruitment of an ethnically and racially diverse study population at MGH, we plan to 
advertise in communities with high proportions of minority individuals such as East Boston, Somerville, 
Jamaica Plain, Revere, Everett and Malden (MA). These advertisements will include public transportation 
postings, community newspapers, and putting up flyers. In the past, these strategies have worked 
effectively. Another resource we will use is MGH’s RSVP for Health, a database consisting of more than 
8,000 volunteers who expressed interest in research. This database can be used to send out postings to 
volunteers based on gender, ethnicity, and race allowing for targeted recruitment of minorities and women. 
Further, we will recruit through MGH’s community clinics (e.g., North Suffolk Mental Health, MGH 
Charlestown, MGH Chelsea and MGH Revere). Lastly, we will review recruitment regularly at team 
meetings to track progress and adjust recruitment strategies as needed. 
 
NKI & NYU: Two of the study sites, at the New York University and the Nathan Kline Psychiatric Institute, 
are situated in greater New York City, one of the largest and most diverse cities in the world. It is expected 
that the study sample recruited at NYU and NKI will closely approximate the racial and ethnic composition 
of the greater New York City. The racial and ethnic distribution in Manhattan is: White, not Hispanic or 
Latino 46.8%; Hispanic or Latino 26.0%; Black or African American 18.2%; Asian 12.8%; American Indian 
and Alaska Native 1.2% (https://www.census.gov/quickfacts/table/PST045215/36061); the catchment area 
of the NYU affiliated hospitals in Brooklyn includes 22% Hispanics, 23% white non-Hispanics, 26% Asians 
and 24% blacks. The Nathan Kline Institute (NKI) is located in Rockland County, NY.  It is expected that 
the study sample recruited at NKI will closely approximate the racial and ethnic composition of the region: 
White/non-Hispanic origin: 63.9%, Hispanics: 16.8%, Black: 12.9%, Asian: 6.6%, Multiracial: 1.9%, 
American Indian/Alaska Native 0.5%, Pacific Islander 0.1%. Prior trials conducted at NYU and NKI have 
consistently obtained a demographic mix that is representative of the greater New York City population. In 
clinical trials over the past 5 years at NYU and NKI, our gender, racial and ethnic average recruitment was 
as follows: Female: 55%; Caucasian (non-Hispanic): 38%; Hispanic: 23%; African-American: 25%; Asian: 
13%; Other: 3%. 
 
4.4 Duration of Study Participation 
Study participation should last between six and twelve weeks. Participants are required to attend one 
remote screen visit and five clinic visits (second screening visit and four scanning/t-PBM sessions) and 
answer questions during a single follow-up phone call. If scheduled for consecutive weeks, participants 
will complete the study in six weeks. However, for logistical regions the time between screening 
completion and the first scanning/t-PBM session can be as long as four weeks; in addition, as long as two 
weeks may pass between each scanning/t-PMB session. 
 
4.5 Total Number of Participants and Sites  
We expect to enroll a total of 62 participants across three sights (NYUMC, NKI, and MGH). Of these, we 
expect 7 will be enrolled and screened at NYUMC; 14, at NKI. Of the New York cohort, we expect 15 to 
be eligible and subsequently scanned and treated with r-PBM at NKI.  Further we expect 21 will be 
enrolled and screened at MGH and a subset of 15 eligible participants scanned and treated at MGH.  
 

Study number: i20-00217 
 
Page 20 
Version: 2.3, 4 NOV 2021 
 
 
In summary, recruitment will end when approximately 62 participants are enrolled. It is expected that 
approximately 62 participants will be enrolled in order to produce 30 eligible participants. 
 
Table 2: Expected Enrollment Per Site 
 
Enrolled/Screened 
Scanned and treated with t-PBM 
NYUMC 
12 
5 (at NKI) 
NKI 
19 
10 
MGH 
31 
15 
 
Site Management Plan: 
 
The PIs will have weekly teleconference meetings during which any adverse events (AEs), unexpected 
problems, interim results or planned protocol modifications will be discussed. The PIs will also meet in-
person at a minimum of twice yearly to review all aspects of study progress and safety. 
 
The Innovative Clinical Research Solutions (ICRS) group at the Nathan Kline Institute (NKI) will be the Data 
Coordinating Center (DCC), providing a comprehensive web-based data acquisition and management 
system, (Acquire) to process, edit and store all study data in a centralized, secured, and password-
protected database. Individual sites will enter data directly into the centralized Acquire database. 
 
Study participant identifiers will be securely stored at each 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 local IRB and Institutional regulations. 
4.5.1 Research Use of Stored Human Samples, Specimens, or Data 
• Intended Use: Data collected under this protocol may be used to study mood and anxiety 
disorders. No genetic testing will be performed. 
• Storage: Samples will not be stored. Data will be stored using codes assigned by the 
investigators. Data will be kept in password-protected computers. Only investigators will have 
access to the samples and data. 
• Tracking: A tracking file will link identification codes with identifying information, but this file will be 
password-protected and stored on a computer that can also only be accessed with a password. 
 
4.6 Participant Withdrawal or Termination 
4.6.1 Reasons for Withdrawal or Termination 
 
Participants are free to withdraw from participation in the study at any time upon request. An investigator 
may terminate participation in the study 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 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Subject fails to adhere to protocol requirements so that the integrity of the data is compromised 
(e.g. subject fails to respond to attempts to schedule subsequent visits such that more than 
allotted time passes between scanning/treatment visits). 
4.6.2 Handling of Participant Withdrawals or Termination 
Every effort will be made to conduct the follow-up assessment via phone with all withdrawn or terminated 
participants. The phone assessment includes 
 

Study number: i20-00217 
 
Page 21 
Version: 2.3, 4 NOV 2021 
 
 
If a site is unable to contact a subject or if the subject fails to appear for a visit, three documented phone 
calls should be made, followed by a letter (or its equivalent).  The letter should detail the need for the 
subject to appear for a visit, the site’s unsuccessful attempts to contact the subject, and that failure to 
contact the site will result in the subject being withdrawn from the study. 
 
If the certified letter is returned to the site as undeliverable or the letter is delivered but the subject does 
not contact the site and no other contact is made with the subject or the subject’s caregiver, then the 
subject will be considered Lost to Follow-up and discontinued from the study.  All attempts to contact the 
subject will be documented.  
 
4.7 Premature Termination or Suspension of Study 
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 all investigators, and the funding agency. If the study is 
prematurely terminated or suspended, the PI will promptly inform the IRB and will provide the reason(s) 
for the termination or suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, data quality are addressed and 
satisfy the sponsor, IRB and/or FDA. 
 
5 Study Agent (Study drug, device, biologic, vaccine etc.) and/or 
Procedural Intervention 
5.1 Study Agent(s) and Control Description 
LightForce® EXPi Deep Tissue Laser TherapyTM System, Transcranial PhotoBioModulation-1000 (tPBM-
2.0)  
 
As described in Section 2.2, the tPBM-2.0 is an investigational device based on LiteCure’s LightForce® 
EXPi Deep Tissue Laser TherapyTM System. For the investigational study, the EXPi System’s beam delivery 
- EmpowerTM, is modified to non-invasively deliver Near-Infrared Radiation (NIR) to subjects diagnosed with 
MDD. The modified system is also configured to provide sham (placebo) treatment. The device is 
manufactured and supplied by LiteCure LLC, 101 Lukens Dr, Suite A, New Castle, DE 18720. 
 
The tPBM-2.0 is considered a Class II medical device per 21 CFR 890.5500 and 878.4810 and is 
manufactured per 21 CFR 820. It utilizes a laser diode source with a maximum continuous (CW) output of 
≤30 Watts at a wavelength of 808 nanometers (nm) and nominal beam diameter of 40mm at the outside 
aperture. 
 
The tPBM-2.0 operates in one of five modes: NIR low irradiance (50 mW/cm2), NIR middle irradiance (300 
mW/cm2), continuoushigh irradiance (700 mW/cm2), NIR  pulsedhigh radiance (peak irradiance 833 
mW/cm2) and sham. The device’s behavior, performance/output of all visible and audible indicators 
including the graphic user interface, is identical for all modes, which differ only with respect to the 
parameters of laser emission. In simple terms, NIR modes of the tPBM-2.0 produces laser energy; sham 
mode does not produce laser energy. Therefore, since the laser radiation emitted during NIR mode is 
invisible to the naked eye, the modes are indistinguishable from one another. 

Study number: i20-00217 
 
Page 22 
Version: 2.3, 4 NOV 2021 
 
 
 
The tPBM-2.0 consists of a therapeutic laser console (that produces laser energy as NIR), and an optical 
delivery system consisting of a flexible, double-sheathed optical fiber connected to a custom helmet 
(cap). The cap is configured to deliver NIR light to EEG sites F4 and F3 (or in close proximity if covered 
by hair), covering a total surface treatment area of approximately 24 cm2[12 cm2 x 2]. It also includes laser 
safety eye ware with an optical density rating >5.0 at 808 nm. Participants will be blinded to the order in 
which they experience each of the four modes. The treatment mode administered at each session will 
depend on a pre-determined randomization scheme  
 
The therapeutic laser console is the only component of the device that is not MRI compatible. It will be 
stored in an equipment room located in Zone 2 (area with no detectable magnetic field but to which 
access is restricted due to scanner proximity). An MRI-compatible optical fiber will connect the laser 
console to the MRI-compatible cap. The safety eye wear is also MRI compatible.  
 
Aside from the cap, the tPBM-2.0 is the same device as LiteCure’s EXPi System – Model LTS-2500, which 
is marketed under FDA’s 510(K) # K107637. 
 
The cap is a custom 3D-printed headgear made of plastic and serves to hold the laser probe in place, 
between the MRI coil and the subject's head. The cap is provided by the device manufacturer 
(LiteCure) and is very similar to those used in our previous t-PBM studies. The laser probe (attached to the 
cap) will be connected to the laser console with a multimode MR-compatible optical fiber. The distal end of 
the optical fiber is fitted with ceramic ferrules, which will be affixed to the cap. The cap (headgear) contains 
clamps which secure the ferrules. The cap will be used in place of the wand. The cap is the only modification 
of the device delivery system, and it was required in order to do the t-PBM inside the MRI scanner. 
 
The t-PBM-2.0 is a nonsignificant risk device because it: 
 (1) Is NOT intended as an implant and DOES NOT present a potential for serious risk to the health, safety, 
or welfare of a subject;  
(2) Is NOT purported or represented to be for a use in supporting or sustaining human life and DOES NOT 
present a potential for serious risk to the health, safety, or welfare of a subject;  
(3) Is NOT for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or 
otherwise preventing impairment of human health and presents a potential for serious risk to the health, 
safety, or welfare of a subject; or  
(4) DOES NOT otherwise present a potential for serious risk to the health, safety, or welfare of a subject.  
 
Further, 
 
• 
The t-PBM-2.0 maximum dose administered in this study does not exceed the Maximum 
Permissible Exposure (MPE) for skin – Center for Devices and Radiological Health 
(CDRH), 21CFR1040.10 and 21CFR1040.11;  
• 
The t-PBM-2.0 is substantially equivalent to the OmniLux New U which the FDA has 
already categorized as a non-significant risk device;    
• 
Currently FDA-cleared lasers are typically available over-the-counter and are considered 
safe to use without professional supervision.  
 
At NKI both research coordinators and co-investigator Dr. Kate Collins, PhD, LCSW will operate the study 
device and perform other procedures under the close supervision of Dr. Iosifescu (PI). As in our previous 
studies with photobiomodulation at NKI, all study personnel involved in operating the laser will complete 
(and have valid training certificates for) the American Institute of Medical Laser Applications Medical 
Laser Safety training. In addition, they will be trained by the device manufacturer directly in device 
operation. Dr Iosifescu, the NKI research nurse (Sheela Sajan, RN), and one of the NKI research 
coordinators already have experience with the device, having administered t-PBM treatments in a prior 
study at NKI. 

Study number: i20-00217 
 
Page 23 
Version: 2.3, 4 NOV 2021 
 
 
5.1.1 Acquisition 
The t-PBM 2.0’s will be provided and shipped to sites by LiteCure® 
5.1.2 Product Storage and Stability 
The device(s) will be stored in MRI equipment rooms at NKI and MGH. These rooms are secure and well-
ventilated and have fire extinguishers readily available. The devices will be placed on flat hard surfaces 
with adequate airflow (including a minimum of 10cm clearance around the back of the device).  
5.1.3 Dosing and Administration 
Across the four visits participants experience one session each of: 1) sham t-PMB; 2) low-irradiance t-PBM; 
3) middle-irradiance t-PBM; and 4) high-irradiance t-PBM. The sequence in which the particular t-PBM 
parameters (summarized in Table 1) are utilized will be random; both participant and study staff will be blind 
to the parameters.  
5.1.4 Duration of Therapy 
Participants will undergo three sessions of active and one session of sham t-PBM, all during MR 
scanning. The duration of irradiation is 0, 3.33 or 20 minutes, depending on randomization; however, 
each session will last a total of 20 minutes to maintain blinding. 
5.2 Study Agent Accountability Procedures 
LiteCure will ship one device each to NKI and MGH. Sites will document the date and condition of the 
devices at reception and eventual return (via mail) at study conclusion.  
6 Study Procedures and Schedule 
6.1 Study Procedures/Evaluations 
Note that as many procedures as possible can and will be conducted remotely, via telephone or WebEx. 
Procedures marked with an asterisk (*) will require in person clinic visits. 
6.1.1 Study Specific Procedures versus Standard Clinical Care 
All procedures described in sections 6.2 and 6.3 will be performed as part of the study. None are part of 
standard clinical care. 
6.2 Study Schedule 
6.2.1 Screening Phase 
Duration: Up to 4 weeks, usually requires 1 remote session and 1 clinic visit. 
(Additional visits may be required to repeat laboratory testing in the case of suspect results, etc.) 
 
 
Study staff will: 
• 
Obtain informed consent of potential participant verified by signature on 
written informed consent for screening form. 
o 
If the first screen visit occurs remotely, the staff will obtain 
informed consent of the participant via WebEx (for explanation 
and discussion of form) and eConsenting via RedCap. 
• 
Obtain contact and demographic information required for study 
participation. 
• 
Administer the Montreal International Neuropsychiatric Interview (MINI), 
the Inventory for Depressive Symptomatology, Clinician-Rated scale 
(IDS-C), the Montreal Cognitive Assessment (MoCA), the Antidepressant 
Treatment Resistance Questionnaire (ATRQ),  the MRI safety checklist, 

Study number: i20-00217 
 
Page 24 
Version: 2.3, 4 NOV 2021 
 
 
and the Columbia Suicide Severity Risk Scale (C-SSRS), to determine 
eligibility based on inclusion/exclusion criteria. 
• 
Administer the NIS-Skin Color Scale (NIS-SCS). 
• 
Review medical history to determine eligibility based on 
inclusion/exclusion criteria. 
• 
Review concomitant medications and therapies to determine eligibility 
based on inclusion/exclusion criteria. 
• 
*Perform medical examinations needed to determine eligibility based on 
inclusion/exclusion criteria (includes recording vital signs). 
• 
*Collect blood (if indicated)/urine for laboratory testing to determine 
eligibility based on inclusion/exclusion criteria (see section 6.2.2). 
• 
*Test study device fit.  
• 
Verify inclusion/exclusion criteria. 
Schedule study visits for participants who are eligible and available for the duration of the study. Test 
Fit:Study staff will introduce the participant to the study device and confirm that they will be able to fit 
comfortably in the scanner while wearing it. We will exclude any participant who cannot fit.  
  
6.2.2 Clinical Laboratory Evaluations 
 
*Screening laboratory tests will include: 
• 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, platelet 
count. [DISCRETIONARY, may be ordered if physical exam or medical history indicates need.] 
• 
Biochemistry: creatinine, total bilirubin, alanine aminotransferase (ALT), aspartate 
• 
aminotransferase (AST), thyroid stimulating hormone (TSH). [DISCRETIONARY, may be ordered 
if physical exam or medical history indicated need.] 
• 
Urinalysis: dipstick urinalysis, including protein, hemoglobin and glucose; toxicology and (when 
applicable) pregnancy testing. 
 
6.2.3 Experimental Phase 
Duration: 4 visits over 4-8 weeks 
Timing:  No more than 2 weeks between each visit. 
While the provision of study treatment requires clinic attendance, we may conduct other components of the 
experimental visits remotely. 
 
At each of the four visits, study staff will: 
• 
*Record vital signs; 
• 
Administer   
      MADRS,  
      CGI-I (except Visit 1 as this will be considered a baseline rating), 
      CGI-S,  
      C-SSRS, and 
• 
MRI Safety Checklist; Record concomitant medications/therapies; 
• 
*Administer the t-PBM session during MR Scanning; 
• 
Record adverse events as reported by participant or observed by investigator. 
 
In addition, participants will complete: 
• 
PANAS, 
• 
PBQ 
• 
PCQ 
• 
SDQ,  
• 
ASQ, 
• 
SAFTEE 

Study number: i20-00217 
 
Page 25 
Version: 2.3, 4 NOV 2021 
 
 
• 
Neuro-QoL 
• 
Q-LES-Q-SF, and 
• 
TSRQ 
 
MGH Site Neuronavigation: The BrainSigth Neuronavigation System will be used at the MGH site to 
track the initial placement of the laser device on the subject’s forehead and will be utilized to ensure 
accurate replication of positioning at each experimental visit. This is a recording device that does not 
involve any added risk or stimulation. Traditionally, this device is used to record precise location of EEG 
electrodes and transcranial magnetic stimulation (TMS) coils. In our case, we will be using it to record 
the position of the outlet of the laser before every PBM session. The BrainSigth Neuronavigation System 
is FDA approved and is used as indicated. This device bounces light off of trackers that are placed on the 
forehead. Study staff lightly place a wand at various spots on the head. The system correlates the 
position of the wand with that of the trackers to precisely record the location of the head in relation to 
the photobiomodulation stimulation device. This is useful for later analysis, in which we will co-register the 
recorded laser position to the subject’s MRI.  
• 
For the NKI/NYU scans, lipid capsules are affixed to the device for demarcation of device location 
in the scans. 
 
MR: Scanning will begin with acquisition of structural images and (for most subjects) a baseline MR 
thermometry scan. Subsequently we will collect approximately 60 minutes of functional data collection 
including ~20 minutes before t-PBM, ~20 minutes coinciding with t-PBM, and ~20 minutes following t-PBM, 
as well as (for most subjects) a post-t-PBM MR thermometry scan. (For technical and logistical reasons, 
we may opt to skip the thermometry scan for some subjects.) 
 
Note that every scan performed in this study is saved and handled under the standard PHI confidentiality 
restrictions and regulations employed for patients’ information.  At least one scan per subject is additionally 
reviewed by a radiologist or neurologist with experience reading MRI scans, who might then detect an 
abnormality.  If clinically useful information is uncovered, either the Principal Investigator or another clinician 
on the study will speak to the subject in person or on the telephone regarding the new information. A copy 
of the original image report will also be provided to the subject in person and the subject will be encouraged 
to follow up on the discovery with his or her treating physician. 
 
t-PBM sessions: Across the four visits participants experience one session each of: 1) sham t-PMB; 2) 
low-irradiance t-PBM; 3) middle-irradiance t-PBM; and 4) high-irradiance t-PBM. The sequence in which 
the particular t-PBM parameters (summarized in Table 1) are utilized will be random. 
6.2.4 Follow-up Phase 
Duration: 1 phone call  
Timing: Within one week of fourth t-PBM/scan session 
 
Over the telephone study staff will administer the 
• 
CGI-I 
• 
CGI-S 
• 
MADRS, and  
• 
C-SSRS, and  
• 
record concomitant medications/therapies and any adverse events.  
 
Participants will also complete the following self-report scales remotely using Acquire: 
• 
PANAS 
• 
PCQ 
• 
SDQ, 
• 
ASQ, 
• 
SAFTEE, 
• 
Neuro-QoL 

Study number: i20-00217 
 
Page 26 
Version: 2.3, 4 NOV 2021 
 
 
6.2.5 Q-LES-Q-SF. Withdrawal/Early Termination Visit 
If early withdrawal or termination occurs, every effort will be made to schedule and conduct all 
assessments initially scheduled for the Follow-up Study Visit (See Section 6.2.4). 
6.2.6 Unscheduled Visit 
Any unscheduled visits will be documented with notes to file to be kept in study subjects’ binders. 
6.3 Concomitant Medications, Treatments, and Procedures 
All concomitant medications taken, and any other therapies intended to treat MDD that transpire, during 
study participation will be recorded on the case report forms (CRFs). For this protocol, a prescription 
medication is defined as a medication that can be prescribed only by a properly authorized/licensed 
clinician. Medications to be reported in the CRF are concomitant prescription medications, over-the-
counter medications and non-prescription medications.  
6.4 Prohibited Medications, Treatments, and Procedures 
SSRIs, SNRIs, or psychotherapy are permitted but will need to be stable for at least 8 weeks prior to the 
screen. Any device-based interventions for depression will need to be discontinued, at least 8 weeks prior 
to screen.  Rationale: Other treatments initiated or modified close to the study intervention could potentially 
confound the effect of t-PBM on BOLD-MR signal.     
 
If, due to worsening depression or other medical event, a change in antidepressant therapies is required 
during the study, participants may be asked to withdraw at that time at the discretion of the principal 
investigators. 
 
6.5 Prophylactic Medications, Treatments, and Procedures 
N/A 
6.6 Rescue Medications, Treatments, and Procedures 
N/A 
 
6.7 Participant Access to Study Agent at Study Closure 
Participants will not have access to the study agent at study closure. 
7 Assessment of Safety 
7.1 Specification of Safety Parameters  
In addition to recording and classifying adverse events (Sections 7.1 and 7.2), participants will also 
complete the SAFTEE and TSRQ at each visit. 
7.1.1 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal; 
• is associated with a serious adverse event; 
• is associated with clinical signs or symptoms; 
• leads to additional treatment or to further diagnostic tests; and/or 
• is considered by the investigator to be of clinical significance. 

Study number: i20-00217 
 
Page 27 
Version: 2.3, 4 NOV 2021 
 
 
7.1.2 Definition of Serious Adverse Events (SAE) 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
• fatal; 
• life-threatening; 
• requires or prolongs hospital stay; 
• results in persistent or significant disability or incapacity; 
• a congenital anomaly or birth defect; and/or 
• an important medical event. 
 
Important medical events are those that may not be immediately life threatening but are clearly of major 
clinical significance. They may jeopardize the subject and may require intervention to prevent one of the 
other serious outcomes noted above. For example, a seizure that did not result in in-patient 
hospitalization, or intensive treatment of bronchospasm in an emergency department would typically be 
considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  
7.1.3 Definition of Unanticipated Problems (UP) 
 
An unanticipated problem is any incident, experience, or outcome that meets all the following criteria:  
• Is unexpected in nature, severity, or frequency (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc); and 
• Is related or possibly related to participation in the research (i.e. 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 subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
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)). 
 
7.2 Classification of an Adverse Event 
7.2.1 Severity of Event 
 
For AEs, the following guidelines will be used to describe severity. 
 
• 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. 

Study number: i20-00217 
 
Page 28 
Version: 2.3, 4 NOV 2021 
 
 
7.2.2 Relationship to Study Agent 
 
The clinician’s assessment of an AE's relationship to study device is part of the documentation process, 
but it is not a factor in determining what is or is not reported in the study. If there is any doubt as to 
whether a clinical observation is an AE, the event should be reported. All AEs must have their relationship 
to study agent assessed. To help assess, the following guidelines are used. 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the AE’s 
causality based on temporal relationship and his/her clinical judgment. Evaluation of relatedness must 
consider etiologies such as natural history of the underlying disease, concurrent illness, concomitant 
therapy, study-related procedures, accidents, and other external factors. The degree of certainty about 
causality will be graded using the categories below. 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 
reasonable time after administration of the drug, is unlikely to be attributed to concurrent disease 
or other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related,” as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to drug administration makes a causal relationship improbable (e.g., the 
event did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
 
7.2.3 Expectedness 
 
Principal investigators will be responsible for determining whether an 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 in this protocol for the study agent. 
7.3 Time Period and Frequency for Event Assessment and Follow-Up 
 
The occurrence of an AE or 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 RF. 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 number: i20-00217 
 
Page 29 
Version: 2.3, 4 NOV 2021 
 
 
study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
 
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. UPs will be recorded in the data collection system 
throughout the study. 
 
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. 
 
The PI will record all reportable events with start dates occurring any time after informed consent is 
obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At 
each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events 
will be followed for outcome information until resolution or stabilization.  
 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  
 
7.4 Reporting Procedures – Notifying the IRB  
7.4.1 Adverse Event Reporting 
AEs that are unanticipated, determined to be at least “probably related” to the study intervention, and 
reveal a “greater risk of harm” than originally expected will be considered reportable new information and 
reported within 5 business days of the principle investigator(s) becoming aware of the event. 
 
Reports, signed by a principle investigator, will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’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 is 
unanticipated, at least probably related to the study intervention, and reveals a “greater risk of 
harm” than originally expected; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the unanticipated adverse events. 
 
All other adverse events will be reported annually to the IRB. 
7.4.2 Serious Adverse Event Reporting 
All SAEs will be reported to the IRB as soon as possible and certainly within 5 business days of the 
principle investigator(s) becoming aware of the event. 
 
Reports, signed by a principle investigator, will include the following information: 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB project number; 
• A detailed description of the event, incident, experience, or outcome; 

Study number: i20-00217 
 
Page 30 
Version: 2.3, 4 NOV 2021 
 
 
• An explanation of the basis for determining that the event, incident, experience, or outcome 
represents a serious adverse event; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the serious adverse event. 
7.4.3 Unanticipated Problem Reporting 
Unanticipated problems that are determined to be at least “probably related” to the study intervention, and 
reveal a “greater risk of harm” than originally expected will be considered reportable new information and 
reported within 5 business days of the principle investigator(s) becoming aware of problem. Other 
unanticipated problems will be reported within 10 business days of the principle investigator(s) becoming 
aware of the problem. 
 
Reports, signed by a principle investigator, will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’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 is 
unanticipated, at least probably related to the study intervention, and reveals a “greater risk of 
harm” than originally expected; 
• A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the unanticipated problem. 
 
7.4.4 Reporting of Pregnancy 
Any pregnancy will be considered reportable new information and reported as soon as possible and 
certainly within 5 business days of the principle investigator(s) becoming aware of the pregnancy. 
 
7.5 Reporting Procedures – Notifying the Study Sponsor 
 
The study clinician will complete an SAE Report within the following timelines: 
 
• All deaths and immediately life-threatening events, whether related or unrelated, will be recorded 
on the SAE Form and submitted to the study sponsor within 24 hours of site awareness. See 
Section 1, Key Roles for contact information. 
• Other SAEs regardless of relationship will be submitted to the study sponsor within 72 hours of 
site awareness. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the adherence to be stable. Other supporting documentation of the event may be requested by 
the DCC/study sponsor and should be provided as soon as possible.  
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated event or the unanticipated problem in 
the form of a written narrative.  This should include a copy of the completed Unanticipated Problem 
report, and any other diagnostic information that will assist the understanding of the event.  Significant 
new information on ongoing unanticipated adverse effects shall be provided promptly to the study 
sponsor. 
 
The study investigator shall complete an Unanticipated Adverse Device Effect Report and submit to the 
study sponsor and to the reviewing 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 contact information is provided in Section 
1, Key Roles. 
 

Study number: i20-00217 
 
Page 31 
Version: 2.3, 4 NOV 2021 
 
 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated event or the unanticipated problem in 
the form of a written narrative.  This should include a copy of the completed Unanticipated Problem form, 
and any other diagnostic information that will assist the understanding of the event.  Significant new 
information on ongoing unanticipated adverse effects shall be provided promptly to the study sponsor. 
 
The principal investigators are responsible for conducting an evaluation of an unanticipated adverse 
device effect and shall report the results of such evaluation to sponsor, FDA and to all reviewing IRBs and 
participating investigators within 10 working days after first receiving notice of the effect. Thereafter the 
sponsor shall submit such additional reports concerning the effect as FDA requests. 
7.6 Participating Investigators  
Each site will report unanticipated problems and all SAEs to the others within 10 days of site awareness. 
7.7 Study Halting Rules 
If at any time during the course of the study, the DSMB judges that risk to subjects outweighs the potential 
benefits, the DSMB shall have the discretion and responsibility to recommend that the study be terminated. 
7.8 Safety Oversight 
The PIs will regularly monitor potential risks and procedures for protecting risk: Drs. Iosifescu and 
Cassano will monitor the risks of evaluations and treatments provided at NYU, NKI, and MGH, 
respectively. The PIs will have weekly teleconference meetings during which any adverse events (AEs) or 
unexpected problems (UPs) will be discussed. The PIs will also meet in-person or via video conference at 
a minimum of twice yearly to review all aspects of study progress and safety. Each PI is ultimately 
responsible for monitoring the data and safety at that site and will provide continuous, close monitoring of 
adverse events. The investigators and study coordinators will evaluate the progress of the study, 
including periodic assessments of data quality and timeliness, participant recruitment, accrual and 
retention, participant risk versus benefit, performance of the various sites, and other factors that can 
affect study outcome. They will also consider factors external to the study, such as scientific or 
therapeutic developments that may have an impact on the safety of the participants or the ethics of the 
study. 
 
Data and Safety Monitoring Board (DSMB) 
A DSMB will be created as an independent body charged with ensuring that the safety of study subjects 
is protected and that the scientific goals of the study are being met. The DSMB (members and credentials 
listed below) will be responsible for data safety monitoring for the overall study. To support those 
purposes, the DSMB will review any proposed amendments to the study protocol, perform expedited 
monitoring of all serious adverse events, perform ongoing monitoring of drop-outs and non-serious 
adverse events, determine whether study procedures should be changed or the study should be halted 
for reasons related to the safety of study subjects, and perform periodic review of the completeness and 
validity of data to be used for analysis of safety and efficacy. The DSMB will also ensure subject privacy 
and research data confidentiality.   
 
Membership of the DSMB  
The DSMB will consist of the following three members with expertise in the following area(s): clinical trials 
in psychiatric populations with mood disorders, neuromodulation devices, and regulatory aspects of clinical 
research.  
 
1. Dr. Cristina Cusin, M.D.,is the Director of Translational Studies in Depression at Massachusetts General 
Hospital and an Assistant Professor in Psychiatry at Harvard Medical School. Dr. Cusin has significant 
experience with clinical and translational research studies in patients with major depressive disorder, 
including specific expertise in neuromodulation (device-based) therapies including ECT, VNS, DBS.  
 

Study number: i20-00217 
 
Page 32 
Version: 2.3, 4 NOV 2021 
 
 
2. Dr. Manish Jha, M.D., is Assistant Professor of Psychiatry and Neuroscience and Assistant Director of 
the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount 
Sinai, New York, NY. Dr. Jha conducts clinical and translational research studies in patients with major 
depression and related disorders; he has significant expertise with neuromodulation (TMS) in clinical and 
research settings.  
 
3. Dr. Menachem Krakowski, M.D., Ph.D., is a Research Scientist at the Nathan S. Kline Institute for 
Psychiatric Research (NKI) and a Research Associate Professor in the Department of Psychiatry at NYU 
School of Medicine. Dr. Krakowski has significant expertise in conducting clinical trials in subjects with 
severe mental illness and in the regulatory aspects of clinical research (as a long-standing member of the 
NKI IRB).  
 
Monitoring of Safety Data by the DSMB  
The Board will meet, by teleconference, at least bi-annually (every six months), and will have conference 
calls more often as needed. 
 
There are no predetermined stopping rules for the study. Every 6 months the DSMB will review side effects 
and determine whether the study may continue for the next 6 months. 
 
Dissemination of DSMB findings to Sites 
Following the DSMB meetings, the chair of the DSMB will discuss the safety data with the other board 
members, and together they make a determination about continuation of the study. This information is 
communicated both verbally to the PIs (informally at the end of the teleconference), as well as in a written 
report prepared by the Chair and sent to the PIs of both sites following the meeting. 
 
Unblinded Reporting   
Safety information for this study will be reported to the DSMB in an unblinded manner.  A statistical penalty 
will not be assessed for the ongoing unblinded review of safety by the DSMB. Unblinded data will not be 
released to the investigators unless necessary for safety reasons.  
 
Range of Safety Reporting to the DSMB    
The DSMB will review adverse events (AEs) and serious adverse events (SAEs) as recorded in the adverse 
events logs as well as, other data that may reflect differences in safety between treatment groups. This 
includes treatment retention rates, reasons for drop-out, and laboratory values reflecting potential toxicity.  
 
Serious Adverse Events   
Expedited review will occur for all SAEs. For purposes of this study, all SAEs will be reported to the DSMB, 
regardless of any judgment of their relatedness to the study intervention. All relevant information will be 
reported to the DSMB for each SAE including information about the event and its outcome, dosing history 
of the study intervention, concomitant medications, the subject’s medical history and current conditions, 
and all relevant laboratory data.  Notification by e-mail and fax transmittal of all related study forms shall be 
made to the DSMB within 7 days of the occurrence of any SAE. Information will be reviewed and a 
determination made of whether there was any possible relevance to the study intervention.  
 
Non-Serious Adverse Events   
At periodic intervals (biannually during the course of the study and then again at its completion), the DSMB 
will be provided with unblinded summaries of the numbers and rates of adverse events by treatment 
group.  These reports will include types of events, severity, and treatment phase.  Data on individual non-
serious adverse events is not expected to be needed for this review.  
 
Other Safety-Related Reports   
Biannually, the DSMB will also receive unblinded summary reports of treatment retention reasons for drop-
out, and laboratory values reflecting potential toxicity by treatment arm.    
 
Monitoring of Data Quality by the DSMB 

Study number: i20-00217 
 
Page 33 
Version: 2.3, 4 NOV 2021 
 
 
During the course of the study, the DSMB will receive reports on data quality and completeness.  At a 
minimum, these will include an overview of the progress of patient intake and retention; summary reports 
describing patient adherence with visits, evaluations, and dosing as described in the protocol; and a 
summary of the completeness and quality of key data elements needed to characterize patients, their 
dosing, and their primary and secondary outcomes.  These reports will be used by the DSMB to evaluate 
the capacity of the data capture and processing to support scientifically valid analyses.    
 
Annual DSMB Report to Sponsor  
Every twelve months, the DSMB will prepare a summary report of its findings regarding safety and quality 
based on data received to that point in the study.  This report will include a summary of all safety findings, 
as well as an assessment of protocol compliance and data quality.  Any recommendations to improve 
patient safety, 
 
8 Clinical Monitoring 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with applicable 
regulatory requirement(s). Each clinical site will perform internal quality management of study conduct, 
data collection, documentation and completion. An individualized quality management plan will be 
developed to describe a site’s quality management. 
9 Statistical Considerations 
9.1 Statistical Hypotheses 
Since the main goal of the study is to obtain evidence about the mechanism of action, the feasibility of 
implementation, and the potential for efficacy of novel treatment strategies that, if warranted, will be 
tested in future confirmatory studies, the emphasis of the statistical analysis will be on estimation (with 
effect sizes and confidence intervals) rather than on hypothesis testing.   
9.2 Analysis Datasets 
We will have two datasets: 
1) An Intention-To-Treat (ITT) dataset including all randomized participants (those eligible after 
screening); and 
2) A Modified Intention-To-Treat (MITT) dataset including all participants who undergo at least one scan/t-
PBM session. 
 
The MITT dataset will be used for almost all analyses. We will use the ITT dataset only to query whether 
there are any demographic or clinical differences between the groups of subjects that do and do not 
undergo at least one scan. 
9.3 Description of Statistical Methods 
9.3.1 General Approach 
Before any statistical techniques are applied, the distribution of all variables will be investigated using 
descriptive statistics and outliers will be examined.  Where necessary, non-parametric statistical methods 
will be used rather than relying on distributional assumptions.  Since the main goal of the study is to 
obtain evidence about the mechanism of action, the feasibility of implementation, and the potential for 
efficacy of novel treatment strategies that, if warranted, will be tested in future confirmatory studies, the 
emphasis of the statistical analysis will be on estimation (with effect sizes and confidence intervals) rather 
than on hypothesis testing.  Where formal hypothesis testing is employed, significance will be judged at 
5% level, two-sided. 

Study number: i20-00217 
 
Page 34 
Version: 2.3, 4 NOV 2021 
 
 
9.3.2 Analysis of the Primary Efficacy Endpoint(s) 
For each subject at each t-PBM dose (including sham) we will obtain the BOLD signal change measured 
in left and right dorsolateral prefrontal cortical regions of interest. These measures will be modeled as a 
function of dose (considered a categorical variable with 4 levels) using mixed effects models117, including 
random subject intercepts to account for the potentially correlated measures on the same subject.  Since 
the doses will be presented to subjects in a random order, the initial model will also include order of the 
dose (a continuous variable) and all interactions between the dose and the order.  If there is evidence for 
an interaction effect between dose and order, this effect will be investigated to understand how the dose 
effect varies as a function of week of treatment, and in such case effect size of the t-PBM doses will be 
estimated using only the data when the dose was given in the first week.  If there is no interaction 
between dose and order, the order variable and the interactions will be omitted and the resulting model 
will be used to estimate the mean BOLD signal measures at each dose and the differences between each 
active t-PBM dose and sham.   
 
9.3.3 Analysis of the Secondary Endpoint(s) 
For each subject at each t-PBM dose (including sham) we will compute changes in brain temperature 
using data recorded just before and after the t-PBM administration with MR thermometry scans.(Note that 
for technical and logistical reasons, some subjects may not undergo MR thermometry.) We will quantify 
the frequency and severity of suicidal ideation experienced as well as the presence or absence of suicidal 
behaviors after each t-PBM session using the C-SSRS. Finally, we will use the SAFTEE, TSRQ, and 
adverse events logs to determine the frequency and severity of side effects and adverse events. We will 
model these measures as a function of dose (considered a categorical variable with 4 levels) using mixed 
effects models117, including random subject intercepts to account for the potentially correlated measures 
on the same subject.  Since the doses will be presented to subjects in a random order, the initial models 
will also include order of the dose (a continuous variable) and all interactions between the dose and the 
order.  If there is evidence for an interaction effect between dose and order, this effect will be investigated 
to understand how the dose effect varies as a function of week of treatment, and in such case effect size 
of the t-PBM doses will be estimated using only the data when the dose was given in the first week.  
Whenever we find there is no interaction between dose and order, the order variable and the interactions 
will be omitted. The resulting models will be used to estimate the mean of each measure at each dose 
and the differences between each active t-PBM dose and sham.   
 
9.3.4 Safety Analyses 
See Section 9.3.3. 
 
9.3.5 Exploratory Analyses 
We will quantify 1) depression severity using the MADRS and SDQ scores, 2) anxiety severity using the 
ASQ scores, and 3) perceived quality of cognition using the Neuro-QoL scores and perceived quality of 
life using the Q-LES_Q-SF, as assessed at the visit after each dose of t-PBM. 
 
We will model these measures as a function of dose (considered a categorical variable with 4 levels) 
using mixed effects models117, controlling for baseline scores (from the first scan/t-PBM visit) and 
including random subject intercepts to account for the potentially correlated measures on the same 
subject.  Since the doses will be presented to subjects in a random order, the initial models will also 
include order of the dose (a continuous variable) and all interactions between the dose and the order.  If 
there is evidence for an interaction effect between dose and order, this effect will be investigated to 
understand how the dose effect varies as a function of week of treatment, and in such case effect size of 
the t-PBM doses will be estimated using only the data when the dose was given in the first week.  
Whenever we find there is no interaction between dose and order, the order variable and the interactions 
will be omitted. The resulting models will be used to estimate the mean of each measure at each dose 
and the differences between each active t-PBM dose and sham. 

Study number: i20-00217 
 
Page 35 
Version: 2.3, 4 NOV 2021 
 
 
9.4 Sample Size 
We anticipate no more than 20% dropout during the 4-week intervention, which would result in about 24 
observations at each of the 4 doses. This sample size would allow us to estimate the effect size of the 
optimal dose within 0.37 units (80% CI), or 0.57 (95% CI), which is considered an adequate level of 
evidence for the goals of the grant (R61) mechanism. Note that the analytic method is mixed effects model 
which will provide somewhat better power than the one reported above under worst-case scenario. Also of 
note, we observed a large effect size for BOLD signal changes (d=1.54) during t-PBM in the right MFG in 
our preliminary data103 
9.5 Measures to Minimize Bias 
9.5.1 Enrollment/Randomization/Blinding Procedures 
Subjects will be randomized to a specific series order of the 4 t-PBM/sham doses. There are 24 possible 
orders, 8 of which, (obtained from 2 different 4x4 Latin squares) will be used in each site. The study 
statistician (Dr. Petkova) will provide a single list to each site of block randomization of the order in which 
the 4 t-PBM-sham doses will be administered to each participant. This will be programmed in each site’s 
laser device interface. Subjects and will be blind to the intervention assignment. Sham adequacy will be 
tested with questionnaires (PBQ) at every visit. 
 
Blinding is maintained by including a heating element in the device which activates during sham mode, so 
subjects perceive a mild heating at skin level just as they would during active mode.  
 
We expected that, by randomizing the order of the t-PBM doses we will have equal attrition in all t-PBM 
arms, with 24 analyzable data points in all 4 dose groups. Hence, we will not replace participants. 
9.5.2 Evaluation of Success of Blinding 
We will use the placebo blinding questionnaire (PBQ) to evaluate the success of blinding. 
10 Source Documents and Access to Source Data/Documents 
Source data is 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. It is acceptable to use CRFs as source 
documents. If this is the case, it should be stated in this section what data will be collected on CRFs and 
what data will be collected from other sources. 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any 
entry error has been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
 
Access to study records will be limited to IRB-approved members of the study team. The investigator will 
permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, government 
regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.).  

Study number: i20-00217 
 
Page 36 
Version: 2.3, 4 NOV 2021 
 
 
The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
11 Quality Assurance and Quality Control 
QC procedures will be implemented beginning with the data entry system and data QC checks that will be 
run on the database will be generated. Any missing data or data anomalies will be communicated to the 
site(s) for clarification/resolution. 
 
Following written SOPs, the data coordinating center will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the 
applicable regulatory requirements. 
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
12 Ethics/Protection of Human Subjects 
12.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for the 
Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 
and/or the ICH E6. 
12.2 Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the 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. All changes to the consent form 
will be IRB approved; a determination will be made regarding whether previously consented participants 
need to be re-consented. 
12.3 Informed Consent Process 
12.3.1 Consent/Assent and Other Informational Documents Provided to Participants 
Consent forms (submitted with this protocol) describing in detail the study agent, study procedures, and 
risks are given to the participant and written documentation of informed consent is required prior to 
starting intervention/administering study product. During the COVID-19 pandemic, online remote 
consenting via RedCap will be used by the study staff. No study procedures are to occur before the 
participant gives their informed consent, whether that is an eConsent or an in-person consent.  
12.3.2 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Extensive discussion of risks and possible 
benefits of participation will be provided to the participants and their families in person or via WebEx. 
Consent forms will be IRB-approved, and the participant will be asked to read and review the document. 
The investigator will explain the research study to the participant and answer any questions that may 
arise. All participants will receive a verbal explanation in terms suited to their comprehension 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 participants should have the opportunity to discuss the study with their surrogates or think 

Study number: i20-00217 
 
Page 37 
Version: 2.3, 4 NOV 2021 
 
 
about it prior to agreeing to participate. The participant will sign (e-sign if consented remotely) the 
informed consent document prior to any procedures being done specifically for the study. The participants 
may withdraw consent at any time throughout the course of the trial. A copy of the signed informed 
consent document will be given to the participants for their records. 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. 
 
A copy of the signed informed consent document will be stored in the subject’s research record or (if 
digital), on the REDCap server The consent process, including the name of the individual obtaining 
consent, will be thoroughly documented in the subject’s research record. Any alteration to the standard 
consent process (e.g. use of a translator, consent from a legally authorized representative, consent 
document presented orally, etc.) and the justification for such alteration will likewise be documented.  
12.4 Posting of Clinical Trial Consent Form 
The informed consent form will be posted on the Federal website after the clinical trial is closed to 
recruitment, and no later than 60 days after the last study visit by any subject, as required by the protocol.  
12.5 Participant and Data Confidentiality 
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 ; and 
• The rights of a research subject to revoke their authorization for use of their PHI.  
 
Note that any remote data collection will be by telephone or WebEx. Webex is a HIPAA compliant platform 
that enables parties to communicate using a webcam. The study team member conducting the remote visits 
will be located in a private room to ensure confidentiality.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the 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 sponsor. 
 
Authorized representatives of the sponsor and representatives of the IRB may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit 
access to such records. 
 
The study participant’s contact information will be securely stored at each 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 local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at NYU Langone Medical Center. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be identified 

Study number: i20-00217 
 
Page 38 
Version: 2.3, 4 NOV 2021 
 
 
by a unique study identification number. The study data entry and study management systems used by 
clinical sites and by NYU Langone Medical Center research staff will be secured and password protected. 
At the end of the study, all study databases will be de-identified and archived at the NYU Langone 
Medical Center. Anonymized MRI data will be shared with our collaborator and co-investigator, Jacek 
Dmochowski, PhD, of CUNY, such that he will analyze the imaging data we collect. 
 
To further protect the privacy of study participants, the National Institutes of Health, as funding sponsor, 
will automatically generate a Certificate of Confidentiality. 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. 
12.5.1 Research Use of Stored Human Samples, Specimens, or Data 
• Intended Use: Data collected under this protocol may be used to study mood and anxiety 
disorders. No genetic testing will be performed. 
• Storage: Samples will not be stored. Data will be stored using codes assigned by the 
investigators. Data will be kept in password-protected computers. Only investigators will have 
access to the samples and data. 
• Tracking: A tracking file will link identification codes with identifying information, but this file will be 
password-protected and stored on a computer that can also only be accessed with a password. 
 
13 Data Handling and Record Keeping. 
13.1 Data Collection and Management Responsibilities 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, 
cross out the original entry with a single line, and initial and date the change. DO NOT ERASE, 
OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
 
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained 
and captured in a progress note and maintained in the participant’s official electronic study record. 
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and clinical 
laboratory data will be entered into Acquire, a 21 CFR Part 11-compliant data capture system provided by 
NKI’s Innovative Clinical Research Solutions. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents. 
 
13.2 Study Records Retention 
Study documents will be retained for the longer of 3 years after close-out, 5 years after final 
reporting/publication, or 2 years after the last approval of a marketing application is approved for the drug 
for the indication for which it is being investigated or 2 years after the investigation is discontinued and 

Study number: i20-00217 
 
Page 39 
Version: 2.3, 4 NOV 2021 
 
 
FDA is notified if no application is to be filed or if the application has not been approved for such 
indication. No records will be destroyed without the written consent of the sponsor, if applicable. It is the 
responsibility of the sponsor to inform the investigator when these documents no longer need to be 
retained. 
13.3 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly. 
 
These practices are consistent with ICH E6: 
• 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 
• 5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site PI/study staff to use continuous vigilance to identify and report deviations. 
All protocol deviations will be addressed in study source documents. 
 
Protocol deviations must be reported to the IRB per their guidelines. The site PI/study staff is responsible 
for knowing and adhering to IRB requirements.  
13.4 Publication and Data Sharing Policy 
This study will comply with the 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. 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical 
trials registration policy as a condition for publication. The ICMJE defines a clinical trial as any research 
project that prospectively assigns human subjects to intervention or concurrent comparison or control 
groups to study the cause-and-effect relationship between a medical intervention and a health outcome. 
Medical interventions include drugs, surgical procedures, devices, behavioral treatments, process-of-care 
changes, and the like. Health outcomes include any biomedical or health-related measures obtained in 
patients or participants, including pharmacokinetic measures and adverse events. The ICMJE policy, and 
the Section 801 of the Food and Drug Administration Amendments Act of 2007, requires that all clinical 
trials be registered in a public trials registry such as ClinicalTrials.gov, which is sponsored by the National 
Library of Medicine. Other biomedical journals are considering adopting similar policies. For interventional 
clinical trials performed under NIH IC grants and cooperative agreements, it is the grantee’s responsibility 
to register the trial in an acceptable registry, so the research results may be considered for publication in 
ICMJE member journals. The ICMJE does not review specific studies to determine whether registration is 
necessary; instead, the committee recommends that researchers who have questions about the need to 
register err on the side of registration or consult the editorial office of the journal in which they wish to 
publish. 
 
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register 
and report results of certain "applicable clinical trials": 
 
• Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations 
of a product subject to FDA regulation; 
• Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation 
(other than small feasibility studies) and pediatric postmarket surveillance studies. 
• NIH grantees must take specific steps to ensure compliance with NIH implementation of FDAAA. 

Study number: i20-00217 
 
Page 40 
Version: 2.3, 4 NOV 2021 
 
 
14 Study Finances 
14.1 Funding Source 
 This study is financed through a grant from the US National Institute of Health. 
14.2 Costs to the Participant 
There are no costs to the participant. 
14.3 Participant Reimbursements or Payments 
Patients are compensated for expenses of parking and travel associated with study participation, at a rate 
which is reasonable, however unlikely to induce coercion for research participation. We will compensate 
each subject $50 for screening and $75 for each MRI they complete (up to 4 MRIs per subject for a total of 
$300) for time, effort and inconvenience. Subjects will also be reimbursed for transportation costs at each 
visit (maximum $50 per visit). Finally, each subject will receive $50 for completion of the follow-up visit, 
again as compensation for time, effort and inconvenience. 
15 Study Administration 
15.1 Study Leadership 
A Steering Committee (SC), chaired by study PIs Drs. Iosifescu and Cassano and including CUNY Co-I Dr. 
Dmochowski, will serve as the operational governing board.  .  Program personnel from the NIMH and 
external scientists may be appointed at the recommendation of NIMH.  The SC will be tasked with 
monitoring scientific progress, including assessing recruitment, progress of study task milestones, ensuring 
timely publication of abstracts and articles, and ensuring timely submission of data to ClinicalTrials.gov.  
The SC will meet via monthly teleconference or in-person. 
16 Conflict of Interest Policy 
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 trial 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 trial. 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.  
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by the NYU 
Langone Conflict of Interest Management Unit (CIMU) with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study sponsor prior to participation in this study. All 
NYULMC investigators will follow the applicable conflict of interest policies. 
 
 
 

Study number: i20-00217 
 
Page 41 
Version: 2.3, 4 NOV 2021 
 
 
17 References 
 
1. 
Kessler RC, Petukhova M, Sampson NA, Zaslavsky AM, Wittchen HU. Twelve-month and lifetime 
prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods 
Psychiatr Res. 2012;21(3):169-184. 
2. 
Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and 
years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global 
Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-1602. 
3. 
Bloom DE, Cafiero ET, Jané-Llopis E, et al. The Global Economic Burden of Noncommunicable 
Diseases. Geneva: World Economic Forum. 2011. 
4. 
van Beljouw I, Verhaak P, Prins M, Cuijpers P, Penninx B, Bensing J. Reasons and determinants 
for not receiving treatment for common mental disorders. Psychiatr Serv. 2010;61(3):250-257. 
5. 
Jorm AF, Griffiths KM, Christensen H, Parslow RA, Rogers B. Actions taken to cope with 
depression at different levels of severity: a community survey. Psychol Med. 2004;34(2):293-299. 
6. 
Hirschfeld RM, Keller MB, Panico S, et al. The National Depressive and Manic-Depressive 
Association consensus statement on the undertreatment of depression. JAMA. 1997;277(4):333-340. 
7. 
Cassano P, Fava M. Tolerability issues during long-term treatment with antidepressants. Annals of 
Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists. 2004;16(1):15-25. 
8. 
Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments 
(CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 
3. Pharmacological Treatments. Can J Psychiatry. 2016;61(9):540-560. 
9. 
Parikh SV, Quilty LC, Ravitz P, et al. Canadian Network for Mood and Anxiety Treatments 
(CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 
2. Psychological Treatments. Can J Psychiatry. 2016;61(9):524-539. 
10. 
Milev RV, Giacobbe P, Kennedy SH, et al. Canadian Network for Mood and Anxiety Treatments 
(CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 
4. Neurostimulation Treatments. Can J Psychiatry. 2016;61(9):561-575. 
11. 
Survey: Nearly 25% of Americans Own a Wearable Device. 2017; https://blog.wellable.co/nearly-
25-of-americans-own-a-wearable-device, 2019. 
12. 
Henderson TA, Morries LD. Near-infrared photonic energy penetration: can infrared phototherapy 
effectively reach the human brain? Neuropsychiatric disease and treatment. 2015;11:2191-2208. 
13. 
Jagdeo JR, Adams LE, Brody NI, Siegel DM. Transcranial red and near infrared light transmission 
in a cadaveric model. PLoS One. 2012;7(10):e47460. 
14. 
Tedford CE, DeLapp S, Jacques S, Anders J. Quantitative analysis of transcranial and 
intraparenchymal light penetration in human cadaver brain tissue. Lasers Surg Med. 2015;47(4):312-322. 
15. 
Konstantinovic LM, Jelic MB, Jeremic A, Stevanovic VB, Milanovic SD, Filipovic SR. Transcranial 
application of near-infrared low-level laser can modulate cortical excitability. Lasers Surg Med. 
2013;45(10):648-653. 
16. 
Chaieb L, Antal A, Masurat F, Paulus W. Neuroplastic effects of transcranial near-infrared 
stimulation (tNIRS) on the motor cortex. Front Behav Neurosci. 2015;9:147. 
17. 
Henderson TA, Morries LD. SPECT Perfusion Imaging Demonstrates Improvement of Traumatic 
Brain Injury With Transcranial Near-infrared Laser Phototherapy. Adv Mind Body Med. 2015;29(4):27-33. 
18. 
Nawashiro H, Wada K, Nakai K, Sato S. Focal increase in cerebral blood flow after treatment with 
near-infrared light to the forehead in a patient in a persistent vegetative state. Photomedicine and laser 
surgery. 2012;30(4):231-233. 
19. 
Salgado AS, Zangaro RA, Parreira RB, Kerppers, II. The effects of transcranial LED therapy (TCLT) 
on cerebral blood flow in the elderly women. Lasers Med Sci. 2015;30(1):339-346. 
20. 
Tian F, Hase SN, Gonzalez-Lima F, Liu H. Transcranial laser stimulation improves human cerebral 
oxygenation. Lasers Surg Med. 2016;48(4):343-349. 
21. 
Hacke W, Schellinger PD, Albers GW, et al. Transcranial Laser Therapy in Acute Stroke Treatment 
Results of Neurothera Effectiveness and Safety Trial 3, a Phase III Clinical End Point Device Trial. Stroke. 
2014;45(11):3187-3193. 
22. 
Lampl Y, Zivin JA, Fisher M, et al. Infrared Laser Therapy for Ischemic Stroke: A New Treatment 
Strategy Results of the NeuroThera Effectiveness and Safety Trial-1 (NEST-1). Stroke. 2007;38(6):1843-
1849. 

Study number: i20-00217 
 
Page 42 
Version: 2.3, 4 NOV 2021 
 
 
23. 
Zivin JA, Albers GW, Bornstein N, et al. Effectiveness and safety of transcranial laser therapy for 
acute ischemic stroke. Stroke. 2009;40(4):1359-1364. 
24. 
Mohammed HS. Transcranial low-level infrared laser irradiation ameliorates depression induced 
by reserpine in rats. Lasers Med Sci. 2016;31(8):1651-1656. 
25. 
Salehpour F, Rasta SH. The potential of transcranial photobiomodulation therapy for treatment of 
major depressive disorder. Rev Neurosci. 2017. 
26. 
Salehpour F, Rasta SH, Mohaddes G, Sadigh-Eteghad S, Salarirad S. Therapeutic effects of 10-
HzPulsed wave lasers in rat depression model: A comparison between near-infrared and red wavelengths. 
Lasers Surg Med. 2016;48(7):695-705. 
27. 
Xu Z, Guo X, Yang Y, et al. Low-Level Laser Irradiation Improves Depression-Like Behaviors in 
Mice. Mol Neurobiol. 2016. 
28. 
Wu X, Alberico SL, Moges H, De Taboada L, Tedford CE, Anders JJ. Pulsed light irradiation 
improves behavioral outcome in a rat model of chronic mild stress. Lasers Surg Med. 2012;44(3):227-232. 
29. 
Schiffer F, Johnston AL, Ravichandran C, et al. Psychological benefits 2 and 4 weeks after a single 
treatment with near infrared light to the forehead: a pilot study of 10 patients with major depression and 
anxiety. Behav Brain Funct. 2009;5:46. 
30. 
Cassano P, Cusin C, Mischoulon D, et al. Near-Infrared Transcranial Radiation for Major 
Depressive Disorder: Proof of Concept Study. Psychiatry J. 2015;2015:352979. 
31. 
Cassano P, Petrie SR, Hamblin MR, Henderson TA, Iosifescu DV. Review of transcranial 
photobiomodulation for major depressive disorder: targeting brain metabolism, inflammation, oxidative 
stress, and neurogenesis. Neurophotonics. 2016;3(3):031404. 
32. 
Caldieraro MA, Sani G, Bui E, Cassano P. Long-Term Near-Infrared Photobiomodulation for 
Anxious 
Depression 
Complicated 
by 
Takotsubo 
Cardiomyopathy. 
J 
Clin 
Psychopharmacol. 
2018;38(3):268-270. 
33. 
Caldieraro MA, Cassano P. Transcranial and systemic photobiomodulation for major depressive 
disorder: A systematic review of efficacy, tolerability and biological mechanisms. J Affect Disord. 
2019;243:262-273. 
34. 
Disner SG, Beevers CG, Gonzalez-Lima F. Transcranial Laser Stimulation as Neuroenhancement 
for Attention Bias Modification in Adults with Elevated Depression Symptoms. Brain stimulation. 
2016;9(5):780-787. 
35. 
Cassano P, Petrie SR, Mischoulon D, et al. Transcranial Photobiomodulation for the Treatment of 
Major Depressive Disorder. The ELATED-2 Pilot Trial. Photomedicine and laser surgery. 2018. 
36. 
Hipskind SG, Grover FL, Jr., Fort TR, et al. Pulsed Transcranial Red/Near-Infrared Light Therapy 
Using Light-Emitting Diodes Improves Cerebral Blood Flow and Cognitive Function in Veterans with Chronic 
Traumatic Brain Injury: A Case Series. Photomedicine and laser surgery. 2018. 
37. 
Vargas E, Barrett DW, Saucedo CL, et al. Beneficial neurocognitive effects of transcranial laser in 
older adults. Lasers Med Sci. 2017;32(5):1153-1162. 
38. 
Wang Y, Zhang H, Tang S, et al. Assessing regional cerebral blood flow in depression using 320-
slice computed tomography. PLoS One. 2014;9(9):e107735. 
39. 
Nagafusa Y, Okamoto N, Sakamoto K, et al. Assessment of cerebral blood flow findings using 
99mTc-ECD single-photon emission computed tomography in patients diagnosed with major depressive 
disorder. J Affect Disord. 2012;140(3):296-299. 
40. 
Sheehan, D. V., Lecrubier, Y., Sheehan, K. H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., 
Baker, R., & Dunbar, G. C. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): The 
development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. The 
Journal of Clinical Psychiatry, 59 Suppl 20, 22-33;quiz 34-57. 
41. 
Rush, A. J., Carmody, T., & Reimitz, P.-E. (2000). The Inventory of Depressive Symptomatology 
(IDS): Clinician (IDS-C) and Self-Report (IDS-SR) ratings of depressive symptoms. International Journal of 
Methods in Psychiatric Research, 9(2), 45–59. https://doi.org/10.1002/mpr.79 
42. 
Nasreddine, Z. S., Phillips, N. A., Bédirian, V., Charbonneau, S., Whitehead, V., Collin, I., 
Cummings, J. L., & Chertkow, H. (2005). The Montreal Cognitive Assessment, MoCA: A brief screening 
tool for mild cognitive impairment. Journal of the American Geriatrics Society, 53(4), 695–699. 
https://doi.org/10.1111/j.1532-5415.2005.53221.x 
43. 
Chandler GM, Iosifescu DV, Pollack MH, Targum SD, and Fava M. Validation of the Massachusetts 
General Hospital Antidepressant Treatment History Questionnaire (ATRQ). CNS NeurosciTher 2010. 
16(5):322-5. 

Study number: i20-00217 
 
Page 43 
Version: 2.3, 4 NOV 2021 
 
 
44. 
Massey, Douglas S., Martin, J.A. (2003). The NIS Skin Color Scale. 
45. 
Levine, J., & Schooler NR. (1986). SAFTEE: A technique for the systematic assessment of side 
effects in clinical trials. Psychopharmacol Bulletin, 22, 343-381. 
46. 
Watson, D., Clark, L. A., & Tellegen, A. (1988). Development and validation of brief measures of 
positive and negative affect: The PANAS scales. Journal of Personality and Social Psychology, 54(6), 
1063–1070. https://doi.org/10.1037//0022-3514.54.6.1063 
47. 
Montgomery SA and Åsberg M. A new depression rating scale designed to be sensitive to change. 
Br J Psychiatry 1979. 134:382–389. 
48. 
Pedrelli, P., Blais, M. A., Alpert, J. E., Shelton, R. C., Walker, R. S., & Fava, M. (2014). Reliability 
and validity of the Symptoms of Depression Questionnaire (SDQ). CNS spectrums, 19(06), 535-546. 
49. 
Baker, A., Simon, N., Keshaviah, A., Farabaugh, A., Deckersbach, T., Worthington, J. J., Hoge, E., 
Fava, M., & Pollack, M. P. (2019). Anxiety Symptoms Questionnaire (ASQ): Development and validation. 
General Psychiatry, 32(6). https://doi.org/10.1136/gpsych-2019-100144 
50. 
Cella, D., Lai, J.-S., Nowinski, C. J., Victorson, D., Peterman, A., Miller, D., Bethoux, F., 
Heinemann, A., Rubin, S., Cavazos, J. E., Reder, A. T., Sufit, R., Simuni, T., Holmes, G. L., Siderowf, A., 
Wojna, V., Bode, R., McKinney, N., Podrabsky, T., … Moy, C. (2012). Neuro-QOL. Neurology, 78(23), 
1860–1867. https://doi.org/10.1212/WNL.0b013e318258f744 
51. 
Yue L, Humayun MS. Monte Carlo analysis of the enhanced transcranial penetration using 
distributed near-infrared emitter array. J Biomed Opt. 2015;20(8):88001. 
52. 
Hashmi JT, Huang YY, Sharma SK, et al. Effect of pulsing in low-level light therapy. Lasers Surg 
Med. 2010;42(6):450-466. 
53. 
Chung H, Dai T, Sharma SK, Huang Y-Y, Carroll JD, Hamblin MR. The nuts and bolts of low-level 
laser (light) therapy. Annals of biomedical engineering. 2012;40(2):516-533. 
54. 
Mochizuki-Oda N, Kataoka Y, Cui Y, Yamada H, Heya M, Awazu K. Effects of near-infra-red laser 
irradiation on adenosine triphosphate and adenosine diphosphate contents of rat brain tissue. Neurosci 
Lett. 2002;323(3):207-210. 
55. 
Karu TI, Kolyakov SF. Exact action spectra for cellular responses relevant to phototherapy. 
Photomedicine and laser surgery. 2005;23(4):355-361. 
56. 
Drevets WC, Bogers W, Raichle ME. Functional anatomical correlates of antidepressant drug 
treatment 
assessed 
using 
PET 
measures 
of 
regional 
glucose 
metabolism. 
European 
Neuropsychopharmacology. 2002;12(6):527-544. 
57. 
Kennedy S, Konarski J, Segal Z, et al. Differences in brain glucose metabolism between 
responders to CBT and venlafaxine in a 16-week randomized controlled trial. American Journal of 
Psychiatry. 2007;164(5):778-788. 
58. 
Mayberg HS, Brannan SK, Tekell JL, et al. Regional metabolic effects of fluoxetine in major 
depression: serial changes and relationship to clinical response. Biological psychiatry. 2000;48(8):830-843. 
59. 
Videbech P. PET measurements of brain glucose metabolism and blood flow in major depressive 
disorder: a critical review. Acta Psychiatrica Scandinavica. 2000;101(1):11-20. 
60. 
Bansal Y, Kuhad A. Mitochondrial Dysfunction in Depression. Curr Neuropharmacol. 
2016;14(6):610-618. 
61. 
Hroudová J, Fišar Z, Kitzlerová E, Zvěřová M, Raboch J. Mitochondrial respiration in blood platelets 
of depressive patients. Mitochondrion. 2013;13(6):795-800. 
62. 
Iosifescu DV, Bolo NR, Nierenberg AA, Jensen JE, Fava M, Renshaw PF. Brain bioenergetics and 
response to triiodothyronine augmentation in major depressive disorder. Biological psychiatry. 
2008;63(12):1127-1134. 
63. 
Karabatsiakis A, Bock C, Salinas-Manrique J, et al. Mitochondrial respiration in peripheral blood 
mononuclear cells correlates with depressive subsymptoms and severity of major depression. Transl 
Psychiatry. 2014;4:e397. 
64. 
Morava E, Kozicz T. Mitochondria and the economy of stress (mal)adaptation. Neurosci Biobehav 
Rev. 2013;37(4):668-680. 
65. 
Oron U, Ilic S, De Taboada L, Streeter J. Ga-As (808 nm) laser irradiation enhances ATP production 
in human neuronal cells in culture. Photomedicine and laser surgery. 2007;25(3):180-182. 
66. 
Yu W, Naim JO, McGowan M, Ippolito K, Lanzafame RJ. Photomodulation of oxidative metabolism 
and electron chain enzymes in rat liver mitochondria. Photochemistry and photobiology. 1997;66(6):866-
871. 

Study number: i20-00217 
 
Page 44 
Version: 2.3, 4 NOV 2021 
 
 
67. 
de Freitas LF, Hamblin MR. Proposed Mechanisms of Photobiomodulation or Low-Level Light 
Therapy. IEEE J Sel Top Quantum Electron. 2016;22(3). 
68. 
Greco M, Guida G, Perlino E, Marra E, Quagliariello E. Increase in RNA and protein synthesis by 
mitochondria irradiated with helium-neon laser. Biochem Biophys Res Commun. 1989;163(3):1428-1434. 
69. 
Eren İ, Nazıroğlu M, Demirdaş A. Protective effects of lamotrigine, aripiprazole and escitalopram 
on depression-induced oxidative stress in rat brain. Neurochemical research. 2007;32(7):1188-1195. 
70. 
Ozcan ME, Gulec M, Ozerol E, Polat R, Akyol O. Antioxidant enzyme activities and oxidative stress 
in affective disorders. International clinical psychopharmacology. 2004;19(2):89-95. 
71. 
Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S. Major depressive disorder is 
accompanied with oxidative stress: short‐term antidepressant treatment does not alter oxidative–
antioxidative systems. Human Psychopharmacology: Clinical and Experimental. 2007;22(2):67-73. 
72. 
Shungu DC, Weiduschat N, Murrough JW, et al. Increased ventricular lactate in chronic fatigue 
syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in 
disorder pathophysiology. NMR Biomed. 2012;25(9):1073-1087. 
73. 
Spanemberg L, Caldieraro MA, Vares EA, et al. Biological differences between melancholic and 
nonmelancholic depression subtyped by the CORE measure. Neuropsychiatric disease and treatment. 
2014;10:1523-1531. 
74. 
Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. 
Biol Psychiatry. 2010;67(5):446-457. 
75. 
Kohler CA, Freitas TH, Maes M, et al. Peripheral cytokine and chemokine alterations in depression: 
a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017;135(5):373-387. 
76. 
Liu Y, Ho RC, Mak A. Interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha) and soluble 
interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: a meta-analysis 
and meta-regression. J Affect Disord. 2012;139(3):230-239. 
77. 
Yoshimura R, Hori H, Ikenouchi-Sugita A, Umene-Nakano W, Ueda N, Nakamura J. Higher plasma 
interleukin-6 
(IL-6) 
level 
is 
associated 
with 
SSRI- 
or 
SNRI-refractory 
depression. 
Prog 
Neuropsychopharmacol Biol Psychiatry. 2009;33(4):722-726. 
78. 
Lindqvist D, Janelidze S, Hagell P, et al. Interleukin-6 is elevated in the cerebrospinal fluid of suicide 
attempters and related to symptom severity. Biological psychiatry. 2009;66(3):287-292. 
79. 
Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. 
Pharmacol Rev. 2012;64(2):238-258. 
80. 
Duman RS. Pathophysiology of depression and innovative treatments: remodeling glutamatergic 
synaptic connections. Dialogues Clin Neurosci. 2014;16(1):11-27. 
81. 
Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM. Serum BDNF 
concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-
analyses on 179 associations (N=9484). Mol Psychiatry. 2014;19(7):791-800. 
82. 
Rizzi CF, Mauriz JL, Freitas Corrêa DS, et al. Effects of low‐level laser therapy (LLLT) on the 
nuclear factor (NF)‐κB signaling pathway in traumatized muscle. Lasers in surgery and medicine. 
2006;38(7):704-713. 
83. 
Chludzińska L, Ananicz E, Jaros3awska A, Komorowska M. Near-infrared radiation protects the 
red cell membrane against oxidation. Blood Cells, Molecules, and Diseases. 2005;35(1):74-79. 
84. 
Araki H, Imaoka A, Kuboyama N, Abiko Y. Reduction of interleukin-6 expression in human 
synoviocytes and rheumatoid arthritis rat joints by linear polarized near infrared light (Superlizer) irradiation. 
Laser Therapy. 2011;20(4):293. 
85. 
Yamaura M, Yao M, Yaroslavsky I, Cohen R, Smotrich M, Kochevar IE. Low level light effects on 
inflammatory cytokine production by rheumatoid arthritis synoviocytes. Lasers in surgery and medicine. 
2009;41(4):282-290. 
86. 
Anders JJ. The potential of light therapy for central nervous system injury and disease. 
Photomedicine and laser surgery. 2009;27(3):379-380. 
87. 
Giuliani A, Lorenzini L, Gallamini M, Massella A, Giardino L, Calzà L. Low infra red laser light 
irradiation on cultured neural cells: effects on mitochondria and cell viability after oxidative stress. BMC 
complementary and alternative medicine. 2009;9(1):8. 
88. 
Rojas JC, Lee J, John JM, Gonzalez-Lima F. Neuroprotective effects of near-infrared light in an in 
vivo model of mitochondrial optic neuropathy. The Journal of Neuroscience. 2008;28(50):13511-13521. 
89. 
Wong-Riley MT, Liang HL, Eells JT, et al. Photobiomodulation directly benefits primary neurons 
functionally inactivated by toxins: role of cytochrome c oxidase. J Biol Chem. 2005;280(6):4761-4771. 

Study number: i20-00217 
 
Page 45 
Version: 2.3, 4 NOV 2021 
 
 
90. 
Ando T, Xuan W, Xu T, et al. Comparison of therapeutic effects between pulsed and continuous 
wave 810-nm wavelength laser irradiation for traumatic brain injury in mice. PLoS One. 2011;6(10):e26212. 
91. 
Oron A, Oron U, Streeter J, et al. Low-level laser therapy applied transcranially to mice following 
traumatic brain injury significantly reduces long-term neurological deficits. Journal of neurotrauma. 
2007;24(4):651-656. 
92. 
Wu Q, Xuan W, Ando T, et al. Low‐Level Laser Therapy for Closed‐Head Traumatic Brain Injury in 
Mice: Effect of Different Wavelengths. Lasers in surgery and medicine. 2012;44(3):218-226. 
93. 
Xuan W, Vatansever F, Huang L, et al. Transcranial low-level laser therapy improves neurological 
performance in traumatic brain injury in mice: effect of treatment repetition regimen. PLoS One. 
2013;8(1):e53454. 
94. 
Xuan W, Agrawal T, Huang L, Gupta GK, Hamblin MR. Low-level laser therapy for traumatic brain 
injury in mice increases brain derived neurotrophic factor (BDNF) and synaptogenesis. J Biophotonics. 
2015;8(6):502-511. 
95. 
Rojas JC, Bruchey AK, Gonzalez-Lima F. Low-level light therapy improves cortical metabolic 
capacity and memory retention. Journal of Alzheimer's Disease. 2012;32(3):741-752. 
96. 
Uozumi Y, Nawashiro H, Sato S, Kawauchi S, Shima K, Kikuchi M. Targeted increase in cerebral 
blood flow by transcranial near-infrared laser irradiation. Lasers Surg Med. 2010;42(6):566-576. 
97. 
Ho MD, Martin PI, Yee MK, et al. Increased functional connectivity in default mode network 
associated with application 
of transcranial, light-emitting diodes to treat chronic aphasia: case series. Journal of International 
Neuropsychiatry. 2016;22:229. 
98. 
Tanaka Y, Akiyoshi J, Kawahara Y, et al. Infrared radiation has potential antidepressant and 
anxiolytic effects in animal model of depression and anxiety. Brain stimulation. 2011;4(2):71-76. 
99. 
Koenigs M, Grafman J. The functional neuroanatomy of depression: distinct roles for ventromedial 
and dorsolateral prefrontal cortex. Behav Brain Res. 2009;201(2):239-243. 
100. 
Huisa BN, Stemer AB, Walker MG, et al. Transcranial laser therapy for acute ischemic stroke: a 
pooled analysis of NEST-1 and NEST-2. Int J Stroke. 2013;8(5):315-320. 
101. 
Morries L, Cassano P, Henderson T. Treatments for traumatic brain injury with emphasis on 
transcranial near-infrared laser phototherapy. Neuropsychiatric disease and treatment. 2015;11:2159-
2175. 
102. 
Zivin JA, Sehra R, Shoshoo A, et al. NeuroThera(R) Efficacy and Safety Trial-3 (NEST-3): a double-
blind, randomized, sham-controlled, parallel group, multicenter, pivotal study to assess the safety and 
efficacy of transcranial laser therapy with the NeuroThera(R) Laser System for the treatment of acute 
ischemic stroke within 24 h of stroke onset. Int J Stroke. 2014;9(7):950-955. 
103. 
Dmochowski GM, Dmochowski J. Increased Blood Flow and Oxidative Metabolism in the Human 
Brain by Transcranial Laser Stimulation. bioRxiv. In Press  
104. 
Posse S, Wiese S, Gembris D, et al. Enhancement of BOLD-contrast sensitivity by single-shot 
multi-echo functional MR imaging. Magn Reson Med. 1999;42(1):87-97. 
105. 
Chow GC. Tests of Equality Between Sets of Coefficients in Two Linear Regressions. 
Econometrica. 1960;28(3):591-605. 
106. 
Cassano P, Tran AP, Katani H, et al. Selective photobiomodulation for emotion regulation: A model-
based dosimetry study. Neurophotonics. In Press  
107. 
Blanco NJ, Maddox WT, Gonzalez-Lima F. Improving executive function using transcranial infrared 
laser stimulation. J Neuropsychol. 2017;11(1):14-25. 
108. 
Barrett DW, Gonzalez-Lima F. Transcranial infrared laser stimulation produces beneficial cognitive 
and emotional effects in humans. Neuroscience. 2013;230:13-23. 
109. 
Hwang J, Castelli DM, Gonzalez-Lima F. Cognitive enhancement by transcranial laser stimulation 
and acute aerobic exercise. Lasers Med Sci. 2016;31(6):1151-1160. 
110. 
Posner, K., Brown, G. K., Stanley, B., Brent, D. A., Yershova, K. V., Oquendo, M. A., Currier, G. 
W., Melvin, G. A., Greenhill, L., Shen, S., & Mann, J. J. (2011). The Columbia-Suicide Severity Rating 
Scale: Initial validity and internal consistency findings from three multisite studies with adolescents and 
adults. The American Journal of Psychiatry, 168(12), 1266–1277. 
https://doi.org/10.1176/appi.ajp.2011.10111704 

Study number: i20-00217 
 
Page 46 
Version: 2.3, 4 NOV 2021 
 
 
 
111. 
Ritsner, M., Kurs, R., Gibel, A., Ratner, Y., & Endicott, J. (2005). Validity of an abbreviated quality 
of life enjoyment and satisfaction questionnaire (Q-LES-Q-18) for schizophrenia, schizoaffective, and 
mood disorder patients. Quality of Life Research: An International Journal of Quality of Life Aspects of 
Treatment, Care and Rehabilitation, 14(7), 1693–1703. https://doi.org/10.1007/s11136-005-2816-9 
 
 

Study number:  
 
Page 47 
Version: 
 
 
18 Schedule of Events 
 
 
 
Study Phase 
 
Screening 
Experimental 
(4 visits) 
Follow-up 
(1 phone call) 
Consent 
X 
 
 
MINI 
X 
 
 
Demographic data 
X 
 
 
Inclusion/exclusion 
X 
 
 
IDS-C 
X 
 
 
MOCA 
X 
 
 
ATRQ 
X 
 
 
MRI Safety Checklist 
X 
X 
 
NIS-SCS 
X 
 
 
Medical history, PE 
X 
 
 
Safety labs  
X 
 
 
Urine drug screen 
X 
 
 
Pregnancy test 
X 
 
 
Vital signs 
X 
X 
 
Concomitant Meds 
X 
X 
X 
C-SSRS  
X 
X 
X 
CGI-I,S 
 
X 
 
CGI-I, I 
 
X 
 
PCQ 
 
X 
X 
PANAS 
 
X 
X 
MADRS 
 
X 
X 
SDQ 
 
X 
X 
ASQ 
 
X 
X 
AE Form 
 
X 
X 
SAFTEE 
 
X 
X 
Neuro-Qol 
 
X 
X 
Q-LES-Q-SF 
 
X 
X 
TSRQ 
 
X 
 
PBQ 
 
X 
 
Intervention tracking 
 
X 
 
MRI + t-PBM/sham 
 
X