Self-activation of Reward-related Brain Regions in Individuals With and Without Nicotine Dependence
Phase: NA
Conditions: Addiction Nicotine
Sponsor: Duke University

 
 
 
 
 
 
 
 
 
 
 
 
 
Self-activation of Reward-related Brain Regions in Individuals with and without Nicotine Dependence 
 
NCT03170258 
 
Document Date: April 29, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Purpose of the Study 
  
To assess the ability of adults with and without nicotine dependence (ND) to activate reward-related 
brain areas (e.g., ventral tegmental area (VTA), striatum, prefrontal cortex (PFC)). 
To evaluate whether real-time functional Magnetic Resonance Imaging (rt-fMRI) and/or real-time 
electroencephalography (EEG) neurofeedback improves the ability to increase reward-related brain 
activation in individuals with and without ND. 
To examine the relationship between activation of reward-related regions via neurofeedback and 
dopamine availability (as assessed genetically). 
To examine the effects of neurofeedback on clinically-relevant outcomes, including reward responsivity 
and smoking-related behaviors. 
 
Background & Significance 
 
Dopamine: Motivation, Learning and Adaptive Memory. A rich literature spanning diverse methods and 
species provides substantial evidence that the dopamine (DA) system is fundamentally involved in 
reward processing, motivation, learning, and memory. DA plays a critical role in facilitating long-term 
potentiation and maintaining long-term memories. DA is also implicated in tracking motivationally 
relevant information and encoding deviations between expected and received outcomes – so-called 
prediction errors – that drive learning. Thus, DA is critical for learning and memory formation and for 
guiding future adaptive behavior. Research conducted in the sponsoring laboratory was the first to 
demonstrate the importance of correlated activity between the midbrain and hippocampus during 
human learning. Healthy individuals were incentivized with rewards prior to encoding information. 
Correlated activity between the midbrain and hippocampus at the time of the incentive cue, but before 
the stimulus, predicted how well the stimulus would be remembered. That is, activation in mesolimbic 
regions prior to learning predicted subsequent memory success. If midbrain activation can predict 
improved learning, this implies that driving the DA system through instruction, a novel approach we call 
‘cognitive neurostimulation’, has highly significant implications for both basic science and clinical 
applications. Understanding mechanisms of the DA system can improve reward processing, attention, 
motivation, working-memory, and long-term learning and memory, as well as inform personalized, safe, 
effective, and efficient interventions for patients with dysfunctional DA function across disease 
etiologies. 
  
Real-Time neurofeedback. Real-time neurofeedback is a type of biofeedback that provides participants 
with information regarding their brain activity in real time. Real-time neurofeedback, which includes 
both rt-fMRI and rt-EEG, is a rapidly growing technique with direct application to both basic science and 
clinical questions. Unlike traditional fMRI or EEG studies, rt-fMRI and rt-EEG enable data to be analyzed 
immediately and presented to participants as a form of neurofeedback. Rt-fMRI studies have 
demonstrated humans’ ability to modulate their own brain activity in multiple areas. Few studies have 
examined rt-fMRI or rt-EEG and its application to addiction and all extant rt-fMRI studies on nicotine-
dependent individuals focused on reduction of activity in the cingulate cortex and prefrontal cortex. 
Despite the clear relationship between dopamine and addiction – to our knowledge, no study to date 
has examined midbrain self-activation in any addicted population. Rt-neurofeedback provides a salient 
demonstration to participants of how cognitive strategies can produce immediate changes in brain 

function. Such a salient experience is proposed to create a strong memory of the training sessions, 
recruiting engagement of the medial temporal lobe (MTL). The MTL has direct connections to the 
midbrain, where DA neurons are located. Activation of this pathway from the MTL to the midbrain is 
hypothesized to increase DA release, increasing motivation, culminating in behavioral change. We 
predict that enhancing vivid memories of the training session will increase the frequency of subsequent 
self-activation and success of this technique, with the potential of improving smoking cessation 
outcomes in nicotine-dependent individuals. 
  
Nicotine Dependence and Smoking Cessation. Tobacco use is the leading cause of preventable disease 
and death in the United States. Critically, the majority of smokers (70%) express a desire to quit 
smoking, but the vast minority of quit attempts (<5%) are successful long-term (> 3 months). Recent 
theories have proposed that failed quit attempts could in part be due to reward dysregulation in the 
brain that occurs with chronic drug use. Over time, repeated exposure to drugs of abuse increases 
subsequent reward responses to drugs and drug cues. Simultaneously, responses to non-drug rewards 
diminish, eventually failing to motivate behavior. This imbalance in drug versus non-drug reward 
responses may motivate the choice of drug stimuli over non-drug stimuli. If individuals can learn to 
increase the reward response to personalized, non-drug cues, it could motivate their future behavior 
towards non-drug stimuli. Likewise, by balancing out the reward responses to drug and non-drug cues, 
this may reduce the frequency and need for drug interactions, resulting in improved smoking cessation 
outcomes. The proposed personalized study in nicotine-dependent individuals has the potential to 
dramatically improve health outcomes and reduce health care cost nationwide. If successful, this 
protocol could readily be adapted for application to a variety of addictive disorders that act on the DA 
system including cocaine and other stimulants. 
  
Research on self-activation of the DA system is highly relevant to mental health. Several neurologic and 
psychiatric disorders are affiliated with abnormalities in the dopaminergic system, including addiction, 
depression, schizophrenia, and PD2-9. The predominant treatments for these disorders include 
pharmacotherapy and psychotherapy. However, a current barrier to progress in the field is that for 
many diseases neither treatment completely cures the disorder nor alleviates the symptoms. 
Furthermore, pharmacotherapy is associated with adverse side effects while psychotherapy is effortful, 
time intensive, costly, and - perhaps most challengingly - produces effects that are not immediately 
apparent. Therefore patients must persist for long periods of time (e.g., days to months) without any 
direct indication of progress. The NIMH Strategic Research Plan demands novel interventions that are 
personalized, safe, effective, and efficient. This research proposal investigates the development of 
cognitive neurostimulation of the dopaminergic midbrain as a personalized, safe, effective, and efficient 
micro-intervention for nicotine-dependent individuals.  
  
The proposed studies address fundamental unsolved problems in behavioral science and systems 
neurobiology. Understanding if and how rt-fMRI and/or rt-EEG neurofeedback can enable individuals 
with and without nicotine dependence to activate the reward-related regions will advance clinical 
practice by offering a novel micro-intervention for patients with dysfunctional dopaminergic systems 
across disease etiologies. 
 
 

Design & Procedures 
 
We will enroll up to 150 adults between 18-45 years. We will recruit up to 100 adults with nicotine 
dependence and 50 adults without nicotine dependence. We may need to screen additional participants 
in order to achieve 150 completed participants (we estimate screening 250 participants). 
  
Prior to coming to a screening visit, all potential participants will undergo a phone pre-screening using 
an IRB approved phone script to pre-identify potentially eligible participants and to potentially decrease 
screen fail rate. These interested potential participants call or email the site in response to 
advertisements or provide their contact information via the internet (e.g, Facebook ad). The pre-
screening will take place via phone. Participants who pass the pre-screening will complete some or all of 
the following visits: Screening, Camera Return Visit, Real-Time Neurofeedback Visit, Follow-up Phone 
Calls/Debriefing. 
  
Screening Visit: 
Participants with nicotine dependence who pass the pre-screen will come to the lab at Duke to 
complete additional screening. All participants will undergo informed consent. MRI participants will 
complete a urine drug screen. Participants who pass the urine drug screen (results are provided 
immediately) may complete questionnaires on REDCap assessing mood, reward processing, and smoking 
behaviors. We may also ask individuals with ND to complete a carbon monoxide (CO) breath test. If 
individuals fail to pass, they will be offered the opportunity to smoke and come back to get tested again. 
If they fail a second time, they will be excluded from the study. We may also ask individuals if they have 
consumed marijuana within the last 24 hours. If they have, the session will end and they will be asked to 
complete the screening visit another time if they would like. Additionally, we may ask participants to 
provide us with the names and contact information for up to 4 individuals who we can ask to confirm 
smoking status. We may also perform a cotinine test to verify smoking status. Also, individuals may fill 
out a MRI safety screening form confirming they are eligible to be scanned for the MRI visit. 
  
Some participants may also be given a camera to use to capture pictures of personalized rewarding 
objects that are non-smoking (e.g., picture of their pet, favorite book, favorite food) and/or smoking 
related (e.g., photo of their preferred brand of cigarette, their ash tray, etc). No non-smoking drug 
related photos will be accepted. Participants may be loaned the camera for a period of approximately 1-
3 weeks to capture pictures of rewarding objects. We will instruct participants that the camera is to be 
used exclusively for capturing pictures for the study and not for personal use. Participants will also be 
given the option of providing us with relevant photos for the study that they have already taken (e.g., 
existing photos of their pet, favorite restaurant, etc.) Some participants may not be asked to take their 
own pictures for the study protocol and may simply be shown neutral or positive 
pictures/images/objects provided by the experimenters (e.g., shapes, pictures, etc.). Note, no aversive 
images will be shown to participants. Lastly, subjects may be asked to complete the Personal History 
Form self-assessment questionnaire on this day on REDCap. 
  
Camera Return Visit: 
Participants who were loaned a camera will be asked to come to the lab at Duke to return the camera. 
The experimenters will ensure that enough pictures have been acquired to use during the experiment. 

Participants will be given guidelines about what types of pictures are required for the study. Participants 
who choose to provide their own images will be asked to upload them to a Duke Box folder and/or to 
come to the lab and deliver them (e.g., via a thumbdrive). 
  
Participants may also be asked to view and rate the pictures they provide along with neutral and 
positive images we provide (e.g., puppy, flower) on dimensions such as valence and arousal at this visit 
and/or the Neurofeedback visit. 
  
Real-Time Neurofeedback Visit: 
Eligible participants will be scheduled for an fMRI and/or EEG session to assess and measure the ability 
to self-activate reward-related regions. The fMRI session will be conducted at either the Duke-UNC Brain 
Imaging and Analysis Center (BIAC) and/or the UNC Biomedical Research Imaging Center (BRIC), where 
we have secured a contract for neuroimaging data acquisition. Female participants will have a urine 
pregnancy test prior to fMRI scanning; the test will be verified to be negative in order to proceed with 
the scanning session. The EEG sessions will take place in private testing space in the Levine Science 
Research Center or the BIAC. The real-time neurofeedback visit will be scheduled within 60 days of the 
screening visit. We are using this window to allow for limited availability of the MRI scanner as well as 
flexibility to find an ideal time for the participant (e.g., evening or morning scan time). MRI participants 
may fill out a screening form confirming they are still eligible to be scanned or review a completed 
screening form if filled out at the screening visit. A carbon monoxide breath test may also be conducted 
but will not be used in determining eligibility. 
  
Participants may complete some or all of the following tasks: Reward Activation Task, Passive Viewing 
Task, and Reward Learning Task. All of these tasks aim to assess how adults can learn to interact with 
neurofeedback provided from an fMRI or EEG system. The tasks vary slightly from each other in terms of 
stimuli used (personalized pictures, images provided by the experimenters, feedback display, etc.). It 
may be possible that we will not be able to get a good EEG or fMRI signal for some participants, based 
on equipment error or head size. If this occurs, participants will be debriefed and paid for their time. We 
will be sure to emphasize there was no error on the participant’s part, and that sometimes the signal is 
difficult to acquire for a variety of reasons.   
  
Reward Activation Task (ReAcT): Participants may be randomly assigned to one of two groups. One 
group, the Veridical Feedback Group, will receive veridical neurofeedback from a reward related region, 
which may include the VTA, striatum, PFC, etc., while they are inside the MRI or while wearing the EEG 
headset. The other group, the Noise Control Group, will receive noise feedback that they are instructed 
is real or yoked sham feedback that is yoked to a participant’s feedback in the Veridical Feedback Group. 
This group will serve as a critical control condition for the experiment. All participants will be debriefed 
in full about the study groups, random assignment, and the purpose of each group in contributing to our 
understanding of the reward-related brain regions’ role in reward processing in individuals with and 
without ND. 
  
Participants may complete the ReAcT. The ReAcT consists of two types of runs: test runs (one pre-test 
and one post-test) and training runs (see Fig. 1 for a sample task design). For both groups the pre-test 
measures baseline reward-related brain activation prior to receiving rt-fMRI or EEG neurofeedback. For 

the Veridical Feedback Group, the training runs train participants to use rt-fMRI or EEG neurofeedback 
to more efficiently and successfully increase their brain activity. For the Noise Control Group, the 
training runs serve as a control wherein they continue to try to increase brain activity. For all 
participants, the post-test measures if participants are better able to activate the brain after training. 
  
Test runs: For both Groups the pre and post-test runs are identical and contain two or three trial types: 
Activate, Count, and Rest. During Activate trials participants will try to increase reward feelings to 
personalized images of rewarding items (e.g., favorite food, picture of a pet; see Fig. 1). During Count 
trials participants will count backwards, providing a standardized period for all participants. During Rest 
trials, participants are instructed to either not think of anything in particular or to view and think about 
an image shown to them (neutral-positive image). The test runs will have 5-7 repetitions of each trial, 
separated by a jittered inter-trial-interval (ITI). 
  
Training runs: For both Groups training runs will consist of two or three trial types: Activate, Count, and 
Rest. Participants will be given the same instructions as the test runs. The Activate and Rest trials will 
now have an interactive display, e.g., a thermometer, graph, signal bar, etc. Feedback display: For the 
Veridical Feedback Group, during the Activate trials the feedback display will show the average of brain 
activity, represented as percent signal change from baseline. The feedback display will be updated 
approximately every 1-10 seconds. For the Noise Control Group the feedback display will either display 
random values centered at 0 or yoked feedback from a participant in the Veridical Feedback Group. For 
both Groups, during the Rest trials, the feedback display will show random values that do not reflect 
brain activity. The purpose of the rest trial during the training runs will be to serve as a visual control. 
During Count trials, participants will view a neutral-positive cue or image (e.g., shape or picture). Each 
trial type will be repeated 5-7 times, separated by a jittered ITI. 
  
Passive Viewing Task: In the passive viewing task participants will view the same images they provide for 
the ReAcT task. Participants with ND will also view some pictures of personalized smoking cues (e.g., 
cigarette of their choice). MRI participants who are not ND will not view smoking-related images. 
Participants will be instructed to relax and passively view the images. They will be asked to rate the 
images for valence (neutral to positive) and provide intermittent ratings of craving. 
  
Reward Learning Task: In this task, participants will be asked to view various neutral or positive images 
(symbols/pictures/objects, e.g., white square, yellow circle). Some trials will contain the images only and 
some will contain the images along with a feedback display. The feedback display may vary somewhat in 
design and may include feedback designs such as: a thermometer, graph, growing/shrinking balloon, 
etc. Participants goal will be to learn to interact with the feedback display by regulating their thoughts. 
As part of this interaction with the feedback display, participants will rate their level of motivation prior 
to, during, and/or after each feedback trial. 
  
Delay to Smoking Assessment: for ND individuals, we may assess time (in minutes) that participants take 
to smoke their first cigarette (time and space permitting). After the MRI and/or EEG sessions we may 
give participants the opportunity to smoke a cigarette(s) if they would like. If we do the assessment, we 
will measure both the time it takes for them to take their smoking break as well as the number of 
cigarettes smoked. We may additionally collect self-report measures of craving. 

  
Stimuli: 
ReAcT Task: for the Activate trials in the ReAcT task, participants will be asked to provide approximately 
50 pictures of personally rewarding objects or environments from their lives (e.g., family members, pets, 
favorite foods, favorite books, favorite places etc.). Participants will be asked to give the experimenter 
these electronic images (via the loaned camera or another method of their choice, e.g., thumbdrive) at 
least a few days prior to the fMRI session so that the experimenter can program them into the task. By 
doing so, the experimental task is personalized for each participant whereby they view their own 
personally rewarding images while they are inside the MRI machine or wearing the EEG headset. We 
believe this will elicit a much more realistic assessment of participant’s reward sensitivity relative to 
generic images of rewarding items. These images will be stored on a secure server at Duke University. 
They will labeled according to the de-identified participant number and will not be linked to any PHI. For 
the Count and Rest trials in the ReAcT task we will provide generic neutral and positive stimuli as control 
images. 
 
Passive Viewing Task: In the passive viewing task participants will view the same images they provide for 
the ReAcT task. Adults who smoke will also view pictures of personalized smoking cues (e.g., cigarette of 
their choice, favorite place to smoke, etc.). 
 
Reward Learning Task: in this task participants will view various neutral or positive images including 
shapes, objects, scenes, etc. 
  
Collection of psychophysiological data: In conjunction with fMRI data collection, physiological measures 
of heart rate and respiration may be recorded using an MR-safe commercial system (e.g., BIOPAC 
systems, Goleta, CA or the built-in GE equipment) to permit removal of physiological noise from the 
fMRI signal. This equipment is MR safe and has been used extensively at BIAC. Heart rate and respiration 
data will not be collected when using the EEG headset. Eye tracking data may also be collected. We may 
use the Tobii Pro eye tracker X2-60 (https://www.tobiipro.com/product-listing/tobii-pro-x2-60/), which 
is a screen-based eye tracker that sits on the computer. This eye tracker is not placed on the participant 
and therefore causes no physical discomfort and minimal disruption to the participant. 
  
Questionnaire measures: The following self-assessment questionnaires may be completed at the 
Screening Visit. Note, the smoking related measures will only be collected for the smokers. Personal 
History Form, Personalized smoking history questionnaire, the Fagerström Test of Nicotine Dependence 
(FTND; 7 item), Center for Epidemiologic Studies Depression (CES-D; 20 item), the Temporal Experience 
of Pleasure Scale (18 item), Questionnaire of Smoking Urges-Brief (5 item), Contemplation Ladder (1 
item), MNWS (8 item), SDSS (23 item), WISDM (37-item), Other tobacco use questionnaire (2 item), 
MTQ short form (48 item), the Snaith-Hamilton Pleasure Scale (SHAPS; 14 item), the Daily Experiences of 
Wanting and Liking (DEWL; 31 item), the General Self-Efficacy Scale (10 item), and the Multidimensional 
Personality Questionnaire Brief (MPQ; 155 items). We estimate that completion of these questionnaires 
will take approximately 45-60 minutes.  
  
The following self-assessment questionnaires may be completed during the MRI or EEG Visit. Note, the 
smoking related measures will only be collected for the smokers. The Positive Affect Negative Affect 

Scale (20 item), the SHAPS, the DEWL, the BVAQ English Questionnaire (40 item), Personal History Form, 
CES-D, Difficulties in Emotion Regulation Scale (36 item), the General Self-Efficacy Scale, the Fraser 
Imagery Questionnaire (10 item), the Spontaneous Use of Imagery Scale (12 item), and the State and/or 
Trait Anxiety Inventories (20 items each) will index state and trait personality measures. We may 
additionally collect the following smoking-related measures: the Wisconsin Smoking Withdrawal Scale 
(28 item), the MNWS (may be administered pre and post neurofeedback session), Contemplation 
Ladder, the Questionnaire of Smoking Urges58 (may be administered pre and post the neurofeedback 
session). We estimate that completion of these questionnaires will take approximately 35 minutes. 
  
Self-report: participants will be asked to self-report strategies they used to regulate their brain 
activation. They may be asked to write them down or record them using software such as Audacity (see 
Pre-Session Questionnaire, Post-Session Questionnaire, and SB Post Session Questionnaire Final as 
examples). Participants may also be asked to rate their levels of motivation, arousal, enthusiasm, etc. 
throughout the experiment via making responses on a button box or response dial. 
  
Smoking biomarker: To verify smoking status for nicotine dependent participants, we will measure 
expired air CO via a handheld monitor (e.g., Vitalograph). To ensure recency of smoking that is sufficient 
to produce detectable levels of CO, participants with CO levels below the required cutoff will be 
permitted to smoke one of their own cigarettes outside the lab prior to providing a second breath 
sample if they choose to do so. 
  
Genetic measures: Saliva may be collected. If so, we will use a commercially available kit from Oragene 
(http://www.dnagenotek.com/ROW/products/OG500.html). This is a very simple procedure in which 
participants deposit saliva into a plastic tub. It is non-invasive and takes a few minutes. The tubes will be 
de-identified and labeled by participant ID number. They will be stored in a locked cabinet inside secure 
office space. These saliva samples are stable stored at room temperature and can be kept in room 
temperature storage for up to 5 years. Once data collection is complete, we will send them to the Duke 
University DNA Analysis Facility for one time analysis. We will examine genetic markers related to 
dopamine function. Examples include both SNPs (e.g., DRD1, DRD2) and VNTRs (e.g., DAT, MAOA). 
  
Follow-up Phone Call/Debriefing: 
For ND individuals: participants may be called and/or sent a link to a REDCap survey 1 day, 1 week, 
and/or 1 month following the MRI visit to assess if there is any change in their smoking behavior 
following study participation. We will ask participants if they have modified their smoking behavior in 
any way (e.g., # of cigarettes smoked, craving, etc, see Contemplation ladder and rtNic.01 Follow up 
Questionnaire as examples). During the last phone call, we will debrief participants regarding which 
group they were in (Veridical Feedback Group or Noise Control Group) and answer any remaining 
questions they have about the study. 
 
Selection of Subjects 
  
List inclusion/exclusion criteria and how subjects will be identified. 
Inclusion Criteria: 
18-55 years of age 

In good general health 
Male or Female 
For ND individuals: Self-reported smoking ≥ 5 combustible cigarettes per day 
For ND individuals: Afternoon expired CO concentration of ≥ 8 ppm 
For ND individuals: Is willing and able to abstain from smoking for a few hours 
  
Exclusion Criteria: 
Current chronic/significant medical condition 
Current or past 6 month use of prescription medications for psychiatric conditions (e.g., depression, 
anxiety) 
Current or past 6 month diagnosis of anxiety, bipolar disorder, depression, OCD, schizophrenia, 
psychosis, or personality disorder. 
Current substance abuse or dependence or history within the last 6 months (other than nicotine for ND 
individuals) 
For ND individuals: Currently on nicotine replacement therapy 
For ND individuals: Individuals who role their own cigarettes 
For MRI subjects: Positive drug test for anything other than marijuana 
For MRI subjects: Daily cannabis use 
For MRI subjects: Consume more than 21 alcoholic drinks per week 
For MRI subjects: Use harder drugs (e.g., cocaine, methamphetamine) more than 10 times per year 
For MRI subjects: Currently taking medication that directly acts on the dopamine system (e.g., L-DOPA). 
We will record a list of all medications they are currently on and assess if they affect the dopamine 
system. If so, they will be excluded. 
For MRI subjects: Claustrophobia or other contraindications to MRI scanning 
For MRI subjects: If female, pregnancy as determined by urine pregnancy test on the day of MRI 
scanning 
For MRI subjects: Presence of any metal in the body (e.g., implant, non-removable piercing, metal IUD) 
For MRI subjects: Head injury resulting in loss of consciousness 
For MRI subjects: Worked with metal (e.g., welding) or had an injury to the eye involving metal 
For MRI subjects: If they weigh more than 200 pounds, the PIs will make their best judgement based on 
other factors including participant height and prior experience in with MRI scans 
Inability to understand written and/or spoken English language 
Any other participant characteristic, history, and/or behavior that in the opinion of the investigator 
would contraindicate participation in the study. 
Subject Recruitment and Compensation 
Describe recruitment procedures, including who will introduce the study to potential subjects. Describe 
how you will ensure that subject selection is equitable and all relevant demographic groups have access 
to study participation (per 45 CFR 46.111(a) (3)). Include information about approximately how many 
DUHS subjects will be recruited. If subjects are to be compensated, provide specific prorated amounts to 
be provided for expenses such as travel and/or lost wages, and/or for inducement to participate. 
Research participants will be recruited from the Duke University community and surrounding Durham 
area via flyers posted in public places, print advertisements in local publications, advertisements online 
(e.g., Facebook, Reddit, Craigslist, DukeList) and word of mouth. To qualify for the study, participants 
who smoke must self-report smoking greater than or equal to 5 cigarettes per day, but otherwise be in 

good health (see criteria above). Non-smokers must be in good health (see criteria above). They can and 
may be members of the Duke community (i.e., either students or employees). 
  
Participants will be compensated $35/hour for behavioral portions of the proposed studies (e.g., 
screening visit, camera return visit, follow-up phone calls and portions of the MRI session that occur 
outside of the MRI), and $50/hour when they are inside the MRI machine. When applicable, participants 
will receive a $20 bonus for taking and/or providing good quality pictures (if needed for the 
experiment). Participants will receive payment via cash or check for their participation at the end of the 
study. 
 
Risk/Benefit Assessment 
 
Only eligible participants as defined by the protocol will be enrolled in the study. Pregnant women, or 
prisoners will not be enrolled in this study. No direct benefits are expected. Knowledge obtained from 
this study may benefit other adults with or without nicotine dependence in the future. 
  
Questionnaires: It is possible that participants can experience frustration from performing the tasks or 
the questions being asked will make them uncomfortable. Participants may refuse to answer any of the 
questions and may take a break at any time during the study. Participants may also stop participation in 
this study at any time. 
  
Confidentiality: There is the potential risk of loss of confidentiality.  Every effort will be made to keep 
participant information confidential, however, this cannot be guaranteed.  
  
fMRI: Although there are no known long-term health risks associated with the magnetic fields and 
radiofrequency energy used to make MR images, safety and comfort issues impose restrictions upon 
who can be scanned. For example, participants who have implanted medical devices, such as 
pacemakers, cannot be safely scanned, nor can participants who have shrapnel or metal debris within 
their bodies. Although pregnancy is not considered a contraindication to clinical MRI scanning and no 
studies have demonstrated that MRI is harmful to a fetus, Duke IRB regulations specifically exclude 
pregnant women from research scanning. Participants who are too large (>250lbs) may not fit 
comfortably in the scanner bore, and participants who feel anxious in confined spaces may not tolerate 
a research scan. In order to protect participants against potential risks of participating in MRI research, 
all participants indicating interest in participating in MRI research complete a preliminary phone or 
email screening to eliminate from participation those who cannot be safely scanned. 
  
EEG: We will use the Emotiv EPOC+ wearable EEG headset (https://www.emotiv.com/epoc/). This 
device is noninvasive and sits comfortably around the participant’s head. It is a wireless EEG headset 
making it more portable and comfortable than a traditional EEG setup. There are no long-term health 
risks associated with EEG. One possible discomfort is minor skin irritation or redness. It is also possible 
that the headset may be uncomfortable for some participants to wear (e.g., result in a headache). 
Participants may take a break or stop participation at any time. 
  
 

Anxiety assessment procedure 
Some participants may feel uncomfortable or confined once positioned within the bore of the MRI 
system. This potential reaction is reduced by discussing the procedure prior to entry into the magnet 
room, by providing the participant with a panic button that they can use to immediately signal the 
experimenter and the MR technician, and by frequently communicating with the participant over the 
intercom during the scan session. In addition, participants may be placed into a practice mock scanner 
prior to the regular scanning session, in order to determine if they will be comfortable in the MRI. This 
mock scanner consists of a decommissioned GE scanner bore without active RF gradients. This facility is 
located adjacent to the research scanners at the BIAC. Nevertheless, if participants continue to feel 
uncomfortable, the imaging procedure is terminated and the participant is removed from the magnet. 
Special protections will also be implemented to prevent claustrophobia or panic attacks during the 
neuroimaging session. A contingency plan has been established by Dr. Adcock and her team and is 
designed to minimize anxiety. The procedure is detailed below: 
  
Experimenter: I’d like to ask you some questions to see how you’re feeling right now. On a scale of 1 to 
10, where 1 is no anxiety, and 10 is the most anxiety you have ever felt, how anxious do you feel right 
now?  
Anxiety Rating: ____________ 
If the Anxiety rating is 7 or higher: Do you feel like you are in control of your anxiety right now, or do you 
feel like you may lose control of your anxiety? 
In control? YES | NO 
If the anxiety rating is 7 or higher AND the participant reports feeling out of control, implement Panic 
Protocol, below. 
If the anxiety rating is 5 or higher, implement Relaxation Protocol, below. 
If the anxiety rating is 4 or lower, offer the Relaxation Protocol, below. 
Panic Protocol 
Experimenter: Let’s take a walk for a few minutes. 
Escort the participant from the experimental area, ideally to a comfortable area where windows and/or 
exits to the outside of the building are visible. (NOTE: if the participant is unwilling to walk with the 
experimenter, proceed to deep breathing, below.) You don’t need to take the most direct route to your 
destination: physical activity such as walking will help to reduce the participant’s anxiety. Try to make 
small talk with the participant as you walk, with the goal of distracting the participant from his/her 
symptoms of anxiety. After walking for a few minutes, invite the participant to sit down and query 
current anxiety using the two questions from the Assessment section, above. Anxiety Rating: 
__________ 
In control? YES | NO 
If the participant’s anxiety has reduced and they are no longer feeling out of control, proceed to the 
Relaxation Protocol, below. If not: 
Experimenter: Okay, I would like us to try some deep breathing exercises to help reduce your anxiety. 
Place your hand on your abdomen right below your ribcage, like this. Experimenter should demonstrate 
this and all steps in the relaxation breathing protocol. Now, inhale slowly and deeply through your nose 
into the “bottom” of your lungs – in other words, send the breath down as low as you can. You should 
feel the hand on your abdomen rise with your breath. Your chest should only move a little bit. 

After you take in a full breath, pause for a moment and then exhale slowly through your nose. (If they 
have a cold or for some other reason nose breathing is difficult, it’s OK if they breathe through their 
mouths.) Exhale fully. As you exhale, allow your whole body to just let go. 
Take a few more breaths like this. 
We are going to do ten breaths like this. Try to keep your breathing smooth and regular, without gulping 
a big breath in or letting your breath out all at once. See if you can count to four on each inhale, and 
count to four on each exhale. Remember to pause briefly at the end of each inhalation. Count from ten 
down to one on each exhalation. If you find yourself getting light-headed, let me know and we’ll stop 
and breathe normally for a while. So do it with me. 
Slow inhale … Pause … Slow exhale: Count ten 
Slow inhale … Pause … Slow exhale: Count nine 
Etc., down to one. 
Query current anxiety using the two questions from the Assessment section, above. 
Anxiety Rating: ____________ 
In control? YES | NO 
If anxiety rating is still 7 or higher, do another round of 10 breaths of deep breathing and reassess 
anxiety. If anxiety rating has not reduced after that, escort the participant to the Duke Emergency 
Department. 
If anxiety rating is reduced and participant is reporting an increasing sense of control over his/her 
anxiety, proceed to the Relaxation Protocol, below. 
Relaxation Protocol 
Escort the participant to a room outside the testing environment where a comfortable chair is available. 
Ask the participant to sit down, and say, 
I would like you to listen to this tape and follow the instructions. It will be guiding you through some 
relaxation exercises. It will take approximately ten minutes to complete the tape. I’ll come back to check 
on you when you’re done. Start the progressive muscle relaxation tape. When the tape is finished, 
assess the participant’s anxiety level a final time. 
Anxiety Rating: ____________ 
In control? YES | NO 
Provide professional referral resources as needed. 
  
Dr. Alison Adcock who is psychiatrist will be on call during all scanning sessions. 
  
Adverse Event and Serious Adverse Event reporting: Adverse events are recorded in an Adverse Event 
Log and reported annually to the IRB via the Continuing Renewal Process. In Accord with the IRB, AEs are 
considered SAEs, if they are serious, unexpected, and related to the protocol. We will report SAEs to the 
IRB within 1 week of occurrence.  
 
Data Analysis & Statistical Considerations 
 
Behavioral, EEG, and genetic data will be analyzed using statistical software including MATLAB, R, 
Python, and SPSS. The genetic information will be sent to the Duke University DNA Analysis Center for 
analysis. Imaging data will be analyzed using commercially available programs including Python, 
MATLAB, and FSL. 

  
For the fMRI data, following data collection, the time series of activation within the VTA107,125 will be 
extracted for each participant. Primary analyses on these data will be conducted on a within and 
between-subject basis as follows: 
  
To assess the ability of adults with and without ND to activate reward-related brain areas (e.g., VTA, 
striatum, PFC). To address this question we will extract time courses from the target areas and examine 
the brain response (BOLD signal) to personalized and non-personalized drug and non-drug cues. 
To evaluate whether rt-fMRI neurofeedback improves the ability to increase reward-related brain 
activation in individuals with and without ND. To address this question we will compare individual’s 
BOLD response to: baseline (passive viewing of reward images), Pre-Test (view personalized and non-
personalized non-drug cues prior to neurofeedback), Training (view personalized, non-drug cues while 
receiving neurofeedback), and Post-Test (view personalized and non-personalized non-drug cues 
following neurofeedback). In this manner we will characterize and quantify individual’s ability to 
increase brain activity to personalized, non-drug rewarding stimuli. 
 
To examine the relationship between activation of reward-related regions via neurofeedback and 
dopamine availability (as assessed genetically). To assess this question we will first send the genetic data 
to the Duke University DNA Analysis Facility for analysis. Once the SNPs and VNTRs have been analyzed 
we will correlate individual’s level of dopaminergic related genetic material (e.g., COMT, DAT) to their 
ability to regulate reward-related activation during the task. 
 
To examine the effects of neurofeedback on clinically relevant outcomes, including reward responsivity 
and smoking related behaviors. To assess this we will examine participants brain activity during the 
Passive Viewing Task and the ReAcT. We will also perform a simple Delay to Smoking Assessment where 
we will measure (in minutes) how long participants take to smoke their first cigarette. We will also 
measure how many cigarettes they smoke during their break. We will correlate individual’s ability to 
increase brain activation to personalized, non-drug cues in the ReAcT with both their time to initiate 
smoking and the number of cigarettes smoked.  
 
Data & Safety Monitoring 
 
Summarize safety concerns, and describe the methods to monitor research subjects and their data to 
ensure their safety, including who will monitor the data, and the frequency of such monitoring. If a data 
monitoring committee will be used, describe its operation, including stopping rules and frequency of 
review, and if it is independent of the sponsor (per 45 CFR 46.111(a) (6)). 
Only participants meeting all inclusion and no exclusion criteria will be enrolled in the study. Pre-
screening for appropriateness to undergo MRI scanning will be completed prior to the procedure to 
make sure to exclude participants who are not safe to undergo MRI scanning such as people who have 
metal implants, non-removable piercings, a copper IUD, have worked with metal, or had an eye injury 
involving metal. Protocols are in place for participants who may experience anxiety or panic attacks 
during study assessments. Urine pregnancy test is required for each female prior to scanning procedure. 
The test must be negative in order to proceed. The PI and her study team will review appropriateness of 
participants for the study.