Transcranial Photobiomodulation for Executive Function in Bipolar Disorder (TPEB)
Phase: PHASE2
Conditions: Bipolar Disorder
Sponsor: Paolo Cassano

 
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Institutional Review Board 
Intervention/Interaction Detailed Protocol 
 
 
Principal Investigator: 
Dr. Paolo Cassano, MD, PhD 
 
Project Title: 
Transcranial Photobiomodulation for Executive Function in 
Bipolar Disorder (TPEB) 
 
NCT Number:  
 
NCT05408637 
 
Version Date: 
May 18th, 2023 
 
 
 
 

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1. 
 Background and Significance 
 
Bipolar disorder (BD) is characterized by debilitating depressive and manic or hypomanic 
episodes, effecting an estimated 45 million worldwide1. The lifetime prevalence rate is estimated 
at 1% for BD in general, with specific prevalence rates of 0.6% for BD type-I, 0.4% for BD type-
II, and 1.4% for subthreshold BD2. BD is among the most impairing psychiatric disorders, typically 
causing pronounced deterioration in quality of life. Furthermore, BD is associated with premature 
mortality due to a suicide rate 10-30 times higher than the general population3. The economic 
burden of BD on society is high, ranking 12th in causing disability worldwide according to the 
World Health Organization4. People with BD are at particular risk of acting impulsively when 
experiencing manic symptoms, with a significant association between impulsivity and severity of 
manic symptoms. However, even when in a euthymic state, people with BD retain high 
impulsivity5. These high-risk, impulsive, unrestrained behaviors can lead to harmful 
psychological, social, and financial outcomes. 
 
FDA-approved medications for manic symptoms, such as Lithium, Carbamazepine, Valproate, and 
antipsychotics, have significant drawbacks due to poor tolerability, including the risk of metabolic 
syndrome, cognitive dulling, sexual dysfunction, and anhedonia. Consequently, nonadherence to 
medications is common in BD, with a reported rate of approximately 50%6. This nonadherence 
carries a high risk of relapse, recurrence of depression, mania and psychosis, hospitalization, and 
suicide attempt, especially after abrupt discontinuation of medications. Overall, nonadherence 
decreases the likelihood of achieving remission and recovery. While medications have been shown 
to reduce impulsivity, with combination antipsychotics and mood stabilizers having a greater effect 
than mood stabilizers alone, on the whole these impulsivity scores continue to be higher than 
healthy controls7.   
 
There is promise in the use of device-based interventions to control manic symptoms. Prior to the 
advent of mood stabilizers and antipsychotic medications, electroconvulsive therapy (ECT) was 
the only −and very effective− intervention for mania, mixed states, and delirious mania8. 
Nowadays, the use of ECT for the treatment of manic symptoms is limited by poor tolerability, 
stigma, access, lack of specialists, cost, healthcare inequity, and national laws. Modern 
noninvasive brain stimulation (NIBs) could potentially achieve the same efficacy of ECT in 
controlling manic symptoms, however with better tolerability, lower stigma, and easier access.  
 
Impulsivity, associated with poor decision-making, is a prominent manic symptom, often 
associated with severe functional impairment. Furthermore, as impulsivity remains high in BD 
subjects outside of a manic state, it may represent a core feature or trait of BD. Recent imaging 
studies have shown hyperactivation of ventral striatum and ventromedial PFC when anticipating 
rewarding outcomes in euthymic patients9 as well as striatal activity during anticipation being more 
strongly modulated by the reward value of prospects in subjects with subsyndromal hypomania10. 
Accordingly, most treatment studies show reduced impulsivity by neuromodulation of the 
prefrontal cortex (PFC). Specifically, high-frequency rTMS (excitation) on right dorsolateral PFC 
(dlPFC) decreases hasty, impulsive choices driven by immediate reward11-14. Therefore, it is 
evident that the dlPFC plays an essential role in some of the cognitive processes of impulsivity. 
Use of NIBs on dlPFC could reduce impulsivity in patients with bipolar disorder, depression, high 

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suicidality, and addictions. Similarly, bilateral, right anodal (excitation) and left cathodal tDCS on 
dlPFC reduces impulsivity14. Therefore, excitation of right dlPFC (R-dlPFC) by NIBs is a potential 
mechanism for treatment of manic symptoms such as impulsivity, while preserving physical 
health, individual functioning, and quality of life.  
 
Mainstream NIBs devices, such as rTMS and tDCS, are limited by the complexity of their 
administration, which necessitates frequent in-office sessions with specialized staff. Mainstream 
NIBs are therefore not scalable to the large needs of our society. Instead, at-home, self-
administered NIBs could lead to broad access to non-stigmatizing, well-tolerated interventions 
for manic symptoms. Transcranial photobiomodulation (t-PBM) with near-infrared light (NIR) 
over the forehead is a novel NIBs, which is inexpensive, user-friendly and can be safely 
administered at home without supervision15.   
 
A substantial body of literature proves that t-PBM with NIR penetrates deeply into the cerebral 
cortex, modulates cortical excitability16,17, and improves cerebral perfusion18-20 and oxygenation21. 
Its safety was demonstrated in 1,410 acute stroke patients22,23. t-PBM improves inhibition, 
attention, memory, working memory and learning24-32, with evidence for cognitive benefits in both 
healthy individuals and in neuropsychiatric patients. t-PBM is ideally suited to excite R-dlPFC 
and to improve inhibition − similarly to rTMS and tDCS − with the substantial advantage that 
t-PBM is also suitable for in-home, self-administration.  In the proposed study, we will test t-
PBM on R-dlPFC to control impulsivity (improve decision making) in patients with a diagnosis 
of bipolar disorder and currently in the spectrum from euthymic to hypomanic. We will also use 
cerebral blood flow as the most reliable biomarker of target engagement of R-dlPFC.   
 
Mechanistically, t-PBM with NIR (wavelength 800–1100 nm) is absorbed by the cytochrome C 
oxidase (CCO) in neuronal mitochondria, leading to an increased synthesis of adenosine 
triphosphate (ATP), along with photodissociation of nitric oxide (NO) and cerebral vasodilation 
and subsequent increase in cerebral blood flow (CBF)33. t-PBM increases cerebral blood flow 
(CBF) based on SPECT18,34, Doppler Ultrasound20,21, and fNIRS reports. This proposal will use 
the fMRI BOLD signal as the biomarker of CBF change induced by t-PBM. The BOLD signal 
was previously validated as a marker of target engagement and as a predictor of treatment outcome 
in other NIBs35,36. t-PBM to the R-dlPFC led to both increase of BOLD signal and to cognitive 
improvement in adults with cognitive deficits37. By engaging the CBF (BOLD), we will test the 
propensity of t-PBM to modulate R-dlPFC in patients with impulsivity due to bipolar disorder. 
 
At MGH, we are conducting a single-blind, sham-controlled (paired sample) study to test the effect 
of bilateral t-PBM on fMRI BOLD signal (dlPFC) in adults (n=15) with major depressive disorder. 
We have demonstrated feasibility for multiple t-PBM sessions per week and for the delivery of t-
PBM within MRI scanner, while recording BOLD signal (NCT04366258). A collaboration 
between MGH and colleagues in Italy piloted bilateral t-PBM in adults (n=4) with BD38. t-PBM 
was helpful in alleviating BD residuals, including impulsivity and irritability. 
 
 
 
2. 
Specific Aims and Objectives  
 

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1. To test the effect of a single t-PBM session on cerebral blood flow (CBF), while irradiating 
R-dlPFC, in subjects with impulsivity due to BD 
Hypothesis: a single t-PBM session on the R-dlPFC will significantly increase BOLD-signal at the 
R-dlPFC, relative to sham.    
2. To test the effect of repeated t-PBM sessions on CBF, after irradiating R-dlPFC, in 
subjects with impulsivity due to BD 
Hypothesis: repeated t-PBM sessions on the R-dlPFC will significantly increase BOLD-signal at 
the R-dlPFC at day 5 relative to baseline.    
3. To test the effect of repeated t-PBM sessions on impaired decision making, in subjects 
with impulsivity due to BD 
Hypothesis: repeated t-PBM sessions on the R-dlPFC will significantly improve decision making 
− increase in net gain at the Iowa gambling task, decrease in Barratt Impulsiveness Scale (BIS) 
score at day 5 and follow-up visit relative to baseline, decrease in BRIEF-A score at day 5 and 
follow-up visit relative to baseline, and a decrease in I-7 Impulsiveness and Venturesomeness 
Questionnaire score at day 5 and follow-up visit relative to baseline. 
4. To test the effect of repeated t-PBM sessions on manic symptoms (MOODS-SR) in 
subjects with BD 
Hypothesis: repeated t-PBM sessions on the R-dlPFC will significantly decrease the total Mood 
Spectrum-Self Report (MOODS-SR) score at day 5 and follow-up visit relative to baseline. 
Dimensional improvements will be analyzed as a secondary step. 
 
 
3. 
General Description of Study Design 
 
This is a single-blind study to test the neuropsychological and clinical effects of t-PBM with NIR 
in BD. For our primary aim of examining the effect of tPBM on CBF, the study is additionally 
sham-controlled. Twenty patients with a diagnosis of bipolar disorder, not currently in a 
depressive, manic, or mixed state episode, will undergo one sham and one NIR- t-PBM session 
on day 1 (within MRI scanner), and one daily NIR- t-PBM session from day 2 to 5. On day 5, the 
NIR t-PBM session will also occur in the MRI scanner. The fMRI scan will measure BOLD 
changes during sham t-PBM (day 1) and during NIR t-PBM (day 1 & 5), on R-dlPFC. 
Impulsivity will be assessed by the BIS at pre-screen (for inclusion criteria), baseline, treatment 
day 5, and the follow-up visit; and by the gambling tasks at baseline, after the first NIR t-PBM 
(day 1), after the fifth NIR t-PBM (day 5), and at the follow-up visit. Other aspects of 
impulsivity and executive functioning will be assessed by the I-7 and BRIEF-A at baseline, day 
5, and the follow-up visit. The MOODS-SR-Last Week will be administered at baseline, day 5, 
and the follow-up visit to assess change in mood, particularly hypomanic symptoms. At 
screening, subjects will complete the MOODS-SR Lifetime. 
 
 
 
4. 
Subject Selection 
 
We intend on enrolling 30 subjects diagnosed with bipolar disorder, with the goal of 
randomizing 20 subjects.  

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Inclusion criteria for this study include: 1) adults between the ages of 18 and 65, 2) diagnosis of 
bipolar disorder assessed with M.I.N.I. diagnostic interview, 3) currently experiencing symptoms 
of impulsivity as per BIS total cut-off score equal or greater than 70, 4) if of child-bearing potential 
must agree to use adequate contraception (e.g. oral contraceptives, intrauterine device, double 
barrier methods, or total abstinence from intercourse), and 5) vision corrected to normal with 
contacts/vision does not require glasses or other visual aids. 
 
Exclusion criteria for this study include: 1) currently in depressive, manic, or mixed episode; 2) 
currently psychotic; 3) judged to be at serious and imminent suicidal risk (C-SSRS≥4); 4) currently 
in alcohol or substance use disorder (meeting criteria in the past 3 months as assessed with M.I.N.I. 
diagnostic interview); 5) unstable medical conditions; 6) inability to consent or to complete study 
procedures; 7) 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; 8) changes in medications or use of augmentative devices and other 
interventions in the 2 weeks prior to the study; 9) participation in other clinical research trials that 
may influence primary outcomes or adherence to the proposed study, as assessed by the PI and the 
Co-Is; and 10) current pregnancy.  
 
Source of subjects will include outpatient clinics at MGH and McLean, the Translational and 
Clinical Research Center, and Registries/Patient Databases such as the RPDR and Patient 
Gateway Announcements and or Invitations. We will recruit primarily through referrals from 
physicians, flyers, online advertisements, and platforms such as Partners Rally and 
ResearchMatch. We will respond to all individuals who express interest in the study, whether it 
is from an online recruitment source or through a referral from outpatient clinics at MGH. 
Clinical research coordinators will primarily handle recruitment and outreach, though some tasks 
may fall to other members of study staff, like interns. Physicians may send referrals directly to 
Dr. Cassano, who will forward the information to a CRC to make contact.  
 
We will not discriminate against any group of persons. Based upon the composition of the 
patient population at MGH and Boston, we anticipate that at least 50% of the participants will be 
women. The percentage of minority participants is expected to be at least 20%, consistent with 
previous studies in our lab and at MGH. We expect a roughly equal distribution across sex and 
ethnicity, as has been previously demonstrated with BD, with the potential for slightly more 
diagnoses of BD type-I among men and BD type-II among women.  Fetuses, children, prisoners, 
and institutionalized individuals will not be recruited, because they are beyond the scope of the 
objectives. We will review recruitment regularly at team meetings to track progress and adjust 
recruitment strategies as needed. 
 
 
We are only enrolling English-speaking participants in this study since the measures used are 
developed and validated in the English language and because non-English speaking subjects may 
not be able to understand study procedures, which could undermine the validity of the results. 
 
 
 

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5. 
Subject Enrollment 
 
Individuals interested in participating in the study will contact study staff through online 
recruitment platforms, such as Partners Rally and ResearchMatch. Additionally, patients may be 
referred to the study from outpatient clinics at MGH. All interested individuals will undergo a 
screening by trained study staff to ensure eligibility and, importantly, their capacity for 
voluntary, informed consent. Study staff will describe the study and go through informed consent 
procedures. Subjects will read the consent form without any time constraints and will be 
provided the opportunity to ask any questions related to study procedures. Individuals will be 
officially enrolled upon signing the consent form. This study will not change the clinical care 
that subjects receive, meaning that all subjects participating in the study will receive the same 
clinical care as those who are not.  
 
Individuals interested in participating will first be phone-screened for eligibility prior to signing 
the consent form. The PI and licensed physician co-Investigators with detailed knowledge about 
the study aims, logistics, procedures, risks, benefits, and alternatives will obtain written informed 
consent from subjects who meet criteria for this study. Individuals will be given the opportunity 
to take time to consider participation prior to signing the consent form. Since Dr. Ellard’s 
patients might be offered the participation in this study, the PI, Dr. Cassano, or other licensed co-
Is will review the consent and co-sign the consent for any study subjects referred to the study by 
Dr. Ellard. This measure will be implemented to prevent any type of coercion. 
 
All subjects participating in the study will receive the same standard of care as those who are not. 
There are additional study procedures that subjects will undergo, though this should have little to 
no impact on clinical care. Further, study participation will not impact access to standard of care, 
meaning that participating in the study will not prohibit subjects from receiving standard 
treatments for bipolar disorder. 
 
t-PBM is not considered standard of care and is therefore an alternative treatment for bipolar 
disorder. Standard of care for bipolar disorder includes, but is not limited to, psychotherapy, 
medications (such as mood stabilizers, anti-depressants, or anti-psychotics), or device-based 
treatments (such as ECT). Information on standard of care for bipolar disorder will be provided 
to all subjects. Subjects may continue with their current treatment regimen throughout the study. 
 
The MGH Brain Photobiomodulation Clinic (Director: Paolo Cassano, MD PhD) has historically 
served as a resource for subjects enrolled in t-PBM clinical trials who then wish to continue with 
specialized supervision. Study staff will offer access to the clinic to all subjects upon study 
completion. 
 
Participants will be compensated $125 for each of the following visits: Baseline, Treatment 1, 
Treatment 5, and Follow Up. For each of these visits, the participant receives $25 for attending 
the appointment, $50 for completion of the first gambling task, and $50 for the completion of the 
second gambling task. Participants who complete all portions of the study will receive a total of 
$500. Subjects who end study procedures prematurely will be compensated for all completed 
study procedures. Subjects will be mailed a check at the conclusion of their study participation. 
 

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While participants will always receive the full $50 for completing each gambling task, they will 
be told that their real-world earnings are based on their performance on the gambling task. They 
will be told that the maximum amount of real-world money that they can earn in each task is 
$50. Participants will be told that the better they do on the task, the closer they will get to earning 
the full $50, and that their total earnings will be revealed at the final study visit. The purpose of 
these gambling tasks is to investigate various aspects of behavior, such as impulsivity and 
decision-making. In order for these tasks to effectively gather accurate data on these behaviors, it 
is crucial that the participants believe that the amount of money they earn is based on their 
decisions within the task. Upon completion of all study procedures, participants will be informed 
that they will receive the full $50 for each of the eight gambling tasks that they completed. 
 
This deception may result in increased frustration related to performance on the gambling tasks. 
This deception involves no more than minimal risk to the participants. 
 
If participants do not believe that their compensation is affected by their performance on the 
gambling tasks, they will not be sufficiently motivated to perform to the best of their ability. The 
promise of a monetary reward will create a more realistic model of real-world decision making 
and impulsivity, which are the behaviors that these tasks are designed to measure. This deception 
is therefore necessary in order to obtain worthwhile data. 
 
This deception will be disclosed by study staff at the end of the follow up visit. Participants will 
receive a debriefing form explaining the reasoning for a nature of the deception.   
 
 
6. 
STUDY PROCEDURES 
 
Study Visits  
  
Contact with potential participants 
 
Initial contact made with potential research subjects will include only the minimum PHI (name 
and email). Study staff will obtain written or verbal consent to continue correspondence through 
unencrypted emails or will send detailed study and PHI information using the “Send Secure” 
function. Emails not sent using “Send Secure” to participants will contain and automatic email 
signature alerting them that the email is not encrypted. If participants are uncomfortable 
receiving information unencrypted, they should alert study staff who will then proceed to 
communicate securely with the participant. If an individual contacts the study staff by email first, 
it is implied that email communications are acceptable. Study staff will verify that individuals 
are comfortable with unencrypted emails and obtain written or verbal consent to proceed with 
unencrypted email communication. 
 
Pre-Screen  
  
Prior to enrolling in the study, interested individuals will be contacted by trained study staff for a 
pre-screening, which can be completed over the phone or via a REDCap link. The trained study 
staff will review study details and procedures and will ask a series of questions and administer 

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two questionnaires (the ASRM and the PHQ-9) to assess eligibility for the study. Additionally, 
study staff will either administer the Barratt Impulsiveness Scale (BIS) over the phone or send 
interested individuals the REDCap survey link to assess if their impulsivity levels meet our 
inclusion criteria. Prior to collecting any information, individuals will be asked to provide verbal 
authorization to write down their responses and will be given the option to not answer questions 
if they do not wish to do so. Individuals will also be given the opportunity to provide verbal 
consent regarding unencrypted emails. If the individual is eligible for the study, they will be 
invited to a screening visit. If the individual is not eligible or decides not to enroll, any 
information collected during the phone call will be destroyed to protect privacy. If an individual 
is eligible for the study and enrolls, the information collected during the pre-screening phase will 
be added to their research file. Individuals will be sent a copy of the consent form for their 
review via email and the screening visit will be scheduled. Individuals will be reminded not to 
discuss medical information through unencrypted emails. Individuals will be instructed not to 
sign the consent form until after they’ve discussed it with the clinician during the screening visit. 
  
Screening  
  
Subjects will review the consent form with the study clinician (PI or Co-I; MDs) and be given 
the opportunity to ask questions. Consent will be obtained by a licensed physician investigator. If 
the screening visit is conducted remotely using Zoom, the consent form will be collected 
electronically using REDCap following the MGH eConsent Template. Subjects will then receive 
an electronic copy of the consent form through their provided email which they can download 
and keep for their records. This is an automatic function of REDCap. If the screening visit is 
conducted in-person, the consent form may be collected on REDCap or on paper. If the consent 
form is signed on paper, subjects will receive a paper copy of the consent. Subjects will be 
considered enrolled in the study once they sign the consent form. 
  
Subjects will be asked a series of questionnaires to assess eligibility for the study, including the 
Mini International Neuropsychiatric Interview (MINI), and the Columbia Suicide Severity 
Rating Scale (C-SSRS). Demographic information, concomitant medications and therapies, prior 
treatment history, and medical history will be collected. Subjects will complete an MRI 
Screening Form and the MOODS-SR Lifetime. Screening will also include a dipstick toxicology 
urinalysis and, if applicable, a dipstick pregnancy test. If the subject is eligible, they will be 
invited to continue to the baseline visit. If not eligible, the subject will not be invited 
to continue with the study.  
  
Baseline Visit 
 
Adverse events, as well as concomitant medications and therapies, will be collected. Participants 
will complete the Young Mania Rating Scale (YMRS), the BIS, the BRIEF-A, the I-7, the 
CAST-IRR, and the SAFTEE. A licensed clinician will administer the C-SSRS and the CGI-S. 
Skin color will be recorded using the NIS-SCS. Participants will complete two computerized 
gambling tasks: The Iowa gambling task and the Delgado gambling task. The order of 
administration of the gambling tasks will be randomized. This appointment will last 
approximately 90 minutes. 
 

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Treatment 1 
  
Vitals will be assessed and recorded. The MRI Safety Checklist will be completed and signed 
before the MRI. Participants will undergo an MRI Scan. While in the scanner, participants will 
first undergo a structural scan and resting state scan, followed by a functional scan during which 
the participants will receive a sham t-PBM treatment. This scan will be followed by a pre-
stimulation resting-state functional acquisition. At this time, active t-PBM will be administered, 
immediately followed by a post-stimulation resting state scan. Participants will then complete the 
Delgado gambling task. A functional sequence will be collected during the administration of the 
gambling task. Finally, participants will undergo a post-stimulation resting state functional scan. 
The MRI will last approximately 75 minutes in total.  
 
Participants will know that they are receiving both active and sham treatment, but they will not 
be told in which order the treatments will be delivered. Participants will complete the PBQ, 
CAST-IRR, TSRQ, and the Iowa Gambling Task at the conclusion of the visit. Study staff will 
complete an intervention tracking form. 
 
Treatments 2-4 
  
Treatments 2, 3, and 4 should ideally occur once daily during the three days following the first 
treatment administration. If necessary, this window can be extended so that these three treatment 
visits occur within ten days of the Baseline/Treatment 1 visit (in this case, the timing of follow 
up visits will be adjusted accordingly). Adverse events and concomitant medications and 
therapies will be assessed and recorded at each visit. Participants will complete the TSRQ and 
CAST-IRR after treatment administration. Study staff will complete an intervention tracking 
form for each study visit. 
  
Treatment 5 
  
Treatment 5 should ideally occur the day after Treatment 4. If necessary, this window can be 
extended so that this visit occurs within ten days of the Treatment 1 visit (in this case, the timing 
of follow up visits will be adjusted accordingly). Adverse events, concomitant medications and 
therapies, and vitals will be assessed and recorded. The MRI Safety Checklist will be completed 
and signed before the MRI. Participants will complete the MOODS-SR, the BIS, the BRIEF-A, 
and the I-7.  
 
Participants will undergo an MRI Scan. A structural scan and a pre-stimulation resting state 
functional scan will be collected first. Active t-PBM will be administered immediately after the 
resting-state scan, followed by a post-stimulation resting state functional scan. Participants will 
then complete the Delgado gambling task. A functional sequence will be collected during the 
gambling task administration. The MRI will last approximately 45 minutes in total.   
 
Participants will complete the SAFTEE, the CAST-IRR, the TSRQ, and the Iowa gambling task 
after the MRI/t-PBM session. Study staff will complete an intervention tracking form.  
 
Clinical Check-in Call 

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A licensed study clinician will call the participant (phone or video call) approximately 2-3 days 
after the final treatment session. Adverse events and concomitant medications and therapies will 
be assessed and recorded. The clinician will administer the C-SSRS and the CGI-S/I. The 
clinician may use the PHQ-9 and/or ASRM to guide their call with the study participant, though 
these scales do not need to be completed in full. The purpose of this call is to check in on the 
general safety and well-being of the participant. 
 
Follow Up Visit  
  
The follow up visit takes place approximately one week after the final treatment session. This 
visit will be completed in person. Adverse events and concomitant medications and therapies 
will be assessed and recorded. Participants will complete the MOODS-SR, the BIS, the BRIEF-
A, the I-7, the SAFTEE, the Delgado gambling task, and Iowa gambling task. The order of 
administration of the gambling tasks will be randomized. A licensed clinician will administer the 
C-SSRS and the CGI-S/I.  
 
Communication with participants throughout the study: 
Participants who consent to text messaging, in addition to standard email and phone 
communication, will receive a text message reminder before every scheduled visit. Text 
messages will be sent via Updox Secure Text Messaging and SMS. Updox is an online 
messaging service that specializes in secure healthcare communication.  
 
Participants who consent to text messaging will receive a text message the day before each 
scheduled study visit. This message will be sent as a SMS text message letting the participant 
know they have received a secure message from the MGH Photobiomodulation Lab with a link 
to access the message. The first message received will instruct them to enter in their full name 
and create a PIN to access the message. Each time a message is received they must enter their 
unique PIN number to access the message. Study staff do not have access to anyone’s personal 
PIN numbers. Individuals are able to respond back to the message they receive with questions or 
for more information if necessary.   
 
  
tPBM Administration  
  
The t-PBM-NIR device used in the study is the Litecure’s LightForce® EXPi Deep Tissue Laser 
Therapy TM System, Transcranial PhotoBioModulation-1000 (tPBM-2.0). The tPBM-2.0 is an 
investigational device based on LiteCure’s LightForce® EXPi Deep Tissue Laser Therapy TM 
System. For the investigational study, the EXPi System’s beam delivery - Empower TM, is 
modified to non-invasively deliver Near-Infrared Radiation (NIR) to subjects diagnosed with 
Bipolar Disorder. 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.  
 

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The treatment program (using the parameters outlined below) will be programmed into the 
device. The console displays the time and energy delivered and automatically turns itself off 
once the treatment is completed.   
  
Table 1. tPBM Parameters  
Measure (unit)  
Value  
 
 
Wavelength (nm)  
808nm 
Exposure time (s) 
 
333 
Area of exposure (cm2)  
24 
Irradiance, Power Density (mW/cm2)    
300 
Fluence (J/cm2) 
100 
Total Energy (kJ) 
2.4 
NIR Source 
Laser 
Laser Output (W) 
3.5 per fiber (7 total) 
Wave Mode 
Continuous 
Anatomical Targets 
F4 & F8 (proximity) 
Device  
Litecure’s LightForce® EXPi Deep 
Tissue Laser Therapy TM System, 
Transcranial PhotoBioModulation-1000 
(tPBM-2.0) 
   
  
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 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 site F4 (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.  
 
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.  
 

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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 cap is a component of 
the tPBM-2.0 device; it is not a separate device. The cap is used to apply NIR to EEG site F4. 
  
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 DOES NOT present 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.   
• The MGB IRB determined a similar PBM device as NSR for the ELATED-3 study (IRB 
Protocol Number 2016P001490). The ELATED-3 device operated at significantly higher 
irradiances than the current PBM device. The FDA determined that an IDE was not 
required for the ELATED-3 device. 
• The current PBM device was deemed to be NSR by the NYU Langone Health IRB in 
previous studies. 
 
The tPBM-2.0 device is currently being used in two other approved studies at MGH: 
Transcranial Photobiomodulation for Alzheimer’s Disease (Protocol #2020p003051) and 
Transcranial Near Infrared Radiation and Cerebral Blood Flow in Depression (Protocol 
#2020p000845). 
 
Safety data from the use of the t-PBM 2.0 device in currently active studies at the time of initial 
review 
 

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TRIADE (Protocol #2020p000845) – Adverse Events: As of May 4th, 2022, Cumulative data 
from all three study sites 
 
Adverse Event 
Number 
Participants 
Number 
Incidences 
Severity  
Study 
Intervention 
Relationship 
Resolved  Expected 
 
 
 
 
Mild= 1 
Moderate= 2  
Severe= 3 
1= Not related 
2 = Unlikely  
3 = Possibly  
4 = Probably  
5 = Definitely  
1= yes 
0= No 
1= yes 
0= no 
SKIN WARMING 
9 
12 
1,1,1,1,1, 
1,1,1,1,2, 
1,1 
5,5,3,4,4, 
4,4,5,3,5 
5,4 
1,1,1,1,1, 
1,1,1,1,1 
1,1 
1 
INSOMNIA 
3 
4 
2,1,2,2 
3,4,3,4 
1,1,1,0 
1 
EARLY MORNING 
AWAKENING 
1 
1 
3 
4 
1 
1 
DISCOMFORT 
DURING MRI 
2 
2 
1,2 
5,3 
1,1 
1 
PANIC ATTACK 
DURING MRI 
1 
1 
2 
4 
1 
1 
ANXIETY DURING 
MRI 
1 
1 
1 
1 
1 
1 
HEADACHE 
8 
8 
1,2,1,2, 
2,1,2,1 
1,3,3,3, 
1,1,4,4 
1,1,1,1, 
1,1,1,1 
1 
CLAUSTROPHOBIA 
1 
1 
1 
4 
1 
1 
BLURRY VISION 
1 
1 
1 
2 
1 
0 
SEIZURE 
1 
1 
2 
2 
1 
0 
PANIC ANXIETY 
3 
3 
1,1,2 
4,1,1 
1,1,1 
1,0,1 
PAIN ON 
FOREHEAD 
1 
1 
1 
4 
1 
1 
BURNING 
SENSATION ON 
SKIN 
1 
1 
2 
5 
1 
1 
PANIC ATTACK 
WITH 
DISSOCIATION 
1 
1 
1 
0 
1 
0 
RENAL INFECTION 
1 
2 
3,3 
1,1 
1,1 
0,0 
MOTOR VEHICLE 
ACCIDENT (NO 
PHYSICAL 
INJURY) 
1 
1 
1 
1 
1 
0 
NIGHTMARES 
1 
1 
1 
4 
1 
1 
STYE 
1 
1 
1 
3 
1 
0 

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WORSENING 
ANXIETY 
1 
1 
2 
2 
0 
1 
“MIND FOG” 
AFTER MRI 
1 
1 
1 
4 
1 
1 
 
 
 

 
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TRAP-AD (Protocol #2020p003051) – Adverse Events: As of May 4th, 2022, Cumulative data from all three study sites 
 
ADVERSE EVENT 
NUMBER 
PARTICIPANT
S 
NUMBER 
INCIDENCE
S 
SEVERITY  
STUDY 
INTERVENTIO
N 
RELATIONSHI
P 
RESOLVE
D  
EXPECTE
D 
 
 
 
Mild= 1 
Moderate= 2  
Severe= 3 
0= Not related 
1 = Unlikely  
2 = Possibly  
3 = Probably  
4 = Definitely  
1= yes 
0= No 
1= yes 
0= no 
ANKLE EDEMA 
1 
1 
3 
0 
1 
0 
CHEST TIGHTNESS 
1 
1 
3 
0 
1 
0 
DIARRHEA 
2 
2 
1,1 
0,0 
1,1 
0,0 
DIZZINESS 
3 
4 
1,1,1,1 
1,0,2,2 
1,1,0,1 
0,0,1,1 
FATIGUE 
2 
2 
1,1 
1,2 
0,0 
0,1 
FEELINGS OF 
UNEASINESS 
1 
1 
1 
2 
1 
0 
HEAD WARMING 
3 
13 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1 
4,4,4,4,4,  
4,4,4,4,4, 
4,4,4  
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1 
HEADACHE 
2 
2 
1,1 
2,3 
0,1 
1,1 
INSOMNIA 
1 
2 
1,1 
2,0 
1,0 
1,1 
ITCHINESS ON 
UPPER BACK 
1 
1 
1 
0 
0 
0 
JAW PAIN/TEETH 
CLENCHING 
DURING SLEEP 
1 
1 
1 
1 
0 
0 
LIGHTHEADEDNES
S 
1 
1 
1 
0 
1 
0 
POSITIONAL 
VERTIGO IN MRI 
1 
1 
1 
0 
1 
1 

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RASH (UPPER 
BACK) 
1 
1 
1 
1 
1 
1 
SEEING LIGHT 
DURING 
TREATMENT 
1 
1 
1 
4 
1 
1 
SKIN REDDENING 
3 
27 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1 
1,1 
4,4,4,4,4, 
4,4,4,4,4, 
4,4,4,4,4, 
4,4,4,4,4, 
4,4,4,4,4, 
4,4 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1 
Skin warming 
(forehead) 
6 
22 
1,1,1,1,1 
11,1,1,1, 
1,1,1,1,1, 
2,1,1,1,1, 
1,1 
4,4,4,4,4, 
4,4,4,4,4, 
4,4,4,4,4, 
4,4,4,4,3, 
4,4 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1,1,1,1, 
1,1 
Stomach Discomfort 
1 
1 
1 
1 
1 
0 
Vivid Dreams 
2 
2 
1,1 
2,2 
1,1 
1,1 
Vomiting 
1 
1 
1 
0 
1 
0 
 
  

 
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Assessments  
 
Adverse Events Form 
 
The Adverse Events Form captures any adverse event (serious or otherwise) that the subject 
experiences while participating in the study. Events may occur during or outside of study 
procedures. 
 
Altman Self-Rating Mania Scale (ASRM) 
 
The ASRM is a 5-item self-rated mania scale designed to assess the presence and/or severity of 
manic symptoms over the past 7 days. This scale will be administered as part of the pre-
screening phase. 
 
Barratt Impulsiveness Scale (BIS)39 
 
The BIS is a 30-item measure of cognitive and motor impulsivity rated on a 4-point Likert scale 
(1 = rarely/never to 4 = almost always/always). It captures three factors: Motor Impulsiveness, 
Non-Planning Impulsiveness, and Attentional Impulsiveness. The BIS has demonstrated high 
internal consistency and validity across populations. 
 
Behavior Rating Inventory of Executive Function – Adult Version (BRIEF-A)40 
 
The BRIEF-A is a 75-item self-report scale to assess executive function. It consists of two 
indices: The Behavioral Regulation Index and the Metacognitive Index. The Behavioral 
Regulation Index measures inhibition, set shifting, control, and attention monitoring. The 
Metacognitive Index measures ability to initiate tasks, working memory, planning/organization 
ability, task monitoring, and organization. The BRIEF-A has demonstrated good internal 
consistency and validity across several clinical populations and non-clinical controls. 
 
Concise Associated Symptom Tracking Irritability Scale (CAST-IRR) 
 
This instrument is a five item self-report that assesses irritability over the last 24 hours. 
 
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) severity of impairment (CGI-S) and (b) clinical improvement (CGI-I).  
 
Columbia Suicide Severity Rating Scale (C-SSRS) 41 
 
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). 

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Concomitant Medications and Therapies Form 
 
This form records all ongoing medications, as well as other therapies, and will be completed at 
every study visit, including the screening visit, as a safety-monitoring tool.  
 
Iowa Gambling Task 
 
In this computerized task, participants play a game of chance in which they can win or lose fake 
money. Participants are presented with four cards and are asked to choose one. Their choice 
results in a gain or loss. Participants are given feedback on each choice. This task is designed to 
measure impulsivity. 
 
Delgado Gambling Task (IGT) 
 
In this computerized task, participants play a game of chance in which they can win or lose fake 
money. Participants are given a target number. They are then presented with a sequence of cards. 
Before each card is presented, participants are asked to guess whether the number on the next 
card will be higher or lower than the target number. They are then given feedback on their 
choice. This task is designed to measure reward-processing. 
 
I-7: Impulsiveness and Venturesomeness Questionnaire 
 
The I-7 is a self-report scale of 54 items and three subscales. Of the 54 items, 19 measure 
Impulsiveness, 16 measure Venturesomeness, and 19 measure Empathy. Answers are marked as 
“Yes” or “No.” 
 
Mini International Neuropsychiatric Interview (M.I.N.I)42 
 
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). For the purposes of this study, we will only use modules 
related to mood, psychosis, and substance abuse. 
 
MOODS-SR – Last Week & Lifetime 
 
This 161-item self-report scale assesses manic-depressive symptoms. Participants are asked to 
answer “Yes” or “No” to each question. Subdomains measure Moods, Energy, Cognition, and 
Rhythmicity. Time frame is either lifetime or the last week, depending on scale used. 
 
MRI Safety Checklist 
 

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This form identifies risk factors that may make MRI participation unsafe. 
 
New Immigrant Survey-Skin Color Scale (NIS-SCS)43 
 
The NIS-SCS 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.  
 
Patient Health Questionnaire (PHQ-9) 
 
This nine-item self-report measure assesses the presence and severity of depressive symptoms 
over the past 14 days. This scale will be administered as part of the pre-screening phase. 
   
Perceived Blinding Questionnaire (PBQ) 
 
The PBQ is a self-report questionnaire to determine the degree to which the participant believes 
they are receiving active treatment or sham. 
 
Prior Treatment Log 
 
This form captures information regarding prior treatments for bipolar disorder or other mental 
health concerns. 
 
Systematic Assessment for Treatment Emergent Events (SAFTEE)44 
 
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. 
 
t-PBM Self-Report Questionnaire (TSRQ) 
 
An open-ended questionnaire focusing on potential inconveniences and discomforts from the t-
PBM treatment. 
 
Young Mania Rating Scale (YMRS) 
 
This 11-item clinician-rated scale is used to assess the presence and severity of manic symptoms. 
   
MRI Scanning  
  

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The collection of MRI images will take place in a 3T magnet scanner with multi-
channel receivers. All protocols have been developed and validated at the Martinos Center for 
biomedical imaging.  
 
Participants will undergo conventional high-resolution 3D T1-weighted MPRAGE scans, resting 
state functional connectivity MRI sequences, and task-based functional connectivity MRI 
sequences. 
 
We will examine areas pertaining to impulsivity, mood, and executive function, including but not 
limited to the Salience Network, Central Executive Network, Limbic Areas, Default Mode 
Network, and the dlPFC.  
 
This data will be used to test the effect of a single t-PBM session on cerebral blood flow (CBF), 
while irradiating R-dlPFC (SA1), in subjects with impulsivity due to BD and to test the effect of 
repeated t-PBM sessions on CBF (SA2). 
 
 
7. 
Risks and Discomforts 
 
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. 
 
Delay in Initiation of New, or Changes in Ongoing, Bipolar Treatment: While this study is not 
testing t-PBM as a treatment for bipolar disorder, it is possible that participants will experience 
improvements to their symptoms while undergoing t-PBM. 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 of t-PBM on cerebral blood flow.  
 
Further, study participation requires stable BD treatment during and two-weeks prior to 
enrollment. Subjects should not change medications, treatments, or therapeutic interventions two 
weeks prior to study enrollment or during study participation as to avoid interference with t-PBM 
treatment. However, without adjustment of medication it is possible that participants’ symptoms 
may worsen while participating in the study. This may include increased disturbances in mood, 
anxiety, sleep, appetite, energy, or cognition. This could result in work loss, loss of social 
function, and possibly increased risk of suicide. Therefore, there is some risk to halting 
medication changes while in the study. However, the risk will be minimized as there are several 
safety precautions in place and participants will have frequent contact with study clinicians. The 
clinical monitoring in this study exceeds that of standard care for BD. The potential benefits of 
improving impulsivity and cognition offset the risk of worsening BD symptoms. 
 
Risks of Clinical Decompensation: If a patient has worsened to such a degree that further 
participation would put them at risk, then they will be discontinued from the study. In such cases, 
the patient is immediately transferred to standard clinical treatment and exited from the research. 

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 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.   
 
Suicidality Standard Operating Plan (SOP): If a subject spontaneously expresses suicidal 
ideation and the thoughts are passive, vague, or infrequent, the study team will respond with 
close monitoring of the subject. This may include phone calls, video calls, or in-person check-ins 
between the study clinician and the subject. If the suicidal ideation includes more specific 
thoughts, intent, and/or plans, if the subject responds “Yes” to questions 4 or 5 of the C-SSRS, or 
if the subject answers 1, 2, or 3 to Question 9 of the PHQ-9, then they will be proactively 
discontinued from the study and referred to adequate care.  
 
Risks associated with study tasks: Performing tasks can result in frustration related to difficulty 
with performance, or boredom during longer sittings. Participants may refuse to answer 
questions that make them uncomfortable. 
 
Risks of Magnetic Resonance Imaging: MRIs use powerful magnets to make images. There are 
no known radiation risks associated with MRI. However, individuals with metal implants, such 
as surgical clips or pacemakers, should not have an MRI. All credit cards and other items with 
magnetic strips should also be kept out of the MRI room. People who feel uncomfortable in 
confined spaces (claustrophobia) may feel uncomfortable in the narrow tube. The MRI makes 
loud banging noises as it takes images. Earplugs can be used to reduce the noises. The MRI can 
be stopped at any time at subject’s request. If the study subject is or suspects they are pregnant, 
they should not participate in this study. Study staff will assess chance of pregnancy. If there is 
any uncertainty, a study physician can recommend a pregnancy test. The MRI has the potential, 
during normal routine use, to cause localized warming of participant’s skin and of the underlying 
tissues. The participant will be instructed to immediately inform study staff if they experience 
discomfort due to warming and the procedure will be stopped.   
  
Some people experience dizziness or rarely nausea when going into an MRI scanner and these 
sensations may be more common in scans with higher magnetic fields. In most cases, these 
symptoms only last a short time. However, some people may experience them throughout the 
scan and/or continue to experience them for a short period of time after (generally, less than half 
an hour). No case of permanent problems is known. 
 
Risks of tPBM: 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 

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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 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.      
 
8. 
Benefits 
 
The effects of the current proposal on impulsivity in individuals with bipolar disorder are yet 
unknown. It is possible that subjects may experience improvements in impulsivity, cognition, or 
other symptoms of bipolar disorder. Participants in this study will improve our understanding of 
the pathology underlying bipolar disorder and their participation may lead to the development of 
novel therapeutics.  
 
 
9. 
Statistical Analysis 
 
Preprocessing of MRI and fMRI data will be performed with the FreeSurfer software package, 
scripted in Bash. Slice-time correction, motion-correction, and co-registration of functional 
BOLD scans, Time of Repetition (TR), and participant will then be performed. BOLD signals 
will then be smoothed to a full-width half maximum (FWHM) of 3mm and z-scored at every 
voxel.  
 
t-PBM related increase of BOLD percent signal change (PSC) averaged across all ROI voxels 
will be assessed during the first scanning session where the participant receives both sham and 
NIR over the R-dlPFC. PSC of t-PBM related increase in BOLD both during and after 
stimulation will be the dependent variable with the independent variable being the condition of t-
PBM during the first session (sham vs. NIR). 
 
BOLD signal will again be assessed during the 5th NIR session as a PSC across all ROI voxels in 
comparison with the BOLD PSC from the first NIR session to observe any BOLD changes after 
5 NIR treatment sessions. The dependent variable will the BOLD signal and the independent 
variable will be the timepoint: day 1 vs. after 5 sessions (day 5). 
 
For both gambling tasks, the gambling task net gain score will be analyzed for changes from 
baseline to after treatment on day 1, baseline vs day 5, and baseline vs follow up. The BIS, 
BRIEF-A, and I-7 will be analyzed for changes from baseline to day 5 and follow up. Here, the 
dependent variable will be the gambling tasks’ net gain scores, BIS, BRIEF-A, and I-7 total 
score. The independent variable is the timepoint baseline vs. day 5 (for the gambling tasks) and 
follow up.The MOOD-SR will also be analyzed for a decrease in impulsivity at each timepoint 
of baseline vs. day 5 and follow up. A General Mixed Models Regression will be used with time 
as a fixed effect and subject as a random effect.  
 
Secondary analyses will also be performed for the BIS, BRIEF-A, I-7, MOOD-SR, SAFTEE, 
and TSRQ. Each scale and their respective subscales will be analyzed for specific changes at 

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each timepoint to better understand the effect t-PBM NIR has on the symptoms and presentation 
of BD. These additional analyses will also be helpful in assessing the initial safety profile of t-
PBM in this psychiatric population.  
 
Power and Detectable Effects: The study is powered (G*Power 80%) to answer Aim #1 for a 
moderate effect size (Cohen’s d≥0.5), based on a Wilcoxon signed-rank test (matched pairs; one-
tailed; alpha=0.05). Dmochowski et al. demonstrated a BOLD increase as high as 31% (dlPFC) 
within a single t-PBM session and in healthy subjects (pre- and post-t-PBM; Cohen’s d=0.374). 
In our current design, we will compare NIR versus sham (also within a t-PBM session) in 20 
subjects with impulsivity due to BD, therefore we anticipate a larger effect size. 
 
 
 
10.   Monitoring and Quality Assurance 
 
At enrollment, each subject will be assigned a unique ID number that will be used in place of a 
subject’s name across all study forms and documents. Documents will be stored separately from 
other materials in a locked filing cabinet that is only accessible by study staff. Subjects may 
request that their data be withdrawn by contacting Dr. Cassano (contact information provided on 
the consent form). Experienced, doctoral-level clinicians will be available to participants by 
phone, or in-person if necessary, to discuss any concerns throughout the study. This will be 
clearly communicated orally and in writing to subjects. 
 
The data gathered from the project will include imaging and treatment data. Information relating 
to the data derived from this study will be made available to Partners IRB. The information 
collected in the study will be used only for research purposes. There are no plans to share any of 
the collected data with anyone outside of the immediate study staff. 
 
Paolo Cassano, MD, PhD (Neuropsychiatry), Director of Photobiomodulation at MGH 
Depression Program and at MGH Neuropsychiatry will provide his expertise on t-PBM and its 
effects on psychiatric conditions. Joan Camprodon, MD, MPH is Chief of the Division of 
Neuropsychiatry at MGH and directs the Laboratory of Neuropsychiatry and Neuromodulation. 
His will provide his expertise in imaging studies of neuromodulation. Kristen Ellard, PhD Is the 
director of Dimensional Neuroimaging Research within the Division of Neuropsychiatry and will 
provide her expertise in bipolar disorder and neuroimaging. Dr. Cassano, Dr. Camprodon, and 
Dr. Ellard all have extensive clinical research and data safety monitoring experience. Dr. 
Cassano, as the principal investigator, will discuss safety concerns with research study team 
(CRCs and post-doc) and bring any concerns to the other co-Is, if needed. Dr. Camprodon will 
provide safety monitoring and insight for neuroimaging and Dr. Ellard will provide her insight 
for safety of bipolar disorder subjects. In addition to these internal monitors, Dan Iosifescu, MD, 
MSc., will serve as the independent monitor for the study. He is the Director of Clinical 
Research at the Nathan Kline Institute in New York and has extensive experience within the field 
of Psychiatry and t-PBM as a PI and co-I of many studies within the field. He will review the 
annual reports for safety, and findings, and he will provide feedback on the study.  
 

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Study staff will meet on a weekly basis for the duration of the study to review the progress of the 
study, discuss safety concerns that arise, and make recommendations to improve safety 
procedures if indicated. Study staff will also review and monitor data on a weekly basis to ensure 
adherence to protocol and accurate data collection.  
 
Subjects will be thoroughly screened prior to starting any study procedures to ensure they meet 
inclusion criteria and that they have the capacity for voluntary, informed consent.  
 
If the subject experiences any adverse event or discomfort throughout the t-PBM sessions that 
are not able to be alleviated by the PI or study staff, then the application session will be stopped. 
 
An adverse event means any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research (modified from the 
definition of adverse events in the 1996 International Conference on Harmonization E-6 
Guidelines for Good Clinical Practice).  
 
A serious adverse event means any event temporally associated with the subject’s participation 
in research that meets any of the following criteria:  
• 
results in death.  
• 
is life threatening (places the subject at immediate risk of death from the event as it 
occurred). 
• 
requires inpatient hospitalization or prolongation of existing hospitalization.  
• 
results in a persistent or significant disability/incapacity.  
• 
results in a congenital anomaly/birth defect; or  
• 
any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical intervention to 
prevent one of the outcomes listed above (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse). 
 
Expected adverse events and expected serious adverse events will not be accepted by the Mass 
General IRB nor will they be reported unless the sponsor or investigator deems the event to be 
unexpected in nature. Only Unanticipated Problem Involving Risks to Subjects or Others 
(UPIRTSO) and Unanticipated Adverse Device Effect (UADE) Events meeting either of these 
definitions are considered “Unanticipated Problems” and should be reported if they occur during 
the conduct of the study, after study completion, or after subject withdrawal or completion. 
Events meeting these definitions include unexpected or unanticipated drug or device adverse 
reactions attributable to the intervention and that place subjects at increased risk of harm. 
 
In the case of an unexpected adverse event and in accordance with Partners Human Research 
Committee Adverse Event Reporting guidelines, the PI and study staff will complete the 
appropriate adverse event form and send it to the IRB within the required time frame for 
reporting. This documentation will be completed and submitted on Insight within 5 business/7 

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calendar days from the day the investigator first became aware of the event. This report will 
include:  
• a detailed description of the event 
• the basis for determining that the event is unexpected in nature, severity, or frequency 
• the basis for determining that the event is related or possibly related to the research 
procedures 
• the basis for determining that the research places subjects at an increased risk of harm)  
• whether any changes to the research or other corrective actions are warranted. 
 
Experienced, doctoral-level clinicians will be available to participants by phone, or in-person if 
necessary, to discuss any concerns throughout the study. This will be clearly communicated 
orally and in writing to subjects. 
 
All monitoring and quality assurance procedures will be in accordance with the MGH sub-
committee on human studies. The PI will oversee the collection, maintenance, and analysis of the 
data. Research affairs will be contacted immediately in the case of unexpected adverse events 
likely related to the intervention. If an unexpected adverse event or serious adverse event does 
occur, the investigator will consider whether corrective actions should be made to study 
procedures in order to protect the safety and welfare of study subjects. If any changes are made 
the Protocol and Informed Consent Form will be updated and these edits will be submitted as an 
Amendment to the IRB.  
 
If a subject’s clinical condition deteriorates substantially by self-report and clinician assessment, 
the subject will be withdrawn from the study. Subjects may also be withdrawn if the PI feels that 
the study poses a substantial risk to the participant or if the PI decides that a higher level of care 
is needed. 
 
Procedures used in this study are consistent with safe and ethical research practices and do not 
unnecessarily expose subjects to risk. Adverse events are expected to be infrequent given the 
excellent safety profile of t-PBM, but should they arise, the PI will review the adverse event and 
report it to the IRB. Moreover, study staff and subjects may report concerns directly to the IRB. 
 
Every effort will be made to enhance the comfort of subjects while throughout the study 
procedures. Subjects will be informed that they can stop any study procedure at any time if 
needed. 
 
 
 
11.   Privacy and Confidentiality 
 
☒ Study procedures will be conducted in a private setting 
☒ Only data and/or specimens necessary for the conduct of the study will be collected 
☒ Data collected (paper and/or electronic) will be maintained in a secure location with 
appropriate protections such as password protection, encryption, physical security 
measures (locked files/areas) 

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☐ Specimens collected will be maintained in a secure location with appropriate protections 
(e.g. locked storage spaces, laboratory areas) 
☒ Data and specimens will only be shared with individuals who are members of the IRB-
approved research team or approved for sharing as described in this IRB protocol 
☐  Data and/or specimens requiring transportation from one location or electronic space to 
another will be transported only in a secure manner (e.g. encrypted files, password 
protection, using chain-of-custody procedures, etc.) 
☒   All electronic communication with participants will comply with Mass General Brigham 
secure communication policies 
☒ Identifiers will be coded or removed as soon as feasible and access to files linking 
identifiers with coded data or specimens will be limited to the minimal necessary 
members of the research team required to conduct the research 
☒ All staff are trained on and will follow the Mass General Brigham policies and 
procedures for maintaining appropriate confidentiality of research data and specimens 
☒ The PI will ensure that all staff implement and follow any Research Information Service 
Office (RISO) requirements for this research 
☐ Additional privacy and/or confidentiality protections 
 
 
 
12.   References 
 
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