Using Combined EEG and Non-invasive Brain Stimulation to Examine and Improve Reward Functioning in Opioid Use Disorder
Phase: NA
Conditions: Opioid-use Disorder
Sponsor: Rutgers University

Title:  Using Combined EEG and Non-invasive Brain Stimulation to Examine and Improve 
Reward Functioning in Opioid Use Disorder 
NCT number: NCT04432493 
Date: 12/12/2022 

OMB Number: 0925-0001
Expiration Date: 02/28/2023
Section 1 - Basic Information (Study 297707)
1.1. Study Title *
Using combined EEG and non-invasive brain stimulation to examine and improve cognitive control
functioning in opioid use disorder
1.2. Is this study exempt from Federal
Regulations *
❍Yes
●No
1.3. Exemption Number
❏1
❏2
❏3
❏4
❏5
❏6
❏7
❏8
1.4. Clinical Trial Questionnaire *
1.4.a. Does the study involve human participants?
●Yes
❍No
1.4.b. Are the participants prospectively assigned to an intervention?
●Yes
❍No
1.4.c. Is the study designed to evaluate the effect of the intervention on the
participants?
●Yes
❍No
1.4.d. Is the effect that will be evaluated a health-related biomedical or
behavioral outcome?
●Yes
❍No
1.5. Provide the ClinicalTrials.gov Identifier (e.g.
NCT87654321) for this trial, if applicable
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 14

Section 2 - Study Population Characteristics (Study 297707)
2.1. Conditions or Focus of Study
❍
Opioid use disorder
2.2. Eligibility Criteria
Inclusion criteria will be as follows: 1. Opioid dependent individuals according to the ASSIST opioid dependence score (OUD
 group, ASSIST opioid Score >12), or healthy controls with no significant history of opioid use (ASSIST opioid Score
< 11), or other drug-types (ASSIST score < 11 for each drug category). 2. Native English speakers, 3. Males and Females
 aged 18-55 years old, 4. Ability to provide informed written or verbal consent, 5. Only participants who clearly understand
 the research and are able to indicate consent to participate can be enrolled in the study. Exclusion criteria will include
 uncorrectable visual impairment, uninterruptable central nervous system medication, severe brain injury (traumatic or
 acquired). Given the nature of the OUD group, opioid users will only be excluded for severe mental health issues (e.g.
 schizophrenia, bipolar) but not mood disorders such as depression or anxiety, nor will they be excluded for substance abuse.
 Additional exclusion criteria include any TMS contraindications (e.g., pregnancy, braces, history of seizures).
2.3. Age Limits
Min Age:
18 Years
Max Age:
55 Years
2.3.a. Inclusion of Individuals Across the Lifespan
INCLUSION_LIFESPAN_Study1.pdf
2.4. Inclusion of Women and Minorities
Women_minorities_children_R21_opioid.pdf
2.5. Recruitment and Retention Plan
Recruitment_and_Retention_Plan_R21_opioid.pdf
2.6. Recruitment Status
Recruiting
2.7. Study Timeline
TIMELINE.pdf
2.8. Enrollment of First Participant (SEE SECTION
6.3)
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 15

INCLUSION OF INDIVIDUALS ACROSS THE LIFESPAN  
  
Inclusion of Children and Older Adults: We will be including 18-55 year-old individuals in our study. Thus, we 
will not be including children or older adults in this project. Note that the investigators have had ample previous 
experience working with participants in this age range, and all study procedures are appropriate for this age 
range. Children below age 18 and individuals above 55 years old will not be studied in this project because 
separate age-specific projects are warranted, and even preferred, given that 1) normal developmental changes 
in reward processes during childhood are prominent but not yet well understood and 2) normal decline in goal-
directed processes in older age (above age 55) are known to be prominent but not well understood.   
 
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 16

Inclusion of Women, Minorities, and Children 
 
Inclusion of Women: No participant will be excluded on the basis of sex or gender. As described 
above, participants will be recruited from multiple sources, including student populations and the 
general community. We will strive for an approximately equal gender balance for the studies 
proposed here. Given our past inclusion experience, we do not anticipate needing specific 
outreach programs for recruiting women for this project. 
 
Inclusion of Minorities: No participant will be excluded on the basis of race or ethnicity. As 
described above, participants will be recruited from multiple sources, including various student 
populations and the general community. We will make special outreach efforts in recruiting 
African-American participants for our study, since the College of Arts and Sciences at Rutgers-
Newark University where we typically recruit, has an African-American population that under-
represents the demographics of Newark, NJ. We have had success in recruiting African-American 
participants from the general community and from other nearby schools whose enrollment 
includes a greater number of minority students. Specifically, we will strive to match the 
demographics of Newark area, which at the time the 2010 census had the following breakdown: 
 
Racial Categories 
White 26.31% 
Black (African American) 52.35% 
Asian (including Pacific Islander / Hawaii Native) 1.62% 
American Indian / Alaska Native 0.61% 
Other / Unknown 15.22% 
More than One Race 3.85% 
Ethnic Categories 
Hispanic / Latino 33.83% 
Inclusion of Children: Previously, NIH considered individuals under 21 years of age to be 
children, but this has now changed (children are now defined as under 18; see NIH NOT-OD-16-
010). We will be including 18- 55 year olds in our study. Thus, we will not be including children in 
this project. Note that the investigators have had ample previous experience working with 
participants in this age range (e.g., those 18-20 years old), and all study procedures are 
appropriate for this age range. Children below age 18 will not be studied in this project because 
a separate age-specific project is warranted, and even preferred, given that normal developmental 
changes in cognitive control processes during childhood are prominent, but not yet well 
understood. 
 
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 17

Recruitment and Retention Plan 
In total, we plan to collect 60 participants (30 opioid users, 30 controls) over 2 years for the proposed study. 
Participants will be randomized into TMS or sham groups (15 participants per group). Standard practice in 
electrophysiological studies commonly use a minimum of 15 participants per experimental group. Further, basing 
the analyses on our previous results, a priori power analysis indicated that a sample size of 15 would be sufficient 
to detect a significant effect with a power of .82 and an alpha of .05. Potential OUD participants will be recruited 
through the community using an `expression of interest' flyer. The flyer will be distributed throughout pharmacies, 
clinics, universities, community recreation venues, via email, social networking websites and possibly through 
media outlets such as through newspapers and radio. Control participants will be recruited using personal 
networks, advertisements on volunteer job sites and by placing flyers in local community settings. 
 
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 18

TIMELINE  
Months 1–18. Aim 1 and Aim 2 (initiation) Recruiting and testing control and OUD subjects with 
our virtual T-maze task with Ri-TMS capabilities, which is already developed. 
Months 18–24. Completion of Aim 1 and Aim 2. Analyse data from Months 1–18 for publication. 
Prepare and submit manuscript for publication.  
 
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 19

2.9. Inclusion Enrollment Reports
IER ID#
Enrollment Location Type
Enrollment Location
IER 296360
Domestic
Newark
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 20

Inclusion Enrollment Report 296360
1. Inclusion Enrollment Report Title* :
Using combined EEG and non-invasive brain stimulation to examine and improve
cognitive control functioning in opioid use disorder
2. Using an Existing Dataset or Resource* :
❍Yes
●No
3. Enrollment Location Type* :
●Domestic
❍Foreign
4. Enrollment Country(ies):
USA: UNITED STATES
5. Enrollment Location(s):
Newark
6. Comments:
Planned
Racial Categories
Ethnic Categories
 
 
Not Hispanic or Latino
Female
Male
 
Hispanic or Latino
Female
Male
Total
American Indian/
Alaska Native
1
1
0
0
2
Asian
1
1
0
0
2
Native Hawaiian or
Other Pacific Islander
1
1
0
0
2
Black or African
American
7
8
2
2
19
White
7
8
5
5
25
More than One Race
3
3
2
2
10
Total
20
22
9
9
60
Cumulative (Actual)
Racial Categories
Ethnic Categories
 
 
Not Hispanic or Latino
Female
Male
Unknown/
Not
Reported
 
Hispanic or Latino
Female
Male
Unknown/
Not
Reported
Unknown/Not
Reported Ethnicity
Female
Male
Unknown/
Not
Reported
Total
American Indian/
Alaska Native
0
0
0
0
0
0
0
0
0
0
Asian
0
1
0
0
0
0
0
0
0
1
Native Hawaiian or
Other Pacific Islander
0
0
0
0
0
0
0
0
0
0
Black or African
American
0
3
0
0
0
0
0
0
0
3
White
1
4
0
1
1
0
0
0
0
7
More than One Race
0
0
0
0
0
0
0
0
0
0
Unknown or
Not Reported
0
0
0
0
0
0
11
1
0
12
Total
1
8
0
1
1
0
11
1
0
23
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 21

Section 3 - Protection and Monitoring Plans (Study 297707)
3.1. Protection of Human Subjects
Protection_of_human_subjects_R21_final.pdf
3.2. Is this a multi-site study that will use the same protocol to
conduct non-exempt human subjects research at more than one
domestic site?
❍
Yes
●
No
❍
N/A
If yes, describe the single IRB plan
3.3. Data and Safety Monitoring Plan
Data_Monitoring_Plan_R21_opioid.pdf
3.4. Will a Data and Safety Monitoring Board be appointed for
this study?
❍Yes
●
No
3.5. Overall structure of the study team
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 22

PROTECTION OF HUMAN SUBJECTS 
1. 
Risks to the Subjects:  
1.a. Human Subjects Involvement and Characteristics: The subjects participating in this study will be healthy 
adults and individuals with opioid use disorder (ages 18 to 55). Participants will be recruited from the Rutgers 
University-Newark campus and nearby community. Recruitment will be through advertisements posted around 
the Rutgers University campus, advertising in local media, community forums, clinics and from maintained lists 
of volunteers interested in repeated participation behavioral studies. We will be seeking a broad sample of adults, 
such that exclusion criteria will be minimized when possible. Nonetheless, participants will be excluded for the 
following reasons: 1) taking any medication with potential cognitive effects (e.g., sleeping pills); 2) taking any 
psychotropic medications (e.g., antidepressants, anti-anxiety agents, anti-psychotics); 3) the presence of any 
clinically unstable medical disorder, or a medical disorder that affects cognitive or motor function (e.g., epilepsy, 
Parkinson's Disease); 4) present or past head injury with documented neurological sequelae, and/or causing 
loss of consciousness, 5) pregnancy; and 6) history of seizures. Note that the Rutgers University- Newark 
campus and surrounding community have an especially diverse population. Thus, the included participants may 
involve more diversity than most psychological and neuroscientific studies, possibly allowing for scientific findings 
that are more representative of the overall population of the nation and the world (see Inclusion of Women, 
Minorities and Children).  
1.b Sources of Materials: All materials for this project will be collected specifically for research purposes. We 
will collect data regarding brain function using electroencephalography. We will collect behavioral data (reaction 
times and error rates) based on performance of computer-administered cognitive tasks. Additionally, we may 
collect self-report information based on personality questionnaires.  
1.c. Potential Risks: The potential risks of this project include those associated with routine cognitive testing. 
The testing instruments to be used for the project are not invasive and pose minimal risk. The testing procedures 
could induce boredom and fatigue.  
There are no known risks associated with TMS when all technical parameters remain within FDA guidelines and 
the International Federation of Clinical Neurophysiology and the International Society for Transcranial 
Stimulation, and participants with medical contraindications to TMS are excluded. These guidelines will not be 
exceeded in the work proposed. The application of TMS may cause the subject some temporary discomfort, 
such as a mild tingling or minor headache, where the coil is placed on the scalp. An addition risk of TMS is 
seizures, which has occurred following parameters that exceeded clinical safety guidelines. The current study is 
accordance with these guidelines. Robotic neuronavigation for TMS poses minimum risk to the subject. The 
robotic arm does not touch the patient's head. However, there is a theoretical risk of failure of the computer due 
to a program "bug". In the unlikely event of a failure, security mechanisms are in place.  
There are no known risks associated with EEG. EEGs are safe and painless. The greatest inconvenience is the 
electrode gel left in subject’s hair after the cap is removed, but it can easily be rinsed out at the end of the 
experiment in the lab, with no damage to the scalp.  
 
2. Adequacy of Protection against Risk:  
2.a. Recruitment and Informed Consent: Subjects will be recruited from advertisements and existing subject 
pools, at Rutgers University and in the surrounding community, to ensure a diverse sample. Consent will be 
obtained and documented with an institution approved consent form for all subjects. Informed Consent will 
always be obtained before a subject participates in any component of the current protocol. For all participants, 
the consent form will be explained to participants as well as having them read the consent themselves. This 
consent will contain a detailed description of all study procedures, as well as any possible risks and/or benefits. 
The consent will also indicate (and this will be verbally reinforced by the experimenter) that the participant is free 
to withdraw from the experiment at any time without penalty or repercussion. Consent will be documented by 
having the participant and the individuals obtaining consent both sign and date the consent form.  
2.b. Protection Against Risk: The routine testing instruments to be used for the project could induce boredom 
and fatigue. Breaks in experimental sessions will be given whenever the subject requests or obvious fatigue is 
observed. The motivational incentives and self-disclosing questionnaires could cause anxiety or other negative 
reactions. Participants will be fully informed of the nature of these experimental components before beginning 
the session, and explicitly be given the option to decline to participate. Moreover, participants will be assured 
that their data is being obtained only for research purposes, will only be evaluated in the aggregate, and that all 
identifying information will be removed (see below).  
All of the data collected for these studies will be kept strictly confidential. The person's name and identifying 
information will be associated with their study ID in a master file that contains no diagnostic information. This 
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 23

master file will be stored on a computer without Internet access. All other research materials will contain only the 
participant’s study number, and not any identifying information. Only research personnel listed on this application 
will have access to files containing participant identities. Under no circumstances will individually identifiable data 
be released to anyone without the expressed written consent of the participant. In the past we have found that 
all of these procedures are effective at reducing risk for study participants.  
To ensure safe practices in the event of any side effects of TMS exhibited by the subjects, Dr. Huey-Jen Lee, 
MD (a neuroradiologist and Director of Radiology at New Jersey Medical School, Rutgers Newark), will work on 
this project as the contact physician. In the event of a seizure, there is no need to go more than just stay with 
the participant and monitor them for up to an hour for signs of post-seizure confusion. Seizures are thought to 
be caused by group of neurons that become hyper-synchronized and are categorized as “absent-type”, which 
cause lapses in awareness, sometime with staring, and last less than a few seconds. In some cases, confusion 
post-seizures to be expected up to 30 minutes, max. No one has ever developed a recurring seizure disorder 
(epilepsy) after a TMS-induced seizure. Any side effects exhibited by subjects will be reported to Dr. Lee before 
they leave the lab. If post-seizure confusion exceeds 30 minutes, and after consulting with Dr. Lee, we will advise 
and accompany the participant to the University Hospital Emergency Room for safety. We will have subjects fill 
out a short questionnaire at the end of sessions to formally track and document any adverse side effects which 
may occur.  
In the unlikely event of a computer failure during robot-guided TMS, security mechanisms are in place: There is 
an immediate shut off button held by the subject, the experimenter, and one on the robotic arm itself. Once the 
button is pressed, the arm will stop immediately without movement and will remain in the position where it stood 
at the time. 
 
3. Potential Benefits of the Proposed Research to the Subject and Others: There will be no direct benefits 
to individuals for participating in this proposed project, other than the knowledge that they are contributing to our 
understanding of human cognitive and motivational processes and their biological underpinnings. However, the 
risks of this project are relatively small. If successful, substantial knowledge will be gained about cognitive control 
deficits associated with OUD. Furthermore, a closer examination of the role of TMS in modulating ACC activity 
may advance clinical research and treatment development of OUD. In consideration of the small risks and 
substantial scientific benefit of this work, we consider the risk/benefit ratio to be favorable. 
 
4. Importance of Knowledge to be Gained: Cognitive control is critical component of human behavior, and the 
breakdown of this process in OUD may contribute to relapse and treatment failure in this group. A better 
understanding impaired reward processing via electrophysiological methods may highlight a highly sensitive 
biomarker of addiction severity and treatment efficacy. Further, stimulation of a dysfunctional ACC network may 
help to restore cognitive control functioning in opioid users, and may therefore have promising future applicability 
for addiction research. As noted above, the risks of this project are relatively small, and not appreciably greater 
than the risks of ordinary computerized testing and imaging procedures. Thus, given that the risks to participants 
in this study are small, we believe such risks are reasonable in relation to the importance of the knowledge that 
we will gain about the psychological and neural mechanisms of cognitive control in OUD.  
 
Human Subjects Education: In accordance with the NIH policy effective October 1, 2000, this is to certify that 
all key personnel involved in the design and conduct of the human subjects research aspect of the above 
referenced grant have been educated on the protection of human research participants.  
 
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 24

Data safety and monitoring plan 
 
Participant confidentiality. Participants’ records will be kept strictly confidential. Confidentiality will be ensured 
by assigning a random ID number to each participant. Identifying information will be maintained only in a 
password-protected database. All other data and records will contain only the ID number. Electronic data will be 
accessed via password-protected computers that are available only to the PI and co-PIs for this study. Long-
term storage will be necessary to provide sufficient time for follow-up analysis and publication of deidentified 
data. The link between identifiable information and test data, as described in part “2b” above, will be stored 
exclusively in a password-protected database accessible only by the PI and co-investigators for this study.  
 
Participants will also be protected by a Certificate of Confidentiality, which will be obtained from the NIH. This 
Certificate can be used by the researchers to legally refuse to disclose information that may identify participants 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for example, if there 
is a court subpoena. The researchers will use the Certificate to resist any demands for information that would 
identify participants, except in cases where information is requested by personnel of the United States federal 
or state government agency sponsoring the project and that will be used for auditing or program evaluation of 
agency funded projects or for information that must be disclosed in order to meet the requirements of the federal 
Food and Drug Administration (FDA). The Certificate of Confidentiality will not be used to prevent disclosure to 
state or local authorities of child abuse and neglect, or harm to self or others. 
 
 
 
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 25

Section 4 - Protocol Synopsis (Study 297707)
4.1. Study Design
4.1.a. Detailed Description
Thirty opioid dependent and 30 healthy control participants will be recruited for the purposes of this study. Participants
 in each group will be randomized into either TMS or sham conditions (15 participants per group). Standard practice in
 electrophysiological studies commonly use a minimum of 15 participants per experimental group. All participants will
 complete consent protocols, and questionnaires regarding demographic and drug use history, and will be fitted with an
 EEG cap for ERP recording while they engage in a virtual T-maze choice
task. A neuronavigation robot will position the TMS coil over a predetermined area of the brain, and TMS pulses will be
 delivered at 110% of the participants resting motor threshold at 10 Hz continuously over the predefined DLFPC target
 immediately before each of the 20 blocks of 10 trials, for a total of 1000 pulses and 200 trials (fixed at 100 reward and
 100 no-reward). Identical parameters will be applied to the SHAM group with the exception that the TMS coil will be
 flipped 180º to mimic auditory stimulation.
4.1.b. Primary Purpose
Basic Science
4.1.c. Interventions
Type
Name
Description
Device (including
sham)
TMS
Participants will be randomized into either the TMS (active) or SHAM
 group (coil
flipped 180º to mimic auditory stimulation) during task performance. The
 TMS stimulator device used on our laboratory is a MagPro X100 with
 the Cool-B70 figure-of-eight coil (MagVenture, Falun, Denmark). The
 selection of stimulation intensity will be based on Resting Motor Threshold
 (rMT). In keeping within the safety guidelines, stimulation intensity will
 be set as 110% of rMT for the repetitive TMS. 50 rTMS pulses will be
 delivered at 110% of participants’ resting motor threshold at 10 Hz
 continuously over the predefined DLFPC target immediately before each
 of the 20 blocks of 10 trials, for a total of 1000 pulses and 200 trials (fixed
 at 100 reward and 100 no-reward). Identical parameters will be applied to
 the SHAM group with the exception that the TMS coil will be flipped 180º
 to mimic auditory stimulation.
4.1.d. Study Phase
Early Phase 1 (or Phase 0)
Is this an NIH-defined Phase III Clinical Trial?
❍
Yes
●
No
4.1.e. Intervention Model
Parallel
4.1.f. Masking
●
Yes
❍
No
❏
✔Participant
❏Care Provider
❏Investigator
❏Outcomes Assessor
4.1.g. Allocation
Randomized
4.2. Outcome Measures
Type
Name
Time Frame
Brief Description
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 26

Primary
Reward positivity amplitude
During intervention
Our project will utilize a highly sensitive biomarker
 of anterior cingulate cortex (ACC) control and
 reward function –the reward positivity– to image
 ACC function and monitor ACC modulation
 following TMS. Reward positivity amplitude
 will be determined by identifying the maximum
 absolute amplitude of the difference wave within
 a 200- to 400-ms window following feedback
 onset. The difference wave method, which
 was recommended in a recent metaanalysis
 of reward positivity studies [49], isolates the
 reward positivity from other ERP components.
 The reward positivity will be evaluated along front-
central electrodes (Fz, FCz, Cz).
4.3. Statistical Design and Power
Statistical_design_and_power_R21_opioid.pdf
4.4. Subject Participation Duration
Subjects will participate in one session lasting up to 2 hours.
4.5. Will the study use an FDA-regulated intervention?
❍
Yes
●
No
4.5.a. If yes, describe the availability of Investigational
Product (IP) and Investigational New Drug (IND)/
Investigational Device Exemption (IDE) status
4.6. Is this an applicable clinical trial under FDAAA? (SEE
SECTION 6.6)
4.7. Dissemination Plan
Dissemination_R21_opioid.pdf
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 27

Statistical design and power 
This study will adopt a randomized sham-controlled design. Participants will be randomized into either the TMS 
(active) or SHAM group (coil flipped 180º to mimic auditory stimulation) during task performance. Thirty 
dependent opioid users (OUD group) and 30 controls with no history of alcohol or drug dependence will be 
recruited for this study (15 participants per TMS/sham group). Standard practice in electrophysiological studies 
commonly use a minimum of 15 participants per experimental group. Further, based on previous work [27-29] 
an estimated 60 subjects in total will be required to identify a moderate to large main effect on the reward 
positivity, critical F(4, 55) = 4.01, p = 0.05, 85% power. 
Baker, Travis E. 
Human Subject Report (Using combined EEG and non-invasive brain stimulation to examine and
RPPR
Page 28