tDCS to Decrease Opioid Relapse
Phase: NA
Conditions: Opioid Dependence, Craving
Sponsor: Butler Hospital

Clinical Trials #: NCT03842137 
October 22, 2023 
Grant Number: UH3DA047793 
Title: tDCS to Decrease Opioid Relapse 
MPIs: Ana Abrantes, PhD and Michael Stein, MD 

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  BUTLER HOSPITAL CONSENT FOR PARTICIPATION IN A RESEARCH PROJECT  
 
 tDCS to Decrease Opioid Relapse 
 
Sponsorship 
This study is being paid for by the National Institute on Drug Abuse. 
 
Research Project Summary 
You are invited to participate in a study designed to understand how people do after buprenorphine or 
methadone treatment has started and whether a brain stimulation procedure called transcranial direct 
current stimulation (tDCS) affects craving for opioids.  You have been invited to participate because you 
are currently in treatment for opioid use and are starting buprenorphine or methadone treatment. Your 
participation in the study will last approximately 2 weeks. Participation may be in-person, or by 
phone/video formats. It will require up to 7 visits to our research office, and approximately 10 hours of 
your time.  At these visits, you will be asked interview questions by the research staff, have 5 sessions of 
transcranial direct current stimulation (tDCS), and complete 2 electroencephalography (EEG) sessions.  
You may also be asked to complete 2 functional magnetic resonance brain imaging (fMRI) scans.  You will 
be compensated for your time (details below).  
 
In order to decide whether or not you wish to be a part of this research study, you should know enough 
about its risks and benefits to make an informed judgment.  This consent form gives you detailed 
information about the research study which a member of the research team will discuss with you.  This 
discussion should go over all aspects of this research:  its purpose, the procedures that will be performed, 
risks associated with the procedures, possible benefits of participation, and possible alternatives.  Once 
you understand the study, you will be asked if you wish to participate; if so, you will be asked to sign this 
form.  This consent may contain words that you do not understand.  Please ask the investigator or the 
study staff to explain any words or information that you do not clearly understand. 
 
Description of Procedures 
If you decide to participate, you will be asked to do a number of different activities as part of this study.  
 
Assessment Interviews: You will be asked questions by the research staff either in-person or via a 
secured videoconference. These questions will be about you, your physical and mental health, your 
substance use, and your craving for opiates. These research questionnaires will begin today, and again in 
about 1-2 weeks. The assessments will be confidential and may be audio- or video-recorded. The 
recording is for training purposes, to ensure the staff are consistent in conducting the research 
assessment. We will tell you whenever we plan to use an audio-or video-recorder. By signing this consent 
form, you give us permission to audio- or video-record. You may refuse audio- or video-recording of 
interviews at any time and still participate in the study. Recordings will be destroyed at the end of the 
study. You will be asked to provide a urine sample to test for substance use at each study appointment. 
You will also be asked to sign a health information release form for the physician that prescribes your 
buprenorphine or methadone so that we may verify the date that you were prescribed the medication. 
 
tDCS: You will have five sessions of tDCS  during which a very low level electrical current  stimulation is 
delivered to your head. These five sessions will take place over about one week. You will be randomly 
assigned (like the flip of a coin) to receive either active or fake (sham) tDCS. You will not know which 
condition you are assigned. At each session, you will have either the active or sham stimulation for 
approximately 20 minutes.  In order to provide the active or sham stimulation, two wet sponges 
containing electrodes will be placed on your head. These sponges will be held in place by large rubber 
bands. During the tDCS period, these sponges and rubber bands will remain on your head.  During each 
20-minute period, you will also engage in an activity that’s like a computer game. 

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fMRI: You may have two fMRI scans approximately one week apart. If you are asked to participate in fMRI 
scanning, we will either bring you to the fMRI facility at Brown University, about a mile away, or you will 
meet us there, where you will meet a staff member.  While at the facility, you will have a Functional MRI 
(fMRI) scan which takes a picture of your brain working when you’re asked to do certain things.  At the 
beginning of this part of the scan, the research staff will describe the equipment and what you will be 
asked to do, and answer any questions you have.  You will then put on earplugs, lie on the scanner table, 
and the table will slide you into the scanning area.  On a computer screen in front of you, there will be 
several different computer games to complete, one of which will include seeing images of opioids on the 
screen.  During the whole fMRI, which takes about an hour, you will be able to hear and to talk to the 
research staff, and you can stop the task at any time.   You will have one scan this week, prior to beginning 
your tDCS sessions, and another about 7 days later. Each session, including travel to and from the 
scanning facility will take approximately 3 hours. You will be provided transportation (cab rides) for 
research procedures at Butler Hospital and at the fMRI scan facility, and back home after the 
appointments are completed.  
 
EEG: In addition to the interview and questionnaires, you will also complete a computer task where you 
have to match letters to those on screen, lasting approximately 10 minutes. The task is designed to test 
working memory. During this task, you will have a recording of your brain waves through a noninvasive 
procedure called electroencephalography (EEG).  Neurologists have used EEG for many years to evaluate 
the functioning of nerves (“neurons”) in the brain and to diagnose various neurological conditions. The 
EEG recording in this research study, however, will not be used to diagnose any specific brain condition. 
For the EEG procedure, a trained technician will apply a special cap to your head. The cap contains little 
holes and special surfaces (electrodes) that make contact with the skin on your head to record electrical 
signals on your scalp. A special gel will be applied to your head through the holes in the cap to enhance 
the ability to detect the electrical signals from your scalp. Once the cap is on and the gel is applied, you 
will then sit quietly in a chair while the electrical activity of your brain is recorded.  After several minutes 
of quietly sitting, you will complete the 10-minute computer task while the EEG is recording your brain 
activity. One EEG session will be completed this week, prior to beginning your tDCS sessions, and another 
about 7 days later. 
  
Text Messaging 
We would like to contact you by text message for the purposes listed below:  
1. To schedule research-related appointments 
2. To send reminders about appointments  
 
How do Text Communications with CNE Researchers Work? 
Text messages from the study staff will be sent from a phone that is dedicated for use in this research 
study.  The phone will not be monitored for return messages constantly, but it will be checked 
periodically during regular office hours. You can respond to messages from researchers by sending them 
text messages, but there are only certain things you should communicate via text message.  
 
Risks Related to Text Communication 
You should be aware that there are risks associated with sending your health information via text.  There 
is always a risk that the message could be intercepted or sent to the wrong number. Only the research 
team will have access to your text communications.  We will only communicate by text to send you the 
information previously listed.  We will not send text messages that contain urgent information. We will 
not send text messages to a group of recipients. If you share your mobile phone or messages with others, 
you risk losing privacy surrounding your health information and loss of privacy surrounding your 
participation in this study.  You should make sure to protect your phone with a password if you send or 
receive text messages during participation in this study. 
 

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Cautions Related to Text  Communication with Researchers 
Text messages may not be received by researchers on a regular basis. It is possible that a message you 
send will go unnoticed, or will not be read by the research team for days or weeks. You should use the 
telephone to contact the research team for any urgent matters. Medical issues (symptoms, side 
effects, injuries, concerns about effects of study procedures, etc.) should NOT be communicated by 
text message. These should be directed to the research staff by telephone or in person. To discuss 
medical issues, please contact our office at 401-680-4160. 
 
Can we contact you via text messaging?   
YES____________(initial) OR 
NO___________ (initial) 
 
Email 
We would like to contact you by e-mail for the purposes of sending you web-links, which will take you 
online to a secure database where you can complete various study assessment forms during participation 
in this research project. 
 
How do e-mail communications with CNE researchers work? 
You will receive an e-mail message from our research team sent to you from a secure Care New England-
hosted research data system called “REDCap.” The message will include a link for you to click. Clicking the 
link will securely connect you with REDCap, where you will see your study survey. You will respond by 
clicking on buttons you see on the screen. The e-mail messages you receive will not identify you by name, 
and the links to surveys you get through REDCap will be associated only with your e-mail address. Your e-
mail address and any other information that personally identifies you will be removed from the final 
research database when the study is over. 
 
Risks related to e-mail communication 
You should be aware that there are risks associated with sending your health information via e-mail.  
There is always a risk that the message could be intercepted or sent to the wrong e-mail address. E-mail 
messages from research staff may contain health information that identifies you. Information sent by e-
mail could allow others to identify you along with your medical health conditions and psychiatric 
diagnosis (if applicable).  Only the research team will have access to your e-mail communications.  We will 
only communicate by e-mail to send you the information listed above.  We will not send e-mail messages 
that contain urgent information or results of medical tests or diagnostic procedures. We will not send 
messages that direct you to get medical care. 
 
Using this secure e-mail system will help reduce the chance that you will experience loss of confidentiality 
when using e-mail. If you share a home computer with other family members and do not want them to 
know you are participating in this study, make sure you provide an e-mail address that only you can 
access.  Your employer or school will have access to any e-mail communications sent or received on a 
work or school computer. Additionally, when using any public computer you should be careful to protect 
your username and password, and make sure you log-out before getting up from the computer. 
 
Cautions related to e-mail with researchers 
Study participants are required to send any e-mail messages they write to the research team through this 
secure system. E-mails may not be received by researchers on a regular basis. It is possible that a 
message you send will go unnoticed, or will not be read by the research team for days or weeks. You 
should use the telephone to contact the research team for any urgent matters. Medical issues 
(symptoms, side effects, injuries, questions about medications, concerns about effects of study 
procedures, etc.) should NOT be communicated by e-mail. These should be directed to the research 
staff by telephone or in person. To discuss medical issues, please contact our office at 401-680-4160.   
 
Can we contact you via email?   
YES____________(initial) OR 
NO___________ (initial) 

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Risks and Inconveniences 
 
1) Questionnaires 
You may refuse to answer any questions that make you feel uncomfortable and you can stop the interview 
at any time. Most people do not experience any discomfort during these assessments, but others may find 
answering these questions upsetting and uncomfortable.  We will make every effort to minimize any 
discomfort you may feel during this process. Interviews will be conducted in a private area in the hospital 
or via a secured videoconference. You can pause the interview at any time if you need a short break.   
 
All information obtained will be kept confidential.  Your responses to the questions will not be linked to 
any information that can identify you as an individual. Your information will be available only to our 
research staff.  
 
2) tDCS 
tDCS has a risk of skin irritation and temporary redness on your scalp where the sponges and electrodes 
are placed. Local skin burns are also possible; however, these would be considered extremely rare given 
the type of tDCS used in this study. Hypomania (feelings of elevated mood or too much energy), has also 
been reported in a small percent of people who received daily tDCS for depression. In one study where 
daily tDCS was used for depression with or without antidepressant medication, as many as 5-6% of 
people developed hypomania. In most cases, the hypomania went away after stopping tDCS or by making 
adjustments to medications. However, the overall risk of hypomania occurring with tDCS is still unclear. 
Other effects such as temporary headache, nausea, and fatigue are sometimes reported with tDCS. It is 
possible that tDCS may have other unforeseen side effects. We will monitor you closely but if you 
experience discomfort, please tell us immediately. A physician will be on-call during all tDCS procedures. 
We will also check in with you regularly during your weekly visits about any side effects you may be 
experiencing.   
 
3) fMRI 
There are few risks associated with the fMRI procedure, although some people report feeling nervous 
inside the loud scanning machine or uncomfortable in small spaces (claustrophobia). MRI may not be safe 
if you have metal implanted in your body that could interact with the magnetic field in the scanner. Please 
tell us if you have any metallic tattoos or implanted no removable metal on or in your body. You may 
experience some frustration from the computer tasks you complete while you are in the fMRI facility.  
Also, you may experience distress or cravings when you see the images of opioids during the fMRI.  At the 
end of the fMRI session, we will provide you with strategies for managing any remaining distress or 
cravings.   
 
You will be asked to sign a separate consent form which describes the fMRI risks in more details.  
 
Any medical treatment or procedure may have unforeseen side effects.  You should know that the 
prediction of effects from a treatment or procedure for any individual cannot be done with certainty, and 
unexpected potentially harmful effects occasionally occur with the administration of any type of 
treatment.  If you have questions about investigational procedures or treatments, or if you experience any 
disturbing side effects during participation in this study, inform study personnel.   In the event of any 
unexpected, potentially harmful effects of any treatment or procedure administered in this study, we will 
monitor your condition closely and institute appropriate treatment. If significant new knowledge is 
obtained through the course of the research which may impact your willingness to continue participation, 
you will be informed of this knowledge. 
 
4) EEG 
EEG recording is considered “noninvasive” and is therefore considered to be generally safe. There are 
minor inconveniences associated with EEG, such as having residual paste in your hair or on your scalp 

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after the procedure. The paste can be removed with soap and water but we do not have a facility for you 
to shower or thoroughly wash your head in the area where the EEG recordings take place.   It is possible 
you will feel some minor discomfort from having your head in contact with the EEG cap.   Allergic reaction 
or skin irritation from the neoprene material in the EEG cap or from the EEG gel is very rare. 
 
Women Please Note:   
The effects of tDCS, as used in this study, during pregnancy are unknown.  An fMRI scan may be harmful 
to a developing fetus.  Therefore, you may be tested for pregnancy at the time of your admission to the 
study.  Prior to your beginning the study, we will discuss with you in more detail the importance of 
avoiding pregnancy.  We will specifically ask you to let us know if you change your mind and decide to 
become pregnant during the study. 
 
Benefits 
You may benefit by feeling a reduction in your cravings for opiates. However, we cannot guarantee that 
you will benefit. The main benefits of this study are to help researchers and clinicians develop a better 
understanding of craving and substance use after starting buprenorphine or methadone.  
 
Economic Considerations   
You will receive $75 for the baseline interview, $5025 for each of the 5 tDCS sessions, $75 for each EEG 
recording session, and $75 for the final interview. If you are asked to participate in fMRI scanning, you 
will be paid $75 for each fMRI scan. All payments will be in the form of a gift card to a local store or 
supermarket. 
 
Depending on the amount of payment you might receive for your participation in this study, you might 
have to provide your name, address, and taxpayer ID or Social Security number to the Butler/CNE 
Research Accounting Department. In order to receive payment of $300 or more for participation in this 
research, you will have to complete and sign a W-9 form.  If you are paid $600 or more in any calendar 
year for research participation, the IRS will be notified of the total amount you were paid, in accordance 
with federal regulations. You should ask the researcher for more information if you have questions about 
this process. 
 
In Case of Injury   
We will offer you services in Care New England facilities as needed to treat any injury that results directly 
from taking part in this research study.  We reserve the right to bill your insurance company or other 
third parties, if appropriate, for the care you get for the injury.  We will try to have these costs paid for, 
but you may be responsible for some of them.  For example, if the care is billed to your insurer, you will be 
responsible for payment of any deductibles and co-payments required by your insurer.   
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay you or give 
you other compensation for any injury, should one occur.  However, you are not giving up any of your 
legal rights by signing this form.   
 
If you think you have been injured or have experienced a medical problem as a result of taking part in this 
research study, tell the person in charge of this study as soon as possible.  The researcher’s name and 
phone number are listed on the last page of this consent form.    
 
Alternative Treatments/Alternative to Participation  
There are no known effective alternative treatments to manage craving or reduce drug use for persons 
who have recently begun buprenorphine or methadone and are receiving standard medical management. 
 
 

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Financial Disclosure   
None 
 
Voluntary Participation 
You are free to decide whether or not to participate in this study, and you are free to withdraw from the 
study at any time.  A decision not to participate or to withdraw from the study will not adversely affect 
your current or future interactions with Butler Hospital or Care New England. Your participation in the 
study may be terminated by the researchers without regard to your consent; in that case, you are entitled 
to an explanation of the circumstances leading to that decision. 
 
Confidentiality  
Personal identifiers will be removed from any identifiable private information about you (and/or your 
biospecimens) in the final research dataset created by this study. The de-identified information or 
biospecimens may be used for future research studies or distributed to another investigator for future 
research studies without additional informed consent from you (or the legally authorized representative).  
You will not be personally identified in any reports or publications that may result from this study.  The 
confidentiality of the information you provide to us will be maintained in accordance with state and 
federal laws.  If you tell us something that makes us believe that you or others have been or may be 
physically harmed, we may report that information to the appropriate agencies. 
 
Clinically relevant research results, including individual research results, will not be disclosed to you. To 
keep your information safe, we will store all information in locked file cabinets and on password 
protected secure computer servers. To the extent possible, we store identifying information (such as your 
name or address) separately from study data (such as questionnaires that you complete). In addition to 
keeping research data, we will place a note with a brief description of study involvement and procedures 
(including tDCS procedures) in a Butler Hospital medical record. You will not be identified on audio- or 
video-recordings and they will be stored on a secure server which is password protected and only 
accessible to research staff. All identifying information, except what is part of your medical record at 
Butler, will be destroyed 6 years after the completion of the study.  If you tell us something that makes us 
believe that you or others have been or may be physically harmed, we may report that information to the 
appropriate agencies. 
 
General information about this study has been or will be submitted to the federal clinical trial registry 
databank, which can be accessed on the Internet at www.ClinicalTrials.gov.  
 
This research is covered by a Certificate of Confidentiality. Unless you give special written permission, the 
researchers and Butler Hospital cannot give out any information about you that could potentially identify 
you or be used as evidence in a legal case (including any federal, state, or local civil, criminal, 
administrative, or legislative case).  
 
The only situations where researchers would share your information with others are:  
(1) when a specific law (federal, state, or local) requires that potentially harmful things be reported to 
the authorities (such as reporting child abuse, elder abuse or spread of communicable diseases);  
(2) when you have given permission (consent) for the information to be shared in order to help your 
medical treatment; or 
(3) when your information will be used for other scientific research, as allowed by federal regulations 
protecting research subjects. 
 
Authorization for use/disclosure of Health Information that Identifies you for a Research Study 
If you sign this document, you give permission to Drs. Abrantes and Stein (Study Directors) at Butler 
Hospital to use your health information that identifies you, for the purpose of conducting the research 
study described above.  

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Your health information related to this study may also be shared with and used by individuals outside of 
Butler Hospital, including:  
 
The Brown fMRI facility staff. 
 
Other healthcare and public safety professionals, if we are concerned that you are at risk of 
hurting yourself or others. 
 
The health information that we may use or share with others for research purposes includes any 
information that you give us as part of your study participation, information in your ADP medical chart, 
and results of any assessments that we do as part of the study that is relevant to the above individuals. We 
will not collect or share more information than is necessary.   
 
Your health information may also be shared with a public health authority that is authorized by law to 
collect or receive such information for the purpose of preventing or controlling disease, injury, or 
disability, and conducting public health surveillance, investigations, or interventions. The U.S. Food and 
Drug Administration (FDA) may inspect all study records to ensure that the study is being conducted in 
accordance with FDA regulations.  
 
Butler Hospital is required by law to protect your health information. Individuals outside of Butler that 
receive your health information may not be required by Federal privacy laws (such as the HIPAA Privacy 
Rule) to protect it, so we cannot guarantee that they will not share it without your permission. 
 
Please note that:  
 
You do not have to sign this consent form, but if you do not, you may not participate in or receive 
research-related treatment in this study.   
 
Butler Hospital may not withhold treatment or refuse to treat you, based on whether you sign this 
consent form.  
 
You may change your mind and revoke (take back) this consent and authorization at any time. If 
you no longer want to give us permission to use your health information for this research study, 
you must contact the Principal Investigators, Dr. Ana Abrantes or Dr. Michael Stein, and you will 
be instructed to provide a written statement.  
 
Even if you revoke (take back) this consent and authorization, Butler researchers may still use or 
share health information about you that they already have obtained, when doing so is necessary 
to maintain the integrity or reliability of the current research.  
 
You generally will not have access to your personal health information related to this research 
until the study is completed. At the conclusion of the research and at your request, you will have 
access to your health information that Butler Hospital maintains in a designated record set, 
according to the Notice of Privacy Practices provided to you by Butler Hospital. The designated 
record set includes medical information or billing records used by doctors or other health care 
providers at Butler Hospital to make decisions about individuals.  
 
Your health information will be provided to you or to your physician if it is necessary for your 
care.  
 
If all information that does or can identify you is removed from your health information, the 
remaining information will no longer be subject to this authorization and may be used or 
disclosed for other purposes. 
 
This Authorization will expire when all the activities associated with this research study have concluded.  
 
Questions 
Taking part in this study is entirely voluntary. We urge you to discuss any questions about this study with 
our staff members, either in-person or by audio/video platforms. You should take as much time as you 

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need to make your decision. If you decide to participate, you must sign this form to show that you want to 
take part.  
 
 

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Authorization:   
I have read this form and decided that I, _________________________________________________________________ 
 
 
 
 
 
 
 
 (print name of participant) 
will participate in the project described above.  Its general purposes, the nature of my involvement, and 
possible hazards and inconveniences have been explained to my satisfaction. I have received a copy of 
this consent form. 
 
__________________________________________________________ 
 
_____________________________________ 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
__________________________________________________________ 
 
_____________________________________ 
Signature of Principal Investigator 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
~or~ 
__________________________________________________________ 
 
_____________________________________ 
Signature of Person Obtaining Consent 
 
 
 
Date 
Telephone Number of Principal Investigator or Person Obtaining Consent_________________________ 
 
If you have further questions about this project or about research-related injuries, please contact Ana 
Abrantes 401-455-6440.  If you have questions about your rights as a research subject, please contact 
Paul F. Malloy, Ph.D., Vice Chair, Butler Hospital Institutional Review Board, at 401-455-6355. 
 
THIS FORM IS NOT VALID UNLESS THE FOLLOWING BOX HAS BEEN COMPLETED BY THE IRB OFFICE 
 
THIS FORM IS VALID UNTIL 
 
 
    DATE:  
 
 
    IRBNET ID#  
    BUTLER IRB REFERENCE# 
 
 
    BY (ADMINISTRATOR):     
 
 
 
 
 
 
 

Rev. 10/22/23 
 
 
Grant Number: UH3DA047793 
 
Title: tDCS to Decrease Opioid Relapse 
 
MPIs: Ana Abrantes, PhD and Michael Stein, MD 
 
Medical Monitor: Dr. Michael Stein 
 
 
 

Rev. 10/22/23 
2. Summary of the Protocol: 
2.a, 2.b Brief Description of the Protocol, Primary and Secondary Outcome Measures 
This study has two phases.  In phase one (UG3), we propose to use functional magnetic 
resonance imaging (FMRI) and electroencephalographic (EEG) to quantify changes in brain 
function and reported craving before and after administration of five sessions of transcranial 
direct current stimulation (tDCS) targeting the right dorsolateral prefrontal cortex (DLPFC).  
Opioid dependent participants (n=60) who recently initiated buprenorphine or methadone will 
be randomized to tDCS+Cognitive Control Network (CCN) priming stimulation vs. sham 
tDCS+CCN priming. Participants in their first month of prescribed buprenorphine or 
methadone will be assessed using FMRI and EEG, once prior to tDCS and again one week 
later after completion of 5 sessions of tDCS+CCN priming. With a focus on the craving 
outcome, we will use two task-based FMRI paradigms that challenge networks associated with 
craving (CR) and cognitive control (CCN), and will examine these and the salience network 
using resting state functional connectivity. We examine an additional validation measure of the 
effect of tDCS on the DLPFC – an oscillatory target --  EEG frontal theta power during working 
memory(WM). In this UG3 phase, FMRI and EEG will be expected to provide 1) validation of 
expected network and oscillatory changes from tDCS-targeting and 2) an effect size for 
DLPFC vs sham stimulation. Go/no go criteria for the UG3 phase will be demonstration of 
greater FMRI change in any node of the CR or CCN networks or enhanced frontal theta power 
during a WM task AND greater change (at least 10% difference between conditions, 
controlling for baseline craving) in subjective craving measured during a cue reactivity task or 
outside the FMRI following the tDCS+CCN priming intervention compared to sham tDCS+CCN 
priming. 
In the present study, we elected to keep aspects of the tDCS protocol consistent with prior 
studies.  That is, we will place the anode over the right DLPFC (F4 on the EEG 10-20 system) 
and the cathode over the left DLPFC (F3) using 25cm2 sponges at an intensity of 2mA. 
Stimulation will be delivered via two saline-soaked surface sponge electrodes and a battery-
driven, constant current stimulator (NeuroConn DC Stimulator Plus). This device includes a 
study mode, in which subject-specific codes are entered to deliver active or sham stimulation, 
keeping the administrator blinded.  Sham stimulation will use a method in which stimulation will 
be ramped up and back down over a 30-second period at the beginning and end of sham 
tDCS. This approach has been found to be an effective sham condition in previous studies 
using tDCS at 2mA with no difference between sham and active tDCS groups in guessing their 
group assignment.  Each participant will receive 20-minutes of either active or sham tDCS 
+CCN priming during each of the five sessions. During the final 15 minutes of each stimulation 
session, once a participant is settled, s/he will engage in standardized tests from the NIH 
Toolbox that engage the CCN (i.e. CCN priming): Flanker Inhibitory Control and Attention 
Test, List Sorting Working Memory Test, and Dimensional Change Card Sort Test). 
The optimal frequency, duration and number of tDCS sessions to maximize effects on 
craving, or any other construct in this young field, remain obscure. We chose to deliver 5 
sessions of tDCS because this number has been used in prior successful tDCS craving 
interventions and must be balanced against adherence concerns. While we are hopeful that 
participants will complete 5 consecutive days of tDCS, the interruption of weekends and the 
transition from the ADP setting (where the tDCS protocol will start) where days are structured, 
to the community setting, raises the possibility of missed tDCS sessions and therefore we will 
allow these 5 sessions to occur over 10 days if necessary, as has been described in prior 
studies, tracking both average number of sessions received and period of treatment for 
analyses. The sham tDCS condition is included in our design to separate the effects of 
ongoing opioid treatment from the effect of active tDCS on craving. We decided not to include 
a third no-tDCS arm, as this would omit any nonspecific treatment effects (match for attention, 
expectation) of entering a neurostimulation treatment protocol. This protocol will provide a 
basis for future studies of tDCS stimulation parameters (frequency, duration, number) that 
could optimize adherence and treatment effects of drug use outcomes.   

Rev. 10/22/23 
In phase two (UH3), we will perform a larger RCT using the same treatment protocol in 100 
opioid dependent participants who recently initiated buprenorphine or methadone. Participants 
will be randomized to receive five sessions of tDCS+CCN priming stimulation vs. sham 
tDCS+CCN priming. Phase two will address long-term (3-month) neurobehavioral outcomes, 
including opioid relapse, craving, and sustained fMRI changes during a paradigm that 
challenges networks associated with craving (CR) and cognitive control (CCN). During the 12 
weeks of opioid maintenance treatment, we will examine our primary clinical outcome, relapse 
(opioid use on >4 days per month and having an opioid positive urine screen), as well as days 
of opioid use. 
 
2.c Inclusion/Exclusion Criteria: 
UG3/UH3 Inclusion Criteria: (a) current opioid dependence, (b) between 21-50 years of age, 
(c) recent initiation of buprenorphine or methadone (<30 days) 
Exclusion Criteria: (a) diagnosis of organic brain disorder, bipolar disorder, schizophrenia, 
schizo-affective, schizophreniform, or paranoid disorder, (b) current suicidality, (c) evidence of 
neurocognitive dysfunction, (d) contraindications for tDCS (e.g seizure disorder), (e) 
probation/parole requirements or an upcoming move that might interfere with protocol 
participation, (f) planning to terminate buprenorphine or methadone in less than 3 months, and 
(g) scalp lesions near the tDCS electrode sites. 
Exclusion Criteria related to FMRI scanning are: (a) history of neurological disorder (e.g., 
epilepsy, stroke, brain injury with loss of consciousness>10 min), (b) impaired uncorrected 
vision, and (c) MRI contraindications (e.g., claustrophobia, specific metallic implants and 
injuries, and pregnancy). 
tDCS-related considerations: Careful consideration will be given when determining whether 
tDCS is safe for potential participants. Additional exclusion criteria related to tDCS include: 
metal implanted in the cranial cavity, pacemaker, poor cognitive functioning (i.e., Alzheimer’s 
disease or dementia), history of neurological disorder (e.g., epilepsy or other seizure disorder), 
or other significant or chronic medical conditions that affect the brain (e.g., Parkinson’s 
disease, Huntington’s disease, multiple sclerosis, traumatic brain injury). Dr. Stein will have the 
final decision regarding whether a participant is medically stable enough to engage in this trial. 
 
2.d Power Calculation and Sample Size: 
       In the UG3 phase of this project, we plan to enroll 60 participants. With an expected 
attrition rate of 20% (data loss over two sessions due to poor performance or movement 
artifact—a conservative estimate that is a larger loss than in our ongoing FIRST study), our 
final sample size will be 48, or 24 per group. This number provides 82% power for the 
expected effect size of .75, chosen based on prior tDCS studies and our belief that a large 
effect size should be required to continue to the UH3.  In the UH3 phase, we again anticipate a 
20% attrition rate over the 5 tDCS sessions and initial two FMRI scans. If the third scan (at 4 
weeks) is missed, we expect this will be due to treatment drop-out or relapse. With 100 
participants enrolled, we will have a final sample of 80 patients which provides a power of .8 to 
detect a group difference in relapse between relapse and sham of 15% vs 39% at 3 months 
follow-up.   
       Effect size estimates for baseline differences in FMRI signal based upon subsequent 
lapse are not available; however we have taken steps to maximize our ability to detect group 
differences, if present. First, we will use ROI methods, which focus our analyses on more 
functionally homogenous brain regions related to each task. Therefore, we predict larger and 
less variable effect sizes. Second, we have chosen FMRI paradigms with which we have 
already obtained reliable and valid response patterns. Third, the constructs that we propose to 
assess in FMRI paradigms are significantly related to relapse in behavioral studies. 
 
3. Trial Management: 
3.a List of Participating enrolling clinics or data collection centers 

Rev. 10/22/23 
All data will be collected for research purposes only and all records will be stored in locked 
files (physical or on computer) in locked rooms accessible only to research staff. Data 
gathered from people are screened but who do not meet inclusion criteria or decide not to 
participate will be stripped of personal identifiers or links and only demographic characteristics 
and the reason for study exclusion will be kept. Paper forms with personal identifiers (such as 
consent forms or contact information) will be stored in a locked file that does not contain 
subject code numbers. All other data will be stored in files locked in a separate location with 
only code numbers identifying subjects, no personal identifiers. A cross-index of code numbers 
and participant names will be kept in a separate, password-protected computer file that is 
available only to research staff (for collecting follow-ups), the PIs, and mandated auditing 
agencies during audits. 
All de-identified research data will be entered into REDCap. REDCap is a secure, web 
application designed to support data capture for research studies, providing user-friendly web-
based case report forms, real-time data entry validation (e.g. for data types and range checks), 
audit trails, and a de-identified data export mechanism to common statistical packages (SPSS, 
SAS, Stata, R/S-Plus).  Participants may complete surveys in the laboratory or anywhere they 
can access a web browser, including on their Internet-connected smartphone or tablet. The 
system was developed by a multi-institutional consortium and was initiated at Vanderbilt 
University. The CNE RedCap is hosted on a CNE-based server. Network transmissions (data 
entry, survey submission, web browsing, etc.) in REDCap are protected via Secure Sockets 
Layer (SSL) encryption.  Access to REDCap can be restricted at different levels (e.g., research 
assistant, PI, and Co-Investigators).  Exported data from REDCap will be stored on the 
Behavioral Medicine and Addiction Research’s secure password-protected server. 
Final Storage of Paper Data. Only the participants’ study identification number will appear 
on any of the final paper data collection instruments. Once data have been entered and 
passed audit verification, paper copies of data will be housed at a facility that specializes in the 
storage of medical/research information.  Only the subject's study identification number will be 
present on the forms.  Any indication of the subject's name will be removed from the 
questionnaires prior to archiving. The destruction date of these paper files will be at least 7 
years from the termination of the study and will be authorized by the Principal Investigator of 
the research study.   
 
4.c Data Analysis Plan 
Neuroimaging. In the UG3, three sets of analyses will be conducted to examine task-based 
responses to 1) the CR (craving) and 2) n-Back (CCN) challenges, and 3) tonic changes in 
network coherence at rest. 
1) CR: Two 2x2 mixed ANOVAs will be used to determine whether mean response to cues 
during CR decline across nodes of the craving network (VS, amygdala, VMPFC), including 
salience network (AI, ACC) and increases in the CCN (MFG, IPL). Significant pre-post main 
effects and group x treatment interactions are predicted in each. Those who received 
tDCS+CCN priming are expected to exhibit greater change. Follow up analyses of individual 
nodes within each network and whole-brain voxel-wise contrasts will be conducted to inform 
phase 2 analyses.  
2) n-Back: Two 2x2 mixed ANOVAs will be used to determine whether mean response to the 
n-Back challenge increases across nodes of the CCN (MFG, IPL) and the salience network 
(ACC and AI). Significant pre-post main effects and group x treatment interactions are 
predicted in each. Those who received tDCS are expected to exhibit greater change.  Follow 
up analyses of individual nodes within each network and whole-brain voxel-wise contrasts will 
be conducted to inform phase 2 analyses.  
3) Resting state: Two 2x2 mixed ANOVAs will be used to determine whether mean network 
coherence (functional connectivity) decreases across nodes of the craving network (VS, 
amygdala, VMPFC), including the salience network (AI, ACC) and increases in the CCN 
(MFG, IPL). Significant pre-post main effects and group x treatment interactions are predicted 

Rev. 10/22/23 
in each. Those who received tDCS are expected to exhibit greater change.  Parallel 
exploratory analyses will be conducted to examine resting state functional connectivity of the 
salience network and DMN. 
       In the UH3, neuroimaging analyses will generally parallel those described for UG3.  We 
will use a 2x3 ANOVA (three time points) to test the hypothesis that tDCS+CCN priming will be 
superior to sham tDCS+CCN priming on both subjective and fMRI measures of craving and 
cognitive control at the end of 5 sessions and at 3-months post tDCS. This same analytical 
method will be used to test the effect of intervention on days of drug use at the end of 5 
sessions and at 3-months. We will use the Pearson χ2-test of independence to compare 
tDCS+CCN priming to sham tDCS+CCN priming on relapse at 3-months. 
 
FMRI data analyses 
Whole-brain echoplanar FMRI will be conducted using a Siemen’s TIM Trio 3.0 T scanner 
(TR/TE 2500/28ms, FOV=1922 mm, matrix=642, 3mm axial slices). Volumes acquired will be 
228 for the 2-Back, 384 for CR, and 120 during the rest-only imaging run. This procedure 
yields BOLD signal values across time for each voxel.  A whole-brain, high-resolution 
(FOV=2402, matrix=2562) MPRAGE series will be conducted in 1mm sagittal slice thickness for 
anatomical reference. All FMRI processing and statistical analyses will be conducted using 
AFNI software. Data from subjects who exhibit invalid response patterns will be excluded. 
Processing includes concatenation of imaging runs, movement correction, slice-time 
correction, band pass frequency filtering, removal of linear drift, and application of a 6mm 
Gaussian kernel. For active tasks (n-Back and CR), GLM will be used to quantify task-related 
effects per voxel. Task-related response will be calculated compared to the appropriate active 
control tasks. The time course of the challenge of interest (2-Back blocks or opiate cues [CR]) 
and active control tasks (0-Back blocks or neutral images presentations [CR]) will be 
separately convolved with a gamma function and used as predictors.  These procedures 
generate individual activation maps of task-related effects per voxel. These individual datasets 
will be used as dependent measures in tests of our hypotheses using ROI analyses following 
quality control checks and stereotactic standardization. 
A priori task-based FMRI ROI analyses will be our primary method for quantifying changes 
in the craving, salience and cognitive control networks and subsequent hypothesis testing, 
while analyses involving the functionally defined ROIs will serve to validate our a 
priori findings. Mean task-related effect will be determined for each ROI of each individual for 
each condition of each task by averaging all voxels of each ROI. Results of these 
quantifications will be used as dependent measures in hypothesis testing. In primary analyses, 
mean effects will be examined across all nodes of each network, followed by analyses of each 
network node. Functional connectivity analyses will be performed on all networks during 
crosshair fixation (resting). We will use the seed region method. Briefly, BOLD signal will be 
averaged from four 3mm3 seed voxels at the center of mass of each ROI of each network (see 
Table 1) and extracted for each of the time points acquired. These reference series files will be 
used as predictors in one voxel-wise GLM analyses per ROI to identify the strength of the 
relationship between each brain voxel and the average of the seed region over time. Each a 
priori region will serve as a seed region once for its particular network. After Fischer’s 
transformation from r-values to z-values, the resulting mean voxel-wise values will be 
averaged in each target node (i.e., ROI not serving as the seed) following each GLM. For CR, 
these target ROI averages will then be averaged across two seed region iterations (i.e., 
excluding the seed region; this step is not needed for the 2 ROI salience networks). The 
resulting means for the nodes of each network will be averaged across ROIs (3 for craving, 2 
for salience, 3 for CCN) to derive a network coherence metric. Substance use type (heroin, 
prescription pills) will be included as a covariate in statistical models.  
 
EEG analyses. 

Rev. 10/22/23 
EEG Data Processing. Semi-automatic preprocessing for artifact detection will be 
performed using the FASTER algorithm (Nolan, Whelan, & Reilly, 2010).  This EEGLAB 
toolbox uses Welch methods and removes muscle, heart, motion, ocular artifacts, and other 
noise using a multiple step procedure consisting of a) bandpass and notch filtering, b) 
Independent Component Analysis (ICA), c) rejection and/or interpolation of bad 
channels/epochs. The final step of preprocessing includes visual inspection of the data 
rejecting any remaining artifactual epochs. Windows of 1400 ms (1100 -2500 ms after stimulus 
onset) will be included in analysis. Theta band (4 -8 Hz) power in frontal (Afz, Fz) electrodes 
will be averaged across both n-back levels. 
Working Memory and EEG Summary Indices. Working memory performance at each 
assessment will be represented by d’ to capture executive skills without influence by 
demographic variables, psychiatric status, or intelligence quotient (Haatveit et al., 2010).  For 
each participant, and within each n- condition, values for d’ will thus be calculated by dividing 
the difference of Z (false alarms) and Z (“hits”) by the root mean square of 2; d’ captures the 
participant’s ability to discriminate between the two stimulus types (i.e., the 2-back target 
letters and the non-target letters). Difference in theta power between 0-back and 2-back 
conditions (∆theta) will also be calculated at EEG/n-back assessment. Comparison of pre- 
versus post-treatment ∆theta will test the primary hypothesis that opioid dependent 
participants who received the active tDCS intervention will show greater increases in theta 
power after 5 intervention sessions than sham tDCS recipients. Estimation of power spectrum 
density (PSD) values in the beta band (13-30 Hz) will be computed and averaged from 
channels in four regions (frontal, central, temporal, and occipital-parietal) for analysis in 
relation to craving scores. 
EEG outcome measures analyses. We will conduct a repeated-measures ANCOVA with a 
within-subject factor of time (baseline and end-of-stimulation (EOS)), between-subject factor of 
intervention condition (active tDCS and sham) and covariates to test if there is a statistically 
significant difference in in the EEG outcome (∆theta) across treatment groups. Pearson 
correlations will be used to examine beta PSD values in relation to craving scores. A separate 
ANCOVA with the same factors will be used to explore treatment group differences in resting 
state EEG beta PSD values. Covariates for both analyses will include the baseline measure of 
the evaluated outcome, as well as baseline variables found to vary significantly (p < 0.05) by 
intervention arm, or which significantly (p < 0.05) predict attrition at EOS. Post-hoc t-tests will 
be used to probe anticipated significant interactions.  
 
5. Quality Assurance 
All  research  personnel,  will  have  formal  training  in  research  with  human  subjects  (e.g.,  
CITI  training,  NIH  Human  Subjects  training).  Drs.  Abrantes, Stein, and Carpenter  will  
provide  training  to  and  supervise  research  assistants.  Research  assistants  will  also  
have  training  in  Good  Clinical  Practice.   
Drs. Stein and Abrantes will be responsible for quality control of this study. They will review 
recruitment and retention reports, and AE reports on a weekly basis. The MPIs  (or  their 
designee)  will  inspect  BL  documents  (consent  forms,  release  of  information)  for  
completeness  within  a  week  after  they  are  signed.    The MPIs (or their designee)  will  
also  conduct  protocol  and  data  quality  monitoring  twice  a  year  using  a  checklist.  This  
monitoring  will  include  reviewing  other  study  records  to  ensure  completeness. 
 
6. Regulatory Issues 
6.a, 6.c Reporting of SAEs, Non-Medication Trials 
Drs. Abrantes and Stein will be responsible for overseeing the daily safety of all 
participants. There are several ways in which they will become aware of adverse events. First, 
research staff will ask participants about serious adverse events (as defined by Office of 
Human Research Protections (OHRP); e.g., inpatient hospitalization) at each research contact 
point (UG3: baseline, week 2 assessment, 5 tDCS appointments, 2 FMRI; UH3: baseline, 

Rev. 10/22/23 
week 2, 4, 6, 8, 12 assessments, 5 tDCS appointments, 3 FMRI). For monitoring expected 
adverse effects of tDCS, we use the SAFTEE at each session that includes changes in 
physical health status. Deaths are reported by significant others when we try to locate 
participants who missed appointments. Butler Hospital has a psychiatric emergency room 
available 24 hours a day. All research procedures will be supervised by Drs. Stein and 
Abrantes who will be on call 24-hours a day.  
Second, all study staff will be trained in the OHRP definitions of adverse events that are 
also unanticipated problems; serious adverse events; or unanticipated problems that are not 
adverse events. All study staff are required to report any event that might meet one of these 
criteria to one of the PIs immediately both verbally and in writing. When necessary, a report of 
a serious adverse event will result in one of the PIs contacting the participant to further assess 
the event. 
Drs. Stein and Abrantes will meet weekly with research assistants to review staff 
experiences with participants. Based on the sources of information detailed above as well as 
direct patient contact and/or consultation with the scientific team, Drs. Stein and Abrantes will 
determine if the event is: a) a serious adverse event that is also an unanticipated problem; b) 
an unanticipated problem that is not an adverse event. The Butler Hospital IRB require that 
fatalities related to the study be reported within 24 hours, all other serious adverse events 
related to the study be reported within 5 business/7 calendar days, and other serious adverse 
events related to the study be reported at the continuing review (at least annually).  
 
6.d Reporting of IRB Actions to NIDA 
All SAEs will be reported to NIDA within 72 hours of the MPIs becoming aware. 
 
6.e Report of changes of amendments to the protocol 
Changes to the proposal must be approved by NIDA prior to implementation 
 
6.f Trial stopping rules 
This  study  will  be  stopped  prior  to  its  completion  if:  (1)  the  intervention  is  associated  
with  adverse  effects  that  call  into  question  the  safety  of  the  intervention;  (2) any  new  
information  becomes  available  during  the  trial  that  necessitates  stopping  the  trial;  or   
 
6.g Disclosure of Conflict of Interest  
Ana Abrantes: None 
Michael Stein: None 
Linda Carpenter: None 
Lawrence Sweet: None 
 
7. Trial Safety 
7.a Potential Risks and Benefits for Participants 
 
Potential Coercion.  
Risks. It is possible that individuals may feel coerced into participating. 
Minimization. Issues related to coercion can arise from the payments that participants can 
earn from assessment participation. The payments made amount to approximately $20 per 
hour as compensation for assessment and travel time. This rate is consistent with local 
standards for research. 
 
Risks due to tDCS.  
Risks. There is some inherent risk with application of tDCS, mainly risk of skin irritation 
and, as in a small number of case reports, local skin burns where the electrodes are placed. 
Such cases have typically been seen only after repeated daily stimulation to the same region 
(Palm et al., 2008), or after unintentional abrasion of the skin with alcohol swabs prior to 

Rev. 10/22/23 
stimulation (Loo et al., 2011). Though a possible risk, skin burns are rare. In a recent review of 
clinical research with tDCS, Brunoni and colleagues (2012) noted that “tDCS has been tested 
in thousands of subjects world-wide with no evidence of toxic effects to date.” The most 
common side effects include mild local sensations at the electrode sites, including tingling or 
itching, and moderate fatigue, and headache. In research experience totaling 567 tDCS 
sessions, Poreisz and colleagues (2007) reported that no participants requested tDCS be 
stopped or required any medical intervention during or after stimulation. Notably, adverse 
effects did not differ between healthy individuals and patients. Safety testing of tDCS has 
found high tolerability and no reports of discomfort by participants when stimulating for 20 
minutes at either 1 or 2mA for 20 minutes (Iyer et al., 2005). There have also been a small 
number of case reports of hypomania induction during tDCS for depression interventions, in 
both individuals with bipolar and unipolar depression (Arul-Anandam, Loo, Mitchell, 2010; 
Galvez et la., 2011; Baccaro et al., 2010). Most recently, Brunoni, et al (2013) reported during 
a factorial design testing tDCS and the antidepressant sertraline, 7 of 120 participants 
developed mania or hypomania, with 5 of the 7 cases occurring in the combined 
tDCS+sertraline group. As the participants in that study were all drug-free prior to study entry, 
it is unknown whether this was due to starting an antidepressant medication, tDCS, or the 
combination.  
Minimization. To minimize risks due to tDCS, all participants will be carefully screened prior 
to tDCS for contraindications to tDCS. Those with a history of mood symptoms suggesting risk 
for hypomania or bipolar disorder will be excluded. Use of an electrically isolated power source 
(i.e., battery-powered DC stimulation device) also protects against delivery of more intense 
currents than intended. Participants with lesions or open wounds on the scalp will be excluded. 
Participants will be closely observed for signs of skin burns, discomfort, or other stress. During 
stimulation sessions, participants will be closely monitored to ensure the electrode sponges 
stay moist with saline (to enhance conductivity) and in good contact with the scalp in order to 
help prevent burns. Participants will have the option of discontinuing the study at any time and 
will be explicitly instructed to inform the tDCS administrator immediately if they experience any 
discomfort. The tDCS administrator will inform the supervising physician about any participant 
who has significant discomfort or a skin lesion that emerges after tDCS delivery. A Butler 
Neuromodulation Research Facility covering physician is available during all procedures to 
evaluate any participant or research staff identifying a concern related to study procedures. If 
there is any doubt about the mental or physical status of an individual before or after testing, 
the supervising physician will evaluate the participant and make a recommendation for 
cancelling the research procedure and /or arranging follow-up care, as indicated. Telephone or 
in-person follow-up will be arranged as needed and will not be considered a protocol deviation. 
Any participant that has experienced adverse effects will be evaluated, treated as necessary, 
and withdrawn from the study if deemed necessary.  
All tDCS will be administered by a trained member of the research staff who is supervised 
and credentialed by Dr. Carpenter. Butler Neuromodulation Research Facility fees include 
access to a covering physician with neuromodulation training who is versed in the procedures 
of the study and is available to supervise or consult on tDCS administration in this study. This 
physician will be immediately available for management of emergent events. Prior to 
administering tDCS in this protocol, all staff involved in administration of tDCS will be required 
to undergo training and demonstrate competence in the safe delivery of tDCS. Certification in 
Basic Cardiac Life Support, HIPAA, and Good Clinical Practices training are also required for 
use of the Butler Neuromodulation Research Facility. There are multiple components of 
training required of investigators and staff in order to be able to administer tDCS, including 
initial didactic training to introduce concepts critical to tDCS, direct observation of tDCS 
procedures,  practice of the various steps of setting up/administering tDCS on non-patient 
volunteers, including role-plays of scenarios of when the covering physician should be 
consulted to further address adverse events related to the study protocol, and demonstration 
of competency in all aspects of relevant subject assessment and in administration of the entire 

Rev. 10/22/23 
tDCS procedure under direct observation of a qualified tDCS administrator. Competence in 
specific aspects of the procedure comprising best practice standards for tDCS will be 
documented and updated every 2 years. Subject feedback will be solicited to further aid 
training and refine the skills of research staff delivering tDCS in this protocol. 
In order to assess for and monitor presence and tolerability of adverse effects, we will use 
a modified version of a tDCS Side Effects Questionnaire informed by Brunoni and 
colleagues11.  This is a 10-item measure that assess such effects as headache, neck pain, 
scalp pain, skin redness, sleepiness, difficulty concentrating, and acute mood changes.  The 
measure will be administered after each tDCS session.  For each item, participants are asked 
to report how bothersome each symptom on the form has been with response options "None," 
"Mild," "Moderate," or "Severe." For any item rated "severe," or any item which appears to 
significantly increase in severity over the course of the session, the evaluator will notify the 
covering physician immediately and the covering physician will provide further evaluation as 
medically necessary. tDCS administrators are encouraged to contact the covering physician 
about any additional tDCS related concerns and this will not be considered a protocol 
deviation. Reported side-effects endorsed will be reviewed during weekly meetings of study 
staff. Follow-up or further evaluation will occur as necessary. 
In addition, in order to monitor participant safety during the intervention period, we will also 
have participants complete self-report measures to assess for increased manic or hypomanic 
symptoms (from the Altman Self-Rating Mania Scale (ASRM)). The ASRM will be 
administered at baseline and prior to the first and last session of tDCS (sessions 1 and 5). 
Scores ≥ 6 will be considered clinically significant and will require evaluation by a study 
clinician.  Further, we will assess significant changes in affect such as 
anxiety/activation/anergia/sedation from the PANAS scale at the baseline and week 2 follow-
up assessment. Lastly, changes in frequency and dosage of any medication will be monitored 
at every participant contact time point.  The study physician will monitor affective symptom 
changes and make determinations as to whether the participant should discontinue the 
intervention and receive additional mental health treatment. 
 
Risks due to FMRI.  
Risks. The primary FMRI contraindications are claustrophobia, metal implants, and 
pregnancy. Some individuals may experience discomfort from loud noises inside the scanner. 
Minimization. FMRI contraindications, such as claustrophobia or metal implants, will be 
assessed at the time of study screening and again on the day of the scan by research staff. 
The MR technician, who is trained by the Brown University FMRI facility staff in safety 
procedures, will also screen for these concerns immediately prior to the scan and will be 
responsible for participant safety during the scan. A pregnancy test will be required prior to 
study inclusion for all females who report the possibility of being pregnant.  
 
Risks due to cue-reactivity task. 
Risks. There is a risk that participants will find the exposure to opioid-related images (e.g., 
needles, pills) during the cue-reactivity task distressing, due to the task’s intended goal of 
eliciting craving.   
Minimization. We have developed a standardized protocol for minimizing distress related to 
the cue-reactivity task that will be administered to all participants at the end of the fMRI 
imaging session.  First, participants will be given a tailored, pre-generated list of their personal 
motivations for opioid abstinence.  Second, participants will be given a handout with a list of 
various coping strategies (e.g., go to a meeting, call a friend/sponsor, deep breathing, 
mindfulness exercises, etc.).  Third, based on the empirical support for playing Tetris as a 
craving reduction strategy (Skorka-Brown, et al., 2015), they will play a game of Tetris on a 
study iPad for 5 minutes.  Fourth, they will be encouraged to use that day’s usual, prescribed 
buprenorphine or methadone dose. Lastly, Drs. Abrantes and Stein will be available to talk to 
any participant who continues to feel any distress following these minimization procedures. 

Rev. 10/22/23 
 
Emotional Discomfort due to assessments and/or intervention procedures 
 
Risks. During the assessments we will ask participants about their thoughts, feelings, 
behaviors, and symptoms. It is possible that asking participants about this information may 
increase distress or discomfort.  In addition, participants may become bored or tired during the 
EEG assessments and tDCS+CCN sessions. 
 
Minimization. To minimize the risk of distress arising from the assessment procedure, only 
study staff that has been adequately trained in the assessment battery will complete all 
assessments, and senior study staff will supervise all assessment procedures. Individuals will 
also be advised that they may choose not to answer any question which they find upsetting.  
Further, during EEG and tDCS+CCN sessions, participants will be reminded they can stop the 
procedure at any time, if they get tired. All study procedures will be explained to the 
participants with an emphasis on the voluntary nature of the study. Furthermore, staff 
members will be trained to respect participants’ wishes regarding their participation in the 
study or certain aspects of the study’s procedure. There is minimal, if any, additional risk in 
having EEG data recorded; EEG is a safe and painless noninvasive technique that is routinely 
used in clinical medicine.   
 
Benefits  
Participants may benefit by feeling a reduction in their cravings for opiates. However, we 
cannot guarantee that they will benefit. The main benefits of this study are to help researchers 
and clinicians develop a better understanding of craving and substance use after starting 
opioid treatment. 
 
7.b. Collection and reporting of AEs and SAEs 
See 6.a 
 
7.c Management of SAEs and other study risks 
See 6.a and 7.a. 
 
8. Trial Efficacy 
8.a Plans for interim Analysis of efficacy data 
Go/no go criteria for the UG3 phase will be demonstration of greater FMRI change in any node 
of the CR or CCN networks or enhanced frontal theta power during a WM task AND greater 
change in subjective craving measured during a cue reactivity task or outside the FMRI 
following the tDCS+CCN priming intervention compared to sham tDCS+CCN priming. 
 
9. DSM Plan Administration 
9.a Responsibility for data and safety monitoring 
The Data Safety Monitoring Board will be comprised of 2 individuals independent from this 
research project. No member of the board will be a collaborator with the MPI on any other 
studies or have co-published with the MPIs in the past 3 years. They  will  be  qualified  to  
review  the  patient  safety  data  generated  by  this  study.  
They will review rates of adverse events to determine any changes in participant risk and 
will make appropriate recommendations for changes in protocol, which will be submitted to the 
Butler Hospital IRB and NIDA for review.   
 
9.b Frequency of DSM 
Study progress and safety will be reviewed by the MPIs monthly (and more frequently if 
needed). Semi-annually, a progress report will be generated for the DSMB’s review. The full 
DSMB will be convened twice per year to review the semi-annual report and discuss data and 
participant safety.  
 

Rev. 10/22/23 
9.c. Content of DSM Report 
The DSM report will include a brief description of the aim of the trial, baseline and 
demographic information, recruitment and retention, regulatory issues or data quality issues 
that have arisen, and AE/SAEs. The DSM report will be sent to the NIDA Program Officer 
annually. 
The study team will specifically generate the following for the DSM report: 
 
Interim  CONSORT  document  (number  screened,  number  consented,  reasons  not  
eligible,  status  of  all  participants  enrolled  in  the  study,  number  completed  the  study  vs.  
withdrawn)     
 
Actual  vs.  expected  enrollment  numbers  
 
Gender,  age,  race,  and  ethnicity  of  enrolled  participants  
 
List  and  description  of  deaths,    unanticipated  problems,  and  SAEs   
 
Summary  table  of  AEs    
 
List  of  protocol  deviations,  if  any   
 
Ongoing  quality  assurance  and  quality  control  procedures  and  findings.   
 
The DSMB will determine whether 1) AE rates are with pre-study assumptions, 2) whether 
continuation of the study is justified, and 3) conditions under which the study would be 
prematurely terminated.  
  
 
10. DSM Board Plan 
10.a Members and Affiliation 
Noah S. Philip, M.D. – Director of Neuropsychiatric Modulation at the Providence Veterans 
Affairs Medical Center; Associate Professor of Psychiatry and Human Behavior at the Alpert 
Medical School of Brown University. 
 
Edward V. Nunes, M.D. – Deputy Director of Intervention Studies at the New York State 
Psychiatric Institute; Professor of Psychiatry at Columbia University Medical Center. 
 
10.b Frequency of Meetings 
See 9.b 
 
10. c Conflict of Interest 
Pending 
 
10.d. Protection of Confidentiality 
Only de-identified data will be presented in DSMB reports.  
 
10.e Monitoring Activities 
See 9.a 
 
10.f Communication plan to IRB, NIDA, and FDA 
DSMB reports will be submitted to both the Butler Hospital IRB and NIDA. 
 
 
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