Targeting Reward Dysfunction as a Mechanism to Improve Smoking Cessation
Phase: PHASE1
Conditions: Smoking
Sponsor: Maggie M Sweitzer, PhD

 
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TARGETING REWARD DYSFUNCTION AS A MECHANISM TO IMPROVE SMOKING CESSATION 
NCT02927847 
PI: Maggie M. Sweitzer, Ph.D. 
PURPOSE 
The goal of this project is to evaluate the effects of a novel, integrated intervention combining pre-quit use of 
very low nicotine content cigarettes (VLNC’s) with behavioral activation therapy (BA) on neural response to 
smoking and non-smoking rewards and smoking cessation outcomes. It is hoped that the results of this study 
will provide insight into mechanisms contributing to smoking relapse and preliminary data to estimate effect 
sizes for powering future larger scale clinical trials. 
BACKGROUND & SIGNIFICANCE 
Tobacco smoking remains a leading cause of death and disability in the developed world. Many who wish to 
quit smoking are unable to do so.  Although substantial advances have been made to identify neurobehavioral 
mechanisms underlying nicotine dependence, there is a great need to translate these findings into targeted, 
efficacious interventions, and to understand the mechanisms by which successful interventions exert their 
effects.  
Theoretical models and a growing empirical literature suggest that addictive disorders, including tobacco 
dependence, are characterized by mesolimbic hypersensitivity to smoking reward and related cues and 
hyposensitivity to nonsmoking rewards, particularly during withdrawal that occurs during the early stages of a 
quit attempt. Evidence suggests that this dysregulated reward processing may contribute to relapse and thus 
presents a promising target for intervention. The overarching goal of this research is to develop and 
evaluate a novel intervention that directly targets this reward processing imbalance by both a) 
decreasing smoking reinforcement through pretreatment with very low nicotine cigarettes (VLNC’s) 
and b) increasing reinforcement from other non-drug rewards through behavioral activation (BA).  
Smokers who are interested in quitting will be randomly assigned to one of two treatment conditions. In the BA 
+VLNC condition (n = 24) smokers will switch to VLNCs while wearing either a 21mg/d or 14 mg/d nicotine 
patch for 4 weeks prior to their quit date, depending on their initial smoking rate. They will also participate in 
weekly BA treatment sessions. Smokers in the VLNC Only group (n = 24) will undergo the same 
pharmacological pretreatment but will not participate in BA. Following the quit date, both groups will undergo 
standard nicotine replacement therapy. At baseline and pre-quit, BOLD response to smoking and non-smoking 
rewards will be measured using fMRI after 24 hr abstinence. Latency to relapse will serve as a continuous 
clinical outcome measure. A schematic of overall study design is illustrated in Figure 1 below. Prior to initiating 
data collection, we will collect pilot data (n=7) to determine feasibility and acceptability of the proposed 
intervention. 
The proposed research study has the following aims: 1) To examine the effects of BA + VLNC compared with 
VLNC Only on brain and subjective sensitivity to smoking and monetary rewards; 2) To gather preliminary data 
on the effects of combined BA + VLNC compared with VLNC only on smoking cessation outcomes; and 3) To 
examine mediating and moderating effects of pre-and post-treatment brain function on smoking outcomes.   
The proposed research will have significant scientific impact by increasing our understanding of the role of 
reward dysregulation as a mechanism of nicotine dependence. Clinical research and practice will also be 
impacted by determining the efficacy of novel, integrated treatment designed to target reward dysregulation as 

 
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a mechanism to improve smoking cessation outcomes. Results of this study can be used to improve cessation 
treatments for those attempting to quit smoking.   
DESIGN AND PROCEDURES 
An overview of the study design is presented in Figure 1 below. We propose to obtain consent from up to 150 
participants in order to identify 55 who meet all inclusion and exclusion criteria and enroll in the study. At the 
beginning of the study, 7 of these subjects attempted to complete all phases of the study but did not undergo 
fMRI scanning, in order to assess feasibility and acceptability of the treatment protocol prior to beginning full 
recruitment. Following pilot testing, 48 individuals will be enrolled in the full study with the aim of obtaining 
complete, useable datasets from 40 participants. During a phone screening interview, the study will be 
described in detail and preliminary participant characteristics (e.g., age, number of cigarettes per day,) will be 
assessed. Those participants who meet criteria for participation will be invited to our offices for an informed 
consent and screening visit. Potential participants will be instructed to bring a valid government issued photo 
ID to the screening session to confirm age and identity. Identifying information from the phone screen for the 
participants who do not meet inclusion criteria will be kept until recruitment for this study is completed.  
Figure 1. Overview of study design and anticipated sample size for full study 
Screen
n=96
Train
n=48
VLNC+BA; n=24 
n=20
VLNC Only; n=24
n=20
Pre-Quit Treatment
5 weekly sessions
fMRI 1
fMRI 2
Quit Day
8 Weeks Standard NRT + 
2 Therapy Sessions 
Randomize
 
Screening session.  During screening, all aspects of the study will be described to subjects and informed 
consent will be acquired. Breath and urine samples will be collected in order to verify smoking status and 
breath alcohol level (BAL); and measures of smoking history, nicotine dependence, and mood will be collected 
(see Table 1 below for key measures acquired at each visit). Vitals such as heart rate, blood pressure and 
weight/height will also be measured. Urine samples will be obtained in order to screen for illicit drug use and to 
assess pregnancy status. Females who test positive for pregnancy will be excluded from the study and will be 
given options for smoking cessation programs. Use of illegal drugs will be exclusionary. Marijuana use will not 
be exclusionary, but participants must agree to not use marijuana for 24 hours prior to sessions and may not 
mix their marijuana with tobacco (i.e., blunts). Participants will also be interviewed regarding their smoking 
behavior, and will be asked to identify pleasant activities that do or do not include smoking.  
 
Participants must record a breath alcohol level of 0.0 at screening. Volunteers who test positive for alcohol, or 
who indicate that they have smoked marijuana in the past 24 hours, will not be permitted to continue with the 
screening and will be asked to reschedule. If the screening visit is rescheduled due to intoxication, participants 
will be asked to repeat the informed consent process. Volunteers testing positive for alcohol on more than one 
occasion will be excluded from the experiment.  
 
If a participant has a BAL above the legal limit at the screening or any subsequent visit, study staff will ask the 
participant if they drove to the lab. If the participant indicates that they did drive, study staff will provide a safe 
mode of transportation home (e.g. taxi, uber) at no cost to the participant. 

 
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Patients will be asked about medical history and complete the Brief Medical History Questionnaire and BIAC 
Screening Form. We will give subjects the option to view the mock scanner if they have any worries about it. If 
they do not wish to complete the fMRI portion of the study, they will be dismissed with payment.Participants will 
also complete a brief measure of cognitive functioning and a computerized psychiatric screening measure and 
follow-up interviewing to assess current and past psychiatric disorders. Indications of severe psychiatric mental 
health problems (e.g., active psychosis or mania) or suicidality will trigger medical review by the study 
physician and emergency referral to psychiatric services if necessary. Subjects who meet all entry criteria 
listed below will be provided with the option to continue with the training session.  
 
 
Inclusion criteria: 
 
1)   generally healthy; 
 
2)   between the ages of 18 and 55; 
 
3)   intact intellectual functioning (K-BIT2 ≥ 80) 
5)   smoking of at least 5 cig/day of a brand delivering ≥ 0.5 mg nicotine (FTC method) for past 6     
      months 
6)   daily smoking ≥ 2 years lifetime; 
7)   an afternoon expired CO concentration of at least 9 ppm (to confirm inhalation) or morning urinary 
cotinine indicating tobacco use (NicAlert > 3); 
 
8)   interested in quitting smoking within the timeframe of the experiment. 
 
Exclusion criteria: 
1) no desire to quit smoking; 
2) inability to attend all required experimental sessions; 
3) report of significant health problems including but not restricted to chronic hypertension, 
emphysema, seizure disorder, history of significant heart problems; 
4) use of psychoactive medications; 
5) current participation in psychotherapy; 
6) current unstable psychiatric illness as assessed by the SCID; 
7) suicidal ideation with plan or intent; potential subjects who endorse items 4 (Active Suicidal Ideation 
with Some Intent to Act, without Specific Plan) and/or 5 (Active Suicidal Ideation with Specific Plan 
and Intent) on the Columbia Suicide Severity Rating Scale will be excluded from study participation, 
and referred to appropriate psychiatric treatment; 
8) use of other tobacco products or e-cigarettes on > 9 out of the past 30 days; 
9) use of Spectrum cigarettes or low nicotine content cigarettes in past year 
10) quit attempt in past 30 days resulting in greater than 3 days abstinence 
11) primary use of roll-your-own cigarettes 
12) current alcohol or drug abuse; 
13) use of illegal drugs as measured by urine drug screen; 
14) current use of nicotine replacement therapy or other smoking cessation treatment; 
15) presence of conditions contraindicated for nicotine replacement therapy (e.g., skin allergies) 
16) (for full study only) left-handed as measured by a three-item scale used in our laboratory; 
17) (for full study only) presence of conditions that would make MRI unsafe (e.g., pacemaker); 
18) (for full study only) brain abnormality (including but not limited to stroke, brain tumor, and seizure 
disorder); 
19)  (for full study only) claustrophobia 
20) (for full study only) history of fainting 

 
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21) (for full study) No tattoos or permanent make-up above the neck 
22) (for full study) Tissue expanders (plastic surgery) 
23) breath alcohol level > 0.0 (participants failing for BAL will be allowed to rescreen once) 
24) systolic blood pressure > 160 or diastolic blood pressure > 100 (participants failing for blood 
pressure will be allowed to rescreen once) 
25) resting heart rate > 100 (participants failing for heart rate will be allowed to rescreen once) 
26) expired CO concentration of > 80 ppm 
27) household member enrolled in study concurrently 
28) unstable living condition that would compromise compliance to study procedures 
29) pregnant, trying to become pregnant, or breastfeeding 
30) Glaucoma or color blindness or other uncorrected vision problem 
31) Weighing over 300 pounds 
 
Among females, pregnancy at screening as measured by a urine test will be exclusionary. The QuickVue One-
Step hCG Urine Test will be used and performed by research staff who have completed competency training 
from the Duke Office of Clinical Research. Females of child bearing potential must agree to use appropriate 
contraception during the course of the study. They must further agree to notify the study staff if they become 
pregnant during the study. A second urine pregnancy test will be conducted at fMRI session 1 (or treatment 
session 1 for pilot subjects), which takes place before any study product is provided.  
 
Participants will be asked to indicate in the consent form whether they would like to be contacted about future 
studies while the present study is ongoing. Participants will be informed there is no obligation to participate and 
their refusal for future contact will in no way affect their participation in this study. 
 
Participants who complete the screening visit (described above) and meet all study requirements will then 
complete a training session, 2 fMRI sessions, 8 treatment sessions, and 2 follow-up visits. Pilot subjects will 
not complete the fMRI sessions. In addition, pilot subjects will complete an additional 1 hour interview to 
assess their satisfaction and feedback regarding the treatment protocol. This session will take place at the 
conclusion of the final treatment session.  
 
Table 1. Core Measures Table 
Timeframe 
Baseline 
Weeks 1 to 4 
Week 5 
 
Wk 
6  
Wk 
7 
Wk   
8 
Wk 
11 
Wk 
15 
Visit Type 
Screen 
Train 
fMRI 
Treatment 
Sessions 
fMRI 
Treatment 
Session 
 
Treatment 
Sessions 
Follow-up 
Sessions 
Session Number 
1 
1 
2 
3 
4 
1 
5 
 
6 
7 
8 
2 
3 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nicalert 
(cotinine) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Expired CO 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Breath Alcohol 
Level 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 

 
Reward Quit Summary—v13 8/10/2018 
 
5 
 
Pregnancy Test 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Medical & 
Smoking Hx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCID & 
Diagnostic Inter 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mood/Anxiety 
scales 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Nicotine 
dependence 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
K-BIT2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking 
cessation Q’s 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quit Self-
Efficacy  
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Trait anhedonia 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reward scales 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Craving & 
Withdrawal 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Timeline follow 
back 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
Caff-ETOH 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Guessing Task 
(fMRI) 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Cigarette 
Purchase Task 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
EEfRT Task 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cigarette Eval 
Scale 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Provide study 
cigs 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Provide patches 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
 
Patch 
adherence log 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Study cigarette 
log 
 
 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
Health change 
form 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Adverse Events 
Form 
 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
*Screening and training visits may occur on the same day. However, the training visit must occur within 30 days of the 
baseline visit. Quit initiation occurs on treatment session 5.  
Training Session. Participants will complete the training session on a separate day from the screening 
session. Participants will be required to complete both the training session and the first fMRI session within 30 
days of their screening visit. If a participant still wants to be in the study after 30 days, he or she will need to be 
rescreened.  
 

 
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During the training session a breath CO and BAL sample will be collected. For all visits breath alcohol levels 
will be assessed and participants must record a BAL of 0.0. Participants who test positive for alcohol will be 
excluded from participation that day. Participants testing positive for alcohol on more than one occasion will be 
excluded from the experiment. Participants will also complete several brief questionnaires regarding their 
mood, attitudes toward smoking cessation, and behavior, including measures of rewarding activities. 
Participants will have the opportunity to experience the mock MRI scanner and will be trained on the rewarded 
guessing task and behavioral incentive delay task. Participants will then be scheduled for their first fMRI 
session. 
 
fMRI Sessions. Participants will complete two fMRI scanning sessions in which they will complete 1) a five 
minute resting state BOLD scan, 2) 2 8-minute runs of the rewarded guessing task, 3) 2 8-minute runs of the 
behavioral incentive delay task, and 4) a high-resolution anatomical scan. Participants will be scanned at 
baseline (fMRI 1) and after the fourth week of the pretreatment period (fMRI 2). Participants will be asked to 
abstain from smoking for 24 hours prior to their fMRI scans but will be provided with a 21 mg/d or 14 mg/d 
transdermal nicotine patch to wear during this time. Abstinence will be verified by self-report and a CO < 8 or a 
50% reduction from their baseline CO level. Participants who do not meet abstinence criteria will have the 
opportunity to reschedule.  
 
During the first hour of each scanning session, the following measures will be collected: breath CO and breath 
alcohol level; measures of self-reported recent smoking and other tobacco use; measures of recent caffeine 
and alcohol use; measures of smoking withdrawal, nicotine dependence, and mood; and a measure of recent 
rewarding experiences. Participants will also complete a hypothetical cigarette purchase task on the computer 
in order to assess relative reinforcing value of smoking. During this task, participants will be asked about their 
willingness to purchase cigarettes available at different hypothetical prices. Participants will then complete the 
Effort Expenditure for Rewards Task (EEfRT or “effort”), an objective measure of motivation and anhedonia. 
This task is a computerized button-pressing game in which the participant chooses between an easy or hard 
task on each trial in order to earn variable amounts of reward. The hard task requires participants to make 100 
button presses with the non-dominant pinkie finger within 21 seconds. The easy task requires participants to 
make 30 button presses with the dominant index finger within 7 seconds.  
 
Participants will then be escorted to the fMRI suite. Once inside, they will complete additional questionnaires 
regarding their current mood, craving, and withdrawal symptoms. Expired CO will again be measured and 
recorded. The participant will be given specific instructions regarding data collection procedures and be placed 
in the scanner. Following positioning and shimming, an anatomical series will be acquired, followed by the 
resting state scan. BOLD signal will then be acquired during the rewarded guessing task and behavioral 
incentive delay task.  
 
The rewarded guessing task has been previously used in our lab to measure mesolimbic reactivity to smoking 
and monetary rewards. Participants will be instructed that they are playing a game in which they can earn 
money and puffs from a usual brand cigarette by guessing whether an unknown number with a value from 1-9 
is higher than or lower than 5. Each trial begins with a 4-s decision period, in which participants make a guess 
via button press. During a 6-s anticipation period, participants view an image indicating the reward available on 
that trial (50₵, puff, or neutral). During the outcome period, participants see the “actual” number on the screen 
followed by an upward-facing green arrow for win or a yellow circle for non-win (i.e., incorrect response) 
outcomes. Trials are presented in predetermined pseudorandom order. The task will be divided into two 24-trial 
runs (each 8 min). To increase the salience of rewards, participants will remain in the lab for 60 min after the 

 
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scan; they will be given the rewards earned (money and puffs), but otherwise not allowed to smoke. 
Participants will not be required to smoke earned puffs.  
 
The behavioral incentive delay (BID) task was previously developed and validated by Dr. Stacey Daughters, 
modified from the monetary incentive delay task. Participants will complete 40 trials, lasting approximately 13 
seconds each. Each trial begins with a 2-s cue indicating whether it is a “reward” trial (grey triangle) or a 
“neutral trial” (blue circle). Participants are then shown a fixation cross during a brief delay (anticipation period), 
followed by a target symbol in which they must press the space bar as quickly as possible. Required response 
time will be titrated to achieve approximately 67% accuracy for each participant. On-time responses will result 
in presentation of a 3-second photo depicting people engaged in enjoyable activities (reward trials) or 
household objects (neutral trials). Delayed responses will be followed by feedback with no picture presentation. 
Participants will complete 2 runs of the task lasting approximately 8 minutes each. 
 
Following the final functional series, the participant will be removed from the scanner. After being removed 
from the scanner, participants will complete post-session withdrawal and mood questionnaires and provide a 
post-session breath CO sample. Participants will then be escorted to a laboratory testing room and provided 
with rewards earned during the scanner task ($6 and 12 puffs of a cigarette).  Smoking behavior (latency to 
first puff and number of puffs taken) will be observed and recorded. Participants will then complete a measure 
of subjective reactions to smoking their earned puffs (Cigarette Evaluation Scale; CES), and an additional 
measure of recent pleasant events (Pleasant Events Schedule, administered following fMRI 2).  
 
Regardless of when they choose to smoke, participants will remain in the lab for the expected 1 hour waiting 
period.  
 
At the end of the 1 hour waiting period, participants will be provided with additional information about 
subsequent visits: 
• At the end of fMRI 1, participants will be given information regarding upcoming sessions. Participants will 
also set a quit date and schedule remaining treatment and fMRI sessions. fMRI 2 must occur a minimum of 
2 days prior to the designated quit date. 
• At the end of fMRI•2, participants will be reminded of their previously agreed upon quit date and the time 
of their next scheduled session. 
 
Breath alcohol levels will also be assessed prior to each scanning session with a handheld breathalyzer (Alco-
Sensor IV; Intoximeters) and participants must record a BAL of 0.0.  Volunteers who test positive for alcohol 
will be excluded from participation that day.  Volunteers testing positive for alcohol on more than one occasion 
will be excluded from the experiment. Females of child bearing potential will undergo a urine pregnancy test 
immediately before each fMRI scanning session. 
 
Group Assignment/Treatment Sessions. Following fMRI 1, participants will attend 8 60-minute weekly 
treatment sessions.  Four of these will take place before the quit date, one will occur on the quit date, and 3 will 
take place after quitting smoking. Half of the sample (n=24) will be randomly assigned to the BA + VLNC 
condition, which will include behavioral activation treatment as the primary therapy component. The other half 
(n=24) will be assigned to the VLNC Only group, which will include health education, supportive counseling 
and relaxation sessions matched for contact time instead of behavioral activation. Participants in both groups 
will undergo identical study procedures; only the content of the therapy sessions will differ. Participants will not 
be told of their treatment group assignment, and all therapists will provide treatment to participants in both 

 
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groups. Smokers in both groups will switch to VLNCs while wearing either a 21 mg/d or 14 mg/d nicotine patch 
for 4 weeks prior to their quit date. Both treatment groups will include content related to tips and strategies for 
quitting smoking.   
 
Very Low Nicotine Content (VLNC) cigarettes. In both conditions, participants will smoke VLNC cigarettes 
for one month prior to the quit date. VLNCs will be NRC-102 (non-menthol) and NRC-103 (menthol) 
SPECTRUM research cigarettes obtained from the NIDA Drug Supply Program with the following 
specifications: .03  .01 mg nicotine yield and 9  1.5 mg tar. The effects of these cigarettes are currently 
under investigation in our lab (U54DA031659) and have similar specifications as Quest 3 cigarettes (<.05 mg 
nicotine; 9 mg tar) used in prior studies (R01DA025876) in our lab. As in these studies, participants will be 
instructed to smoke the same number of VLNCs as they smoked of their usual brand and will be given a 
comparable supply. 
 
Nicotine patches. Transdermal nicotine skin patches (Nicoderm CQ Rugby®, Leader, or equivalent 
purchased from the Duke Pharmacy) will be used to administer nicotine prior to and after quitting. In both 
groups, participants will start either wearing a 21 mg/d or 14 mg/d patch during the one month they smoke 
VLNCs depending on whether they smoke more or less than 10 cigarettes per day. If participants smoke 10 or 
more cigarettes per day, they will undergo a standard regimen of nicotine replacement following the quit day: 
four weeks of 21 mg/d, two weeks of 14 mg/d and two weeks of 7 mg/d. If they smoke less than 10 cigarettes 
per day, participants will wear six weeks of 14 mg/d and two weeks of 7 mg/d. Participants will be instructed to 
wear one patch per day but to remove it before bed. Nicotine replacement packaging will include specific 
instructions for patch use and contact information including the 24 hr pager number (staffed by the study 
physician). Symptoms associated with nicotine toxicity include, lightheadedness, dizziness, nausea, and 
vomiting. Symptoms considered moderate to severe in nature, will be evaluated by the study medical staff by 
telephone or in person, depending upon the level of severity. Upon evaluation, the subject will then be given 
the choice of continuing in the study at a reduced dose or discontinuing patch use. Dose reduction will consist 
of lowering the dose from 21 mg/d to 14 mg/d to 7 mg/d, to no treatment. This will be done under the guidance 
of the study physician and will be logged. Dose lowering has not been necessary in our previous fMRI studies 
using these patches. The data from participants for whom dose lowering occurs, will not be used in final 
analyses. However, these subjects will be allowed to continue with treatment. 
 
In addition to the above, at each laboratory visit, participants will rate nicotine patch side effects using a 23-
item self-report questionnaire to measure psychological (e.g. Do you feel jittery?) and physical (e.g. Do you 
feel nauseated?) symptoms. Items will be rated on a 7-point Likert scale (1=not at all to 7=extremely). This 
questionnaire has been validated in numerous clinical trials in the Duke CNSCR (PI: Rose). This questionnaire 
will be completed at the beginning of each visit and reviewed immediately by staff in order to identify possible 
adverse reactions. Data from this questionnaire will be monitored and tabulated but not statistically analyzed. 
 
Treatment Sessions. Sessions will occur on a weekly basis and last one hour. The treatment component will 
consist of Behavioral Activation (BA) or Control sessions, depending on group assignment. An overview of the 
content of treatment sessions for each condition is provided below. Therapy session content will be pilot-tested 
prior to beginning full recruitment. In addition to group-specific content, content for both groups will include brief 
discussion (~10 min/session) of standard smoking cessation strategies consistent with clinical guidelines.  
Behavioral Activation. Smokers randomized to the BA+VLNC condition will attend 8 1-hr individual sessions 
(4 pre-quit, 1 quit-day, and 3 post-quit) addressing the following topics: 1) Treatment overview, rationale, and 
monitoring of daily activities, with brief activity scheduling; 2) Identification of values, goals and activities within 

 
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key life areas and brief activity scheduling; 3) Prioritization of life areas and setting weekly activity goals; 4) 
Monitoring progress toward daily goals and contracts for continued success; 5) Continued monitoring, social 
support contracts, and ongoing weekly goals; 6-8) Review and maintenance of skills, continued monitoring and 
goal setting. Treatment manuals will be modeled after the BA Treatment for Smoking (BATS) and Life 
Enhancement Therapy for Substance Abuse (LETS ACT) protocols developed by Dr. Daughters. Sessions 1 
through 5 are designed to cover core content aimed at increasing participants’ engagement in valued life 
activities. Sessions 6 through 8 are added as maintenance sessions to reinforce learned strategies and provide 
additional support once abstinence is initiated.  
 
Control Sessions. Smokers assigned to VLNC Only will attend an equal number of 1-hr sessions to control for 
overall contact time. Content will include health education (e.g., dietary guidelines), supportive counseling and 
relaxation. Supportive counseling will include empathy and supportive listening for concerns raised by the 
participant, but will minimize giving advice. Relaxation has been used in previous research as a control 
condition and is neither harmful nor effective for smoking cessation. The control condition content will similarly 
be modeled after Dr. Daughters’ control treatment manual and government Dietary Guidelines for 2015 - 2020.  
 
Therapeutic content for BA was be pilot-tested among 7 smokers (without fMRI) to determine feasibility and 
acceptability. Objective outcome measures and qualitative feedback will be elicited to determine if changes to 
the treatment protocol are needed prior to beginning full study recruitment. An interview to elicit qualitative 
feedback will be conducted following treatment sessions 7 and 8. 
 
Treatment sessions will be conducted by the PI or other post-doctoral or graduate-level clinical psychology 
students and will be audiotaped to allow for supervision and assessment of treatment fidelity. Student 
therapists will be added as key personnel to the IRB protocol prior to initiating any study-related activities. 
Student therapists will complete a 1 day training provided by the PI, which will include content overview and 
role plays. Therapists will then be observed conducting mock therapy sessions prior to initiating treatment. The 
PI will provide ongoing (weekly) supervision of graduate students, under overall supervision of Dr. Daughters. 
A randomly selected subset of audiotapes (20%) from both BA and control treatment sessions will be 
monitored by Dr. Daughters or another rater not otherwise associated with treatment delivery, using a checklist 
adapted from her existing measures to assess therapist adherence to, and competence with, the protocol and 
discriminability of the two treatments. Feedback and further training will be provided as necessary to address 
deviations from the protocol. 
 
Assessment Sessions. A total of 7 30-min laboratory assessment sessions will be conducted during the 
course of the study. Five of these will coincide with treatment sessions occurring at weeks 1, 3, 5, 6, and 8. 
Additionally, two follow-up sessions will occur at weeks 11 and 16. Each assessment session will consist of:  
obtaining vital signs (e.g., blood pressure, heart rate, weight), breath CO and breath alcohol level; completion 
of self-report measures (e.g. withdrawal, mood, involvement in rewarding activities); and review of study and 
non-study cigarette use and patch use over the previous two weeks. Current medications, changes in health 
status, and side effects will also be reviewed. Dependent measures will be collected by the research assistant, 
who will remain blind to treatment condition. Depending on session, participants will be provided with study 
cigarettes and nicotine patches and instructions for use. During post-quit and follow-up assessment sessions, 
in the case that a participant has relapsed since their last point of contact, a timeline follow-back procedure will 
be conducted in order to establish date of relapse. In addition, participants will be asked for qualitative 
feedback about their experience with the study and the treatment protocol.   
 

 
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Follow-up Phone Calls. Participants will be contacted by phone 6 and 12 months after completing the study 
to complete a brief interview about current smoking status and nicotine dependence. 
 
 
DATA ANALYSIS 
 
The primary dependent measures will be percent signal change in a priori brain regions of interest for 
anticipation of smoking and monetary rewards relative to neutral trials; and smoking cessation outcomes (i.e. 
latency to lapse and relapse). Latency to lapse will be defined as the first cigarette following quitting smoking 
and relapse will be defined as 7 consecutive days of smoking.  Secondary data are self-reported craving, 
mood, anxiety, smoking and nonsmoking reward sensitivity, withdrawal, nicotine dependence, and breath CO 
levels.  
 
To assess Aim 1 hypotheses on the effects of treatment on BOLD response to smoking and monetary 
rewards, a voxel-wise 2 (Group) x 2 (Scan) x 2 (Reward Type) mixed model ANOVA will be conducted in FSL 
within a mask of regions of interest (ROIs) of mPFC, ventral striatum, and dorsal striatum. To test the Aim 2 
hypothesis that the BA+VLNC group will achieve longer continuous abstinence than VLNC only, survival 
analysis using Cox regression will be conducted to compare group differences in days to relapse. To assess 
mediating and moderating effects of brain activation on treatment outcomes in Aim 3, multiple linear 
regression will be conducted using mean percent signal change extracted from anatomical ROIs described 
above. We hypothesize that pre- to post-treatment increases in activation to monetary reward will mediate the 
effect of BA+VLNC treatment on cessation outcomes. We further hypothesize that effects of treatment on 
cessation outcomes will be stronger for those exhibiting greater pre-treatment deficits in monetary reward 
anticipation. 
 
RISK/BENEFIT ASSESSMENT 
 
Women of childbearing potential: 
Pregnant or nursing women will be excluded from the study.  Female participants will undergo a urine 
pregnancy test at screening administered by a trained study staff member. The pregnancy test kits to be used 
are approved by the Department of OBGYN. Subjects must also agree to use contraception during the course 
of the trial. They will be encouraged in the consent form to notify study staff if they believe a change in their 
pregnancy status has occurred during the trial. A second urine pregnancy test will be conducted prior to 
dispensing study medications.  
 
Smoking study cigarettes: 
Participants may experience some minor adverse health effects such as headaches or experience withdrawal 
symptoms which are listed below. In addition, due to the altered nicotine levels, there could be a change in 
their cigarette use including the manner in which they inhale the smoke or increase the number of cigarettes 
smoked per day. This increased rate of smoking may persist after completing the study. Smoking the study 
cigarettes does not provide any less risk than their usual brand cigarette and could pose increased health 
risks. Participants may also experience increases in carbon monoxide, a gas from smoke.  
 
Nicotine Patch: 
Insomnia or abnormal dreams are common and expected side effects associated with 24 hour nicotine 
patches. If a subject complains of disturbed sleep, s/he will be instructed to remove the patch at bedtime and 
apply a new one the next day at the usual time. Skin irritation may occur, although this will be minimized by 
changing the site of patch application daily. If a subject develops itching or a rash at the patch site, s/he will be 

 
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advised to use 1% hydrocortisone cream on the affected area. Symptoms associated with nicotine toxicity 
include lightheadedness, dizziness, nausea, fainting and vomiting. Symptoms considered moderate to severe 
in nature will be evaluated by the study medical staff. Upon evaluation, the participant may be given the choice 
of continuing in the study at a lower dose patch. If it is thought that being in this study is putting the 
participant’s health at risk, they may be asked to stop participating in the study.  
  
Smoking withdrawal: 
Participants may experience smoking withdrawal symptoms during this study. The symptoms can be 
uncomfortable but are typically of minimal risk. At each visit, they will be asked how they feel, and if it is 
thought that being in this study is putting their health at risk, they may be asked to stop participating in the 
study. Smoking withdrawal symptoms include: 
 
a) anger, irritability, frustration 
 
b) anxiousness, nervousness 
 
c) depressed mood or sadness 
 
d) desire or craving to smoke 
 
e) difficulty concentrating 
 
f) increased appetite, hunger, or weight gain 
 
g) insomnia, problems sleeping, or awakening at night 
 
h) restlessness 
 
i) impatience 
 
j) constipation 
 
k) dizziness 
 
l) coughing 
 
m) dreaming or nightmares 
 
n) nausea 
 
o) sore throat 
 
MRI 
MRI provides clinically relevant anatomic and functional information non-invasively and with minimal risk, if the 
well-known contraindications (such as pacemakers) and potential hazards (such as attraction of metallic 
objects) are avoided. To minimize discomfort associated with confinement the small space within the MRI 
machine or loud noises during scanning, participants will be provided with a training session in which they will 
be introduced to all aspects of the scanning procedure using a mock scanner in our laboratory. Participants will 
be reminded of their option to withdraw from the study at any time.  
 
Management of side effects: 
Reports of side effects will be obtained by study technicians and communicated to the principle investigator, 
who will determine the most appropriate course of action, which may include options for termination of study 
participation. Participants will be reminded of their option to withdraw from the study at any time. 
 
Exacerbation of psychiatric symptoms: 
Smoking and nicotine can affect a person’s mood and emotions and are associated with psychiatric disorders 
including major depressive disorder, generalized anxiety disorder, bipolar disorder, and eating disorders. Any 
changes in nicotine or cigarette consumption could adversely affect psychiatric conditions. Mood and anxiety 
will be monitored at each visit over the course of the study. Reports of worsening psychiatric symptoms will be 
communicated to the principle investigator, who will determine the most appropriate course of action, which 

 
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may include options for termination of study participation and referral to more intensive psychiatric treatment.  
 
Suicidality:  
Screening sessions will include assessment of suicidality. If participants endorse suicidal ideation or intent 
during the interview, or by answering the BDI-II suicidality item at 2 (“I would like to kill myself”) or 3 (“I would 
kill myself if I had the chance”) during subsequent visits, the participant will be asked to wait in order to speak 
with a senior staff member. The senior staff member will follow up with the suicidal ideation and intent items of 
the Columbia-Suicide Severity Rating Scale.  Participants indicating “yes” on items 4 (Active Suicidal Ideation 
with Some Intent to Act, without Specific Plan) and/or 5 (Active Suicidal Ideation with Specific Plan and Intent) 
will receive further follow-up. Screening participants will be given the choice of following up with an established 
treatment provider (e.g., paging their psychologist or psychiatrist; following the safety plan established with 
their provider) or if they do not have a current provider, presenting to the nearest emergency department for 
further care. If participants are unwilling to contact a treatment provider or to voluntarily present to the ED, the 
senior staff member will ask them to remain at their current location, and will call EMS. EMS will be provided 
with the interviewee’s name and current location, as well as their stated suicidal intent. A staff member will 
offer to stay on the phone with the interviewee until EMS arrives, and suicide prevention steps will be 
documented in the research record. As noted above, suicidality will continue to be monitored throughout the 
duration of the study, and appropriate steps will be taken if an increase in suicidality is indicated. 
 
Treatment Referral:  
The initial in-person evaluation will include assessment of psychiatric disorders. Participants with unstable 
psychiatric disorders will be excluded from the study and referred for appropriate treatment. Individuals with 
psychiatric symptoms that do not interfere with study participation (e.g., mild depression or anxiety) will be 
allowed to participate provided that a) symptoms are contributing to no more than mild to moderate 
impairment; b) symptoms have been stable with no psychiatric treatment for the past 3 months; and c) 
participant is deemed to be at minimal risk for self-harm based on suicide screening measures. Although 
behavioral activation has empirical support as a treatment for depression, only 50% of participants will be 
randomized to that condition, and no pharmacotherapy will be administered as part of the trial. As such, 
participants will be fully informed that participation in the study is intended to help them quit smoking, but is not 
intended as a primary treatment for depression or other psychiatric disorders. Participants who are 
experiencing more than mild to moderate impairment, or who are primarily seeking treatment for psychiatric 
conditions will be excluded from the study and referred for appropriate treatment. In addition, information 
regarding smoking cessation treatment resources and appropriate referrals will be provided to all participants 
who consent but do not pass screening for whatever reason.  
 
As noted above, worsening psychiatric symptoms among participants who have passed screening may also 
result in referral to more intensive psychiatric treatment, as needed. In this case, participants will be provided 
with referral information and encouraged to seek treatment without the disincentive of being withdrawn from 
the study if they do so, provided that continued study participation does not pose any additional risk.     
 
Confidentiality:  
All research material gathered on participants is confidential and will be appropriately protected. No identifying 
subject information will be revealed without the agreement of the participants. 
 
PARTICIPANT RECRUITMENT AND COMPENSATION 
 

 
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We will advertise in local newspapers, the radio, flyers on bulletin boards and on the internet 
(trianglesmokingstudies.com and craigslist). When we receive calls from potential subjects we will return their 
call and ask information including name, address, age, and smoking, mental, and medical health history. They 
will be given a brief description of our studies and will be asked questions to determine interest and eligibility. If 
they do qualify we will schedule a screening session where we will follow all IRB protocols of informed consent.  
 
We propose to obtain consent from a total of 150 smokers in order to have 40 complete usable data sets for 
the full study. We enrolled 7 smokers as pilot subjects to attempt all aspects of the study except fMRI scanning 
to determine feasibility and acceptability of the treatment protocol prior to beginning full recruitment. As with 
previous studies, we will make every effort to maximize participant retention via a thorough informed consent 
process, careful screening, and other practices (e.g., contacting participants with a reminder phone call the 
night before experimental sessions). 
 
Participants will receive no compensation for the phone screening. They will receive $40 for the initial 
evaluation visit, provided they pass the drug screen, CO, and breath alcohol tests. Participants enrolled in the 
study will receive $10 for completing the training session, $20 for each of the first 5 assessment sessions, $25 
for each of the 2 follow-up assessment visits, and $125 for each fMRI session ($430 total). Participants will not 
be compensated for attendance at individual treatment sessions, but will be reimbursed for parking or 
transportation as needed. In addition, participants can earn a completion bonus of $50 for completing all of the 
first four weekly pre-quit treatment sessions. Participants can also earn an additional $50 on-time bonus for 
completing fMRI2 on time as scheduled and meeting abstinence criteria. As such, total compensation for 
completing all aspects of the study is $550. Participants can also earn $12 during the rewarded guessing task 
completed in the fMRI sessions, and an additional bonus (up to $10) during the EEfRT task completed at each 
fMRI session. Participants that decide to withdraw from the study before fulfilling all of the requested tasks will 
be given compensation for each session completed. 
 
SERIOUS ADVERSE EVENT REPORTING PLAN 
  
The Principal Investigator will report all serious adverse events and unanticipated problems relating to the 
study in an expedited manner to the Duke University Health System (DUHS) Institutional Review Board (IRB) 
office and all applicable regulatory authorities in accordance with the Center’s standard operating procedures.   
 
COSTS TO PARTICIPANTS 
 
There are no costs to participants for taking part in this study. All the study costs, including any procedures 
related directly to the study, will be paid for by the study. Moreover, there are no immediate benefits from 
participating in the study. 
  
DATA SAFETY AND MONITORING PLAN 
 
Data collected for this study are gathered via paper-and-pencil measures, computer-based measures, audio 
recordings, and brain imaging techniques. Data gathered is either automatically downloaded to an excel sheet 
(computer measures) or other electronic data file (brain imaging), or entered by hand (paper and pencil 
measures). All source documents will be stored in participant binders. All paperwork and electronic files will be 
checked by the research scientist for completeness on a daily basis. Research data without identifiers will be 
maintained in a locked room and on password-protected computers in the research staff workplace, with only 

 
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numeric codes identifying subjects. The Subject Identifier will be a numeric code that will include information 
about study number and subject ID number. Study consent forms and any PHI will be stored in a locked file 
cabinet in a separate location from study data. The link between the participant’s names and codes will be 
stored on a password protected spreadsheet on a secure server. Audio recordings of treatment sessions will 
be collected on a password-protected Duke iPad and will be immediately transferred to a secure server after 
the conclusion of the session. All information collected as part of this study will be accessible only to study 
staff. Internal audits to ensure quality assurance occur at the beginning of the study, mid-way through and at 
the end of enrollment.  
 
AE’s will be collected at each assessment visit. Participants will also be instructed to contact study personnel 
at any time should they experience physical discomfort. A 24 hr pager number will be provided for this 
purpose. Should a possible AE be reported during non-business hours, the study physician will assess the 
situation with the participant and make the determination regarding whether immediate care is necessary. The 
participant will be instructed to visit the lab the next day and further collection of information regarding a 
possible AE will take place at that time.  
 
DATA STORAGE AND CONFIDENTIALITY 
 
Participants will be informed, in their consent forms, of the data storage and confidentiality safeguards, which 
are practiced according to current HIPAA regulations. MRI scanning session data is stored on a secure server 
and then transferred to DVD for final storage. All PHI is removed from the scanning data before it is posted on 
the secure server and is coded with a unique id. Except when required by law, the participant will not be 
identified by name, social security number, address, telephone number or any other direct personal identifiers 
in the study records. Dr. Stacey Daughters at UNC-Chapel Hill will be a collaborator for the study, and is listed 
as outside key personnel. Given her role in supervising and evaluating treatment fidelity for the behavioral 
activation and control treatments, she will require access to audio recorded treatment sessions, which includes 
PHI. When needed, audiofiles will be shared using the secure, password-protected Duke Box sensitive folder. 
This folder has been configured to protect PHI and prevent anonymous sharing of data. In addition, password 
protection will require multifactor authentication. Dr. Sweitzer will maintain responsibility for removing files from 
the Duke Box sensitive folder as soon as they are no longer need (e.g., when supervision or evaluation of 
treatment compliance for that session is complete).