Investigating a Response Modulation Hypothesis of Socioemotional Processing Associated With Alcohol Use Disorder
Phase: NA
Conditions: Healthy Volunteers, Alcohol Drinking Related Problems, Alcohol-Related Disorders
Sponsor: National Institutes of Health Clinical Center (CC)

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
1
Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder 
Protocol Number: 18-AA-0098
Version Date: 08 April 2024
Title: Investigating a Response Modulation Hypothesis of Socioemotional Processing associated 
with Alcohol Use Disorder
NIH Principal Investigator: Reza Momenan, Ph.D 
CNIRC Branch
NIAAA
Building 10, Rm 1-5435 SE
9000 Rockville Pike
Bethesda, MD 20892
Phone: (301) 451-6972
E-mail: rezam@nih.gov

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
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TABLE OF CONTENTS
Table of Contents.............................................................................................................................2
Statement of Compliance.............................................................................................................................3
A.
Protocol Summary ................................................................................................................................4
B. Introduction..............................................................................................................................................6
C. Study Objectives.....................................................................................................................................13
D. Study Design...........................................................................................................................................14
E. Study Population ....................................................................................................................................22
e.1: Inclusion and Exclusion Criteria...........................................................................................................23
F. participant discontinuation/ withdrawal................................................................................................29
G. Study Assessments and Procedures.......................................................................................................29
H. Statistical Considerations.......................................................................................................................33
I. Regulatory And Operational Considerations ...........................................................................................37

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
3
STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
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A. PROTOCOL SUMMARY
A.1: Synopsis
Title: Investigating a Response Modulation Hypothesis of Socioemotional Processing associated 
with Alcohol Use Disorder
Study Description: In the first stage, participants will undergo functional magnetic resonance 
imaging while looking at socioemotional stimuli and alcohol cues and will pilot a neurofeedback 
training protocol. Personality traits and executive function will also be investigated. In the 
second stage, inpatient participants with alcohol use disorder will be randomly assigned to 
receive active or sham neurofeedback. Participants will undergo two functional magnetic 
resonance imaging sessions including looking at socioemotional stimuli and alcohol cues, resting 
state fMRI, and real time neurofeedback during alcohol craving. Ability to inhibit attention to 
alcohol cues and craving will be assessed prior to and following the neurofeedback as well. 
Participants will be contacted approximately 1 month, 3 months, and 6 months post release from 
inpatient treatment to assess outcomes.
Objectives: The purpose of this protocol is to understand the mechanism whereby neural 
processes of socioemotional cognition associated with alcohol use disorders lead to negative 
drinking consequences. This study is a two-stage procedure to both provide evidence of a 
response modulation deficit associated with socioemotional processing in individuals with 
alcohol use disorder and investigate how moderating that deficit affects socioemotional 
processing and negative drinking consequences.
Endpoints: Brain engagement during exposure to socioemotional stimuli, alcohol cues, and 
neurofeedback training (fMRI-Scan Portion)
Study Population: Community participants both with and without alcohol use disorder and 
inpatients with alcohol use disorder
Phase: Interventional
Description of Sites/Facilities Enrolling Participants: NIH Clinical Center, Bethesda, MD
Description of Study Intervention:  Realtime fMRI Neurofeedback Training
Study Duration: 5 years
Participant Duration: 1 day – 7 months

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
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A.2: Schema/ Schedule of Activities

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
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B. INTRODUCTION
B.1: Study Rationale
In the current protocol, we plan a two-stage investigation of the response modulation hypothesis 
as a mechanism for abnormalities in socioemotional processing and negative drinking 
consequences in individuals with AUD. In Stage 1, we will conduct a study of implicit 
socioemotional processing while exposed to alcohol versus neutral cues in community AUD 
versus healthy community volunteers (HCVs). Then, in Stage 2, we will use real time functional 
magnetic resonance imaging (rt-fMRI) neurofeedback as an investigational tool to guide 
treatment seeking inpatients with AUD in reducing the salience of alcohol cues. The results will 
be consistent with the hypothesized response modulation hypothesis if individuals who receive 
neurofeedback have a reduction of deficit associated with socioemotional processing, and if the 
individuals who receive neurofeedback have less negative drinking consequences at follow-up. 
A total of 86 individuals with AUD and 30 HCVs will be studied using: a) whole brain 
functional imaging during a socioemotional processing task, b) cognitive and behavioral 
measures of attention, including eye tracking, and c) self report measures of executive function, 
empathy, moral reasoning, and personality. 30 individuals with AUD and 30 HCVs will 
participate in a 1 session initial study of socioemotional processing with a neurofeedback pilot 
component. Then, 56 treatment-seeking patients with AUD will complete two sessions of a rt-
fMRI protocol with active NF (n = 28) or with sham NF (n = 28), and will repeat (a) and (b) 
following neurofeedback. Following departure from inpatient treatment, patients will be 
contacted at three time points (approximately 1 month, 3 months, and 6 months post-treatment) 
to collect outcome data including: alcohol use, community functioning, and aggression, 
victimization, and crime. 
B.2: Background
Alcohol Use Disorder and Socioemotional Processing:
Alcohol use is extremely prevalent in the United States; according to the 2015 National Survey 
on Drug Use and Health, 56% of adults report drinking in the last month (SAMHSA, 2015). 
More importantly, problematic drinking effects nearly half of those drinking alcohol, with 27 
percent of people reporting binge drinking and 7 percent reporting heavy alcohol use in the last 
month; in fact, 23 % of alcohol drinkers in the United States are estimated to have alcohol use 
disorder (AUD). Excessive alcohol use has major impacts on individuals and society; the Centers 
for Disease Control and Prevention estimates that 88,000 people die per year from alcohol 
related causes, that 10% of children in the US lives with parents with alcohol problems, and that 
alcohol misuse costs about $249 billion every year in the United States (Sacks et al., 2015).

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
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Much of this cost of alcohol misuse is related to negative consequences of using alcohol, 
including lost workplace productivity, criminal justice costs, and motor vehicle accident costs. 
There is an established relationship between excessive alcohol use and crime commission (Lee, 
2013; Popovici et al., 2012), financial difficulties (Gual et al., 2009), intimate partner aggression 
(Lewis et al., 2015; Watkins et al., 2015), poor work performance (Gual et al., 2009; Mangione 
et al., 1999), and homicide (Pridemore, 2004). In fact, according to a Bureau of Justice Statistics 
study, 37% of violent criminals report being under the influence of alcohol at the time of their 
offense, and more than 50,000 additional individuals are estimated to be convicted of DUI/DWI 
and alcohol-related public order offenses per year (Snyder et al., 2012).
Negative drinking outcomes may in part be driven by socioemotional processing deficits related 
to alcohol use disorder. Chronic alcohol users are more likely to 
make utilitarian moral judgments (Khemiri et al., 2012), similar 
to other patient groups (Baez et al., 2014; Koenigs et al., 2012); 
this utilitarian moral bias is predicted by deficits in decoding 
emotional facial expressions (Carmona‐Perera et al., 2014). 
Acute alcohol intoxication in social drinkers also increased 
utilitarian judgment (Duke and Bègue, 2015). Moral 
disengagement has also been found to be related to alcohol use 
and binge drinking in adolescents (Newton et al., 2014), while 
moral reasoning impairments are associated with driving under 
the influence of alcohol (Denton and Krebs, 1990; Little and 
Robinson, 1989), and alcohol dependence (Brevers et al., 2013). 
Theory of mind processes may also be selectively impaired by 
alcohol use; one study found emotion recognition deficits in 
individuals with AUD during theory of mind processes but did 
not find deficits in intention attribution (Nandrino et al., 2014), 
while another found that acute alcohol led to reduced emotion 
recognition and identification of social rule violations (Mitchell 
et al., 2011).The neurobiological underpinnings of these 
socioemotional behavior atypicalities are not yet clearly defined, 
though several studies support the sense that these correspond to 
differences in neural engagement. Acute alcohol intoxication leads to more effortful emotion 
regulation, as demonstrated in an EEG study of emotional response inhibition by larger N200 
amplitude during response inhibition for emotional stimuli and reduced P300 during response 
execution for emotional stimuli (Euser and Franken, 2012). fMRI investigation has demonstrated 
that alcohol consumption reduces anterior insula response during emotional face recognition 
(Padula et al., 2011), consonant with studies finding acute alcohol administration leading to 
specific deficits in facial emotion decoding (Attwood & Munafo, 2014; though some studies do 
Figure 1. Neural engagement during moral 
processing related to years of regular alcohol use

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
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not find this i.e.,Felisberti and Terry; Walter et al., 2011). The anterior insula is an area of the 
brain strongly implicated in empathy (Singer et al., 2009). Despite these findings, little work has 
been done on the association between alcohol use disorder and integrated socioemotional 
processing, although there is significant overlap between brain regions involved in moral 
cognition, empathy, and theory of mind (Bzdok et al., 2012). Initial, unpublished work by an 
associate investigator on this protocol found during explicit moral processing, years of regular 
alcohol use was associated with reduced hypothalamic but increased pre-supplementary motor 
(SMA) and temporoparietal junction (TPJ) response, suggesting that problem alcohol users may 
engage the pre-SMA to suppress non-task based activity in hypothalamic and striatal areas while 
relying on TPJ response to make social rule based judgment (see Figure 1; Fede et al., 
unpublished). Indeed, this pattern of compensation during explicit moral processing mirrors 
findings of the neural correlates of explicit moral processing in stimulant users (Fede et al., 
2016).
Response Modulation Hypothesis:
These findings in AUD are consistent with a mechanism for impaired socioemotional decision 
making put forward in the psychopathy literature, termed the response modulation hypothesis 
(Gorenstein and Newman, 1980). Rather than a deficit in empathy or socioemotional processing, 
Newman and colleagues find evidence that psychopaths may fail to modulate attention to 
peripheral stimuli (neutral or negative) outside of goal directed behavior (Lorenz and Newman, 
2002; Newman et al., 1987; Newman et al., 1997). Newman and Lorenz suggest that this can be 
specific to situations in which the dominant cues are particularly salient to the individual 
(Newman and Lorenz, 2003), such as alcohol cues are to an individual with AUD. This failure to 
modulate response (i.e., attend to information on the periphery) results in a lack of awareness 
that behavior is causing problems, and lack of ability to regulate the problem behavior. Although 
premorbid deficits in response modulation may lead to failure to develop the innate mores that 
underlie typical socioemotional function (Blair, 2007), the deficit can be corrected in laboratory 
settings through effortful or external remodulation of focus towards the stimuli of interest; for 
example, psychopaths display a deficit in fear potentiated startle under standard conditions, but 
normal fear potentiated startle response when directed towards threat stimuli (Newman et al., 
2010).   
Despite the extensive literature supporting the response modulation hypothesis in psychopathy, 
no investigation has been done into whether this mechanism may also drive socioemotional 
deficits sometimes associated with alcohol use. We propose that deficits in response modulation 
in the presence of alcohol cues drive atypical socioemotional processing and resulting negative 
drinking behaviors. Previous studies have shown that individuals with AUD have an attentional 
bias towards alcohol stimuli (McAteer et al., 2015; Weafer and Fillmore, 2013), and that the 
presence of alcohol stimuli reduces inhibitory control (Petit et al., 2012; Weafer and Fillmore, 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
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2015). Moreover, individuals with AUD have reduced neural response to emotional stimuli in 
the presence of alcohol cues compared to neutral cues (Gilman and Hommer, 2008). These 
findings are consistent with the response modulation hypothesis, but have not been extended to 
socioemotional processing or behavior.
Establishment of deficits in response modulation as a mediator of the relationship between AUD 
and negative drinking outcomes and other socioemotional problems would provide important 
insights into treatments designed to reduce the impact of AUD. For example, the response 
modulation hypothesis in psychopathy has led to the development of cognitive training that 
improves consideration of contextual information and affective processing (Baskin-Sommers et 
al., 2015) and goal-oriented rather than punishment-oriented incarceration programs that 
significantly reduce recidivism (Caldwell et al., 2007). In the case of AUD, this response 
modulation mechanism would indicate therapies like mindfulness-based relapse prevention, 
which encourages patients to be more aware of internal and external experiences but not to be 
caught up in or dwell on them, allowing patients to choose more modulated responses 
(Witkiewitz et al., 2014). Currently, less than 10% of people affected by AUD receive treatment 
(SAMHSA, 2015). The most effective interventions are brief intervention and motivational 
enhancement, but only around 70% of studies into these interventions indicate an effect of 
treatment (Miller and Wilbourne, 2002). Failure to address specific neural mechanisms may 
contribute to the inconsistent performance of these therapies.
Real Time Functional Magnetic Resonance Imaging Neurofeedback:
Real time fMRI neurofeedback (rt-fMRI-NF) guided neuromodulation is supported by many 
proof-of-concept studies. rt-fMRI-NF training enabled participants to upregulate regional brain 
activity including: the anterior insula (Caria et al., 2010; Ruiz et al., 2013), amygdala (Zotev et 
al., 2011), SN/VTA(Sulzer et al., 2013), and inferior frontal gyrus (Rota et al., 2009), as well as 
to downregulate subgenual anterior cingulate (ACC) activity (Hamilton et al., 2011). Some early 
work supports sustained effects of rt-fMRI-NF. A clinical trial by Young and colleagues found 
two sessions of rt-fMRI-NF focusing on training patients to upregulate the amygdala 
significantly reduced depression symptoms one week later in major depression patients (Young 
et al., 2017). Also, rt-fMRI-NF guided modulation of the rostral ACC was related to reductions 
in levels of chronic pain (deCharms et al., 2005; Emmert et al., 2014; Guan et al., 2015). In some 
cases, training and transfer effects of neurofeedback may be sustained up to 14 months post-
initial training (Robineau et al., 2017).
The rt-fMRI-NF technique has previously been investigated for feasibility in substance use 
samples. It has enabled cocaine users to downregulate the SN/VTA (Kirschner et al., 2017), and 
in smokers, nicotine craving was reduced via downregulation of ventral ACC (Brady et al., 2015; 
Hanlon et al., 2013). Social heavy alcohol drinkers have been able to downregulate their VS 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
10
responses to alcohol cues (Kirsch et al., 2016); in another study, individuals with AUD 
modulated neural response to alcohol cues in individualized ROIs (ACC, dorsolateral prefrontal 
cortex (PFC), or insula), and rt-fMRI-NF corresponded to reduced craving (Karch et al., 2015). 
Initial evidence from conference proceedings indicates that rt-fMRI-NF may also be able to 
reduce short-term impulsivity in social drinkers (Deshpande et al., 2017). Typically, rt-fMRI 
neurofeedback designed to limit craving is administered in one to three sessions, although 
Hanlon and colleagues reported significant feasibility problems with 3 neurofeedback visits 
(2013).
B.3: Risk/Benefit Assessment
Though risks in the study are likely to be minimal, aspects that may cause any form of 
discomfort will be explained to subjects with written details provided in the informed consent 
document. These will include:
Known Potential Risks

Urine Drug Screen: Results of the drug screen will be part of the participant’s medical 
record. This record could be accessed for employment, insurance, or other purposes.

Self-Report Measures: The participant may experience distress related to discussion of 
potentially negative life events, such as interpersonal conflict, legal trouble, and 
addiction. 

Attention Tasks: Participants may experience frustration or boredom while completing 
some of the attention and thinking tests. 

Bar-Like Environment: Subjects will complete tasks in a bar-like environment that is 
designed to make them think about alcohol. Participants may express distress by feeling 
like they want to drink alcohol. 

Alcohol Cues: Participants may experience distress related to craving when shown visual, 
olfactory, and environmental alcohol stimuli. 

Pictures of Negative Things: Some of the pictures viewed in the MRI are disturbing. 
Subjects may feel upset or uncomfortable when looking at the pictures.

Neurofeedback: Participants who participate in ft-fMRI-NF training may experience 
frustration when trying to modulate their brain activity.

MRI Risk: There are no known long-term risks of MRI scans. However, people are at risk 
for injury from the MRI magnet if they have certain metal objects in their bodies. These 
include implanted electrical devices such as pacemakers, cochlear implants, delivery 
pumps or brain stimulators. People with implanted metal such as aneurysm clips (metal 
clips on the wall of a large artery), permanent eyeliner, shrapnel fragments or some dental 
implants and prostheses (including metal pins and rods, heart valves) are also at risk. 
Welders and metal workers are also at risk for injury because of possible small metal 
fragments in the eye.

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The risk of MRI to a fetus is not known. Therefore, volunteers who are pregnant or 
planning to become pregnant during the study cannot participate. For female participants, 
a urine pregnancy test will be given no more than 24 hours before each MRI session. If a 
pregnancy test is positive or uncertain, she may not be in the study.
Individuals with back problems may have back pain or discomfort from lying in the 
scanner. Individuals with fear of confined spaces may become anxious during an MRI.
The noise of the MRI machine can be loud enough to damage one’s hearing, especially in 
people who already have hearing loss. The participant will be fitted with earplugs and/or 
headphones to muffle the sound. The participant may still experience some temporary 
problems hearing soft sounds after the session. 
If the expanding foam is used to stabilize participant’s head in the magnet, it may get 
warm for a few minutes while it expands. It is possible that the participant could feel 
discomfort or get a mild burn from the heat. The chemicals in the foam may cause skin or 
eye irritation if in touch with the participant’s face and eyes. However, to protect the 
participant, the foam is always inside two plastic bags.

Claustrophobia: People with a fear of closed spaces may become scared during an MRI. 

Surveys and Interviews: Questions about money, jobs, housing, crime, and conflicts with 
people may make some people uncomfortable. Interviews, questionnaires, and tasks may 
cause frustration or boredom. 

Costs and stress resulting from discovery of previously undiagnosed abnormalities: It is 
possible that the study procedures will reveal previously undiagnosed abnormalities (e.g., 
the potential finding of a tumor from the brain MRI studies). If this happens it may result 
in stress and time and financial costs to the study participant and their family. The 
investigators are not assuming responsibility for such potential consequences, but will 
make every effort to help such families to deal with whatever findings arise. 

Confidentiality: Participation in research may mean a loss of privacy. Study records will 
be kept as confidential as possible under the law. No individual identities will be used in 
any reports or publications resulting from the study. Study information will be coded with 
a code number unique to the study. All information will be kept in locked files, with 
access limited to study personnel. A Certificate of Confidentiality will protect 
information from legal requests for information disclosure (i.e., subpoenas), although 
may not provide complete protection. 
Known Potential Benefits
Participants may receive no direct benefit from participation in this study. Patients who 
participate in active rt-fMRI-NF training might experience improvements in suppressing craving. 
This study may lead to development of new interventions designed to reduce negative drinking 
outcomes, and may increase the overall understanding of the neural correlates of alcohol use 
disorder.
Assessment of Potential Risks and Benefits

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
12
Risks will be minimized in the following way:

All study participants will be accompanied at the NMR Center by a study team member. 
All study team members have completed CPR Training, NMR Center Safety Training, 
and the NMR Center Emergency Preparedness Training, including standard emergency 
procedures to be followed in the event of a fire (code red) or if a participant is in 
respiratory and/or cardiac arrest (code blue). These procedures include removing and 
evacuating the participant from the scanner, contacting the appropriate emergency 
response teams as well as the MAI of the study, and being aware of the locations of 
emergency items such as the emergency drug box, crash cart, AED, and fire extinguisher. 
Presence of a healthcare professional will not be required in the MR sessions for any 
participants in this study. In the event that a subject communicates distress while 
completing tasks, they will be given the option to choose not to answer any questions and 
can stop at any time. If they are bothered by alcohol craving following exposure to the 
bar-like environment or other alcohol-related cues, we will have staff on hand to talk with 
them about getting help. Subjects will be permitted to stop if they experience distress 
from disturbing images shown in the MRI scanner. If they are still distressed after 
stopping, we can have clinical staff talk to them or give them information about how to 
get help to feel better. Everyone having a MRI scan will be given earplugs and/or 
headphones. If the participant experiences claustrophobia in the MRI machine, they can 
press an alarm in the scanner and we will remove s/he from the MRI machine 
immediately. Subjects can communicate with staff at all times and can be removed from 
the scanner at any time for any reason and be given earplugs or headphones for hearing 
protection. Subjects may stop participation at any time for any reason. Clinical staff are 
available to provide consultation if needed. 
Participants' confidentiality will be maintained by having data coded to mask 
participants’ identities. Further, files containing participant names and the master list of 
participants will be kept in a locked file under the supervision of the Principal 
Investigator. All participants will be provided with a daytime phone number through 
which Dr. Momenan may be contacted to answer questions. 
Discovery of previously unknown abnormalities may result in stress and time and 
financial costs to the study participant and their family. The investigators are not 
assuming responsibility for such potential consequences but will make every effort to 
help such families to deal with whatever findings arise.
All staff will be trained in matters relative to confidentiality and other forms of 
participant risk. If at any time a participant expresses discomfort over any aspect of the 
study, staff will be told to discontinue the distressing activity and seek consultation so as 
to minimize risk. The confidential nature of all data collected in this study will be 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
13
thoroughly explained to potential participants, as will data safeguarding procedures (e.g., 
locked file cabinets, password controlled databases and file servers).
Participants who have any questions regarding their informed consent or any aspects of 
the study at any time will be directed to the Principal Investigator. Participants who have 
questions regarding their rights as Human Research Subjects will be referred to the 
Clinical Center Patient Representative at (301) 496-2626.
Participants who display a clinically significant increase in craving during a study session 
will be counselled by NIAAA medical staff after completing the session. They will then 
be advised of care options available to them. For inpatients, we do not plan for them to 
leave treatment for at least 48 hours after they see the alcohol pictures or until they do not 
feel a craving for alcohol unless they choose to leave “against medical advice.” 
Participants may be monitored for signs of craving-related distress while in the alcohol-
cued environment by study staff in another room through a closed-circuit video display 
(no sound). No data (electronic or otherwise) will be recorded during these 
observations.  Upon observing any visible signs of distress, such as emotional or physical 
reactions the clinical staff (the MAI or CRNPs) will be notified immediately for 
assessment and to provide the appropriate care.

Availability of Medical or Professional Intervention: Risks associated with the study 
procedures described above will be minimized by giving participants freedom to decline 
to answer distressing questions. Adequate preparation before MRI sessions and 
scheduling adequate time to set-up and complete the procedure will minimize pressure on 
subjects. Clinically-relevant incidental findings will be reported to subjects and a referral 
will be made to appropriate treatment settings, facilitated by the study investigators. If 
participants experience distress related to participation in the research study, consultation 
with medical staff or information about community resources can be arranged by the 
study investigators
As described above, the minimal study risks are further minimized through study procedures, 
and the study has the potential to provide information about socioemotional processing and 
negative drinking outcomes. 
C. STUDY OBJECTIVES

Primary Objectives:
1. Use fMRI to investigate whether response modulation deficits in the 
presence of alcohol drive AUD-related abnormalities in socioemotional 
processing.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
14
2. Use rt-fMRI-based neurofeedback to aid self-modulation of alcohol 
craving.

Secondary Objectives:
1. Investigate drinking behaviors and consequences associated with active 
versus sham neurofeedback.
2. Investigate how measures of resting state fMRI change before and after 
neurofeedback.
3. Explore how alcohol use severity is associated with the neural correlates 
of socioemotional processing in an alcohol cued environment.
4. Asses the relationship between behavioral and self-report assessments and 
the functional imaging data.

Tertiary Objective: To explore predictors of future drinking behaviors by 
investigating the associations between baseline measures of alcohol use, personality, 
cognitive function, and socioemotional processing, with future drinking behaviors 
and negative drinking consequences. 
D. STUDY DESIGN
Overall Design

Single Site – NIH Clinical Center, Bethesda, MD

Primary Hypotheses:
Based on the general hypothesis that a deficit in response modulation in the context of alcohol 
cues leads to reduced socioemotional processing in laboratory and real-world scenarios, and 
based on published literature, we predict:
1) During implicit socioemotional picture viewing, in individuals with AUD but not 
HCVs, a) there will be less neural engagement in socioemotional brain regions 
(mPFC, PCC, amygdala, parahippocampal gyrus, TPJ, dlPFC, frontal pole) in 
alcohol-distractor conditions compared to neutral-distractor conditions, b) the ratio of 
eye gaze time on socioemotional compared to distractor stimuli will be lower for 
alcohol compared to neutral distractors, and c) baseline levels of alcohol use severity 
and attentional deficits will predict greater attenuation of neural activity.
2)  a) Active but not sham NF will relate to a within-patient increase in neural 
engagement of socioemotional brain regions (as in 1a) during socioemotional 
processing in the presence of alcohol versus neutral distractor cues and greater whole 
brain connectivity and synchrony during resting state, b) active but not sham NF will 
relate to within-patient reduction in alcohol-cued craving, and c) active but not sham 
NF will relate to within-patient improvement in attention tasks. 
3) In long term follow up, a) greater deficits in alcohol-cued socioemotional processing 
in the brain will predict less time to relapse, more drinking days, less community 
functioning and greater incidence of violence or legal contact, but that b) individuals 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
15
who participated in the active NF protocol would have better outcomes than those 
who participated in sham NF (less drinking days, greater time to relapse, less negative 
drinking consequences and better community functioning), and further c) within-
patient improvement in neural engagement during socioemotional processing in the 
presence of alcohol versus neutral distractor cues would explain the relationship 
between NF and outcomes.
Study Procedures.
For a complete flowchart of procedures, see Figure 2.
Stage 1:
Magnetic Resonance Imaging: All MRI scans will be conducted in a 3 Tesla MRI scanner at the 
NIH Clinical Center. Individuals in the HCV and AUD group will complete one MRI session: 1) 
a localizer, 2) a whole brain structural scan, 3) whole brain socioemotional task fMRI scan, 4) a 
functional locator scan for use during rt-fMRI, and 5/6) two blocks of rt-fMRI-NF. We expect 
that scan order may vary for technical reasons; the actual order of scans will be recorded. 
Participants will then complete post-scan questionnaires about the socioemotional task and rt-
fMRI-NF procedure.

Socioemotional Alcohol Attention Task (SAAT): The task will consist of presentation 
of a picture cue stimulus alongside a picture distractor stimulus. It was designed 
based on the fMRI task of implicit moral processing used in Caldwell et al., 2015. 
The simultaneous presentation of an alcohol distractor follows principles of biased 
competition tasks, such as Pessoa et al., 2002.  Participants will be instructed to press 
a button to indicate if the picture stimuli are “indoors” or “outdoors”. Three types of 
cue stimuli will be used: negative socioemotional (e.g., a child being abused), 
negative emotional (e.g., child crying), and neutral (e.g., a child writing on a 
chalkboard). Two types of distractor stimuli will be used: alcohol and non-alcohol 
neutral. Images will be selected from the International Affective Picture System 
(IAPS) pool, as well as similar images from other sources. Each type of cue stimulus 
will be presented with each type of distractor stimulus. Finally, stimuli will be 
counter-balanced with equal probability across location on screen (left or right) and 
location (indoor or outdoor). Stimuli will be presented in a randomized order. Each 
pair of images will be presented for 3 seconds, with an inter-stimulus interval 
(consisting of presentation of a fixation cross) jittered for 1-3 seconds. 40 of each cue 
stimuli type will be used for 120 (60 alcohol and 60 non-alcohol distractor cues) will 
be used, which are uniformly distributed among stimuli types. The total run time of 
the task will be approximately 10 minutes.
This task is designed to engage socioemotional processing circuits, including medial 
prefrontal, limbic, and temporoparietal areas. An eye-tracking device will be used to 
record eye gaze during SAAT in order to measure time spent actively attending to 
each stimuli. A post-scan questionnaire will ask subjects to rate each distractor 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
16
stimuli on evoked craving and each cue stimuli on arousal, valence, social 
acceptability, and moral content.

Real Time Functional Magnetic Resonance Imaging Neurofeedback (rt-fMRI-NF): 
The rt-fMRI-NF procedure will consist of an alcohol cued rt-fMRI task, such as the 
one used in Karch et al., 2015. In that study, addiction-related cues were presented to 
subjects during fMRI and subjects were instructed to decrease their response to the 
addiction cue (as indicated through real time feedback presented through a graphical 
thermometer). The purpose of this task at this stage is to develop a real-time fMRI 
procedure that effectively allows individuals to moderate craving response to alcohol 
cue stimuli. The following parameters will be used as a starting point for this task. 
However, the individual sessions will also be examined post-hoc and the task may be 
modified as appropriate.
We will use a functional localizer, consisting of alcohol craving, food craving and 
non-craving (neutral, e.g. chair, fan) blocks, to identify typical, non-modulated neural 
brain response to craving signals. Participants will be first shown a block of neutral 
pictures, a block of food pictures, then a block of alcohol pictures (specific to 
beverage type of choice e.g., beer, wine, liquor). Food craving pictures will be used 
during piloting given that HCVs are not expected to have significant craving 
associated with alcohol use. Fixation crosses will be presented in the center of the 
display prior to each block. Four 20 second blocks of each type will be presented. 
Each block will contain 4 images of a specific type. Each image will be displayed for 
5 seconds without any inter-stimulus interval. 
We will display neurofeedback based on mean signal in five regions of interest 
(ROIs): VTA/SN, anterior insula, VS, dlPFC and mPFC/vACC. These regions have 
been used in prior neurofeedback studies, indicating that individuals are capable of 
modulating activity in these regions in response to neurofeedback (Karch et al., 2015; 
Kirsch et al., 2016; Sherwood et al., 2016; Young et al., 2017). The functional 
localizer task will be used to establish baseline alcohol cue related activation in each 
ROI; participants will receive neurofeedback based on percentage signal change from 
that baseline for each ROI. The functional localizer task will also be used to define 
baseline for the ROI-based neurofeedback training procedure, where participants will 
be asked to modulate their neural response during craving from that baseline. 
BOLD fMRI data during rt-fMRI will be processed in real-time using AFNI to 
measure and compute the signal changes associated with craving downregulation, 
which establishes the neurofeedback stimulus display. The stimulus display will 
consist of craving cue images alongside a brain activity “thermometer”. 
Hemodynamic response and signal processing will account for additional delay 
between subject cognition and feedback; BOLD response to a stimulus typically lags 
for about 3-4 seconds, then proceeds over 4-6 seconds, and feedback computation 
takes approximately 1 second. 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
17
A composite index will be calculated from the ROIs as part of the computation in real 
time to provide feedback to the participant on a 100 point “thermometer” scale. We 
expect this composite index to be the average percent signal change from individual 
baseline. Corresponding to downregulation of craving, we expect the VTA/SN, 
anterior insula, VS, dlPFC and ACC/mPFC values to be to be negative, as they have 
been in previous studies of neurofeedback associated downregulation of alcohol 
craving in individuals with AUD (Karch et al., 2015; Kirsch et al., 2016). Participants 
will be told that the level indicated on this 100-point “thermometer” represents their 
response to the alcohol pictures. Baseline will be defined as 80 on this 100-point 
scale.
𝑡𝑒𝑚𝑝𝑒𝑟𝑎𝑡𝑢𝑟𝑒= 80 ― 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 % 𝑠𝑖𝑔𝑛𝑎𝑙 𝑐ℎ𝑎𝑛𝑔𝑒
𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 % 𝑠𝑖𝑔𝑛𝑎𝑙 𝑐ℎ𝑎𝑛𝑔=
𝑆𝑉𝑇𝐴(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒) ― 𝑆𝑉𝑇𝐴(𝑐𝑢𝑟𝑟𝑒𝑛𝑡)
𝑆𝑉𝑇𝐴(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒)
.𝑢𝑉𝑇𝐴(𝑡) + 𝑆𝐴𝐼(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒) ― 𝑆𝐴𝐼(𝑐𝑢𝑟𝑟𝑒𝑛𝑡)
𝑆𝐴𝐼(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒)
.𝑢𝐴𝐼(𝑡)
+ 𝑆𝑉𝑆(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒) ― 𝑆𝑉𝑆(𝑐𝑢𝑟𝑟𝑒𝑛𝑡)
𝑆𝑉𝑆(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒)
.𝑢𝑉𝑆(𝑡)
+ 𝑆𝑑𝑙𝑃𝐹𝐶(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒) ― 𝑆𝑑𝑙𝑃𝐹𝐶(𝑐𝑢𝑟𝑟𝑒𝑛𝑡)
𝑆𝑑𝑙𝑃𝐹𝐶(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒)
. 𝑢𝑑𝑙𝑃𝐹𝐶(𝑡) + 𝑆𝐴𝐶𝐶(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒) ― 𝑆𝐴𝐶𝐶(𝑐𝑢𝑟𝑟𝑒𝑛𝑡)
𝑆𝐴𝐶𝐶(𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒)
.𝑢𝐴𝐶𝐶(𝑡)
𝑢𝑉𝑇𝐴(𝑡) + 𝑢𝐴𝐼(𝑡) + 𝑢𝑉𝑆(𝑡) + 𝑢𝑑𝑙𝑃𝐹𝐶(𝑡) + 𝑢𝐴𝐶𝐶(𝑡)
Notes: S = signal where SROI(t) is the signal associated with craving in the indicated ROI, t = timepoint 
[baseline or current], u = step function where uROI(t) are zero for each subject if the specific ROI does 
not present any signal changes during the localization and 1 otherwise. ROIs are ventral tegmental area 
(VTA), anterior insula (AI), ventral striatum (VS), dorsolateral prefrontal cortex (dlPFC) and anterior 
cingulate (ACC).
Participants will be directed to try to reduce their response to a target level (indicated 
on the thermometer feedback image), and will be given time prior to the task to think 
about individualized strategies to reduce craving response. During initial piloting, the 
only strategy provided to them will be to “try not to crave”. For every trial where the 
target level is hit for at least 1 second, the participant will earn $0.50 and receive 
positive feedback. Each trial will last 15 seconds, with 50 trials per block. Target 
level will increase in difficulty progressively. After 3 successful trials (sequentially), 
thresholds will become further from baseline, leading to a more difficult task. If there 
are 3 unsuccessful trials in a row, the threshold will revert to 50% of the previous 
successful threshold. If response drops below 15% of baseline for three seconds, a 
message will be displayed reminding the participant to pay attention to the task and a 
noise will sound via headphones; participants will lose $0.50 per round where they 
were not attending. This is to ensure participants pay attention to the task. Subjects 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
18
will start with $5.00 “in the bank” to allow for these loses. Although a negative 
monetary value is possible, no money will be owed or taken out of other 
compensation for participation.
All participants will receive active neurofeedback during this piloting phase. No 
control procedure is necessary in neurofeedback piloting of Stage 1 because it aims at 
testing and refining the neurofeedback parameters and procedure. BOLD response 
associated with cue reactivity will be compared between neurofeedback 
downregulation and baseline. Baseline data are those time points collected during  
“functional localizer” described above. It has already been established that 
neurofeedback compared to control allows individuals to regulate neural activity in 
the SN/VTA (Sulzer et al., 2013), VS (Kirsch et al., 2016), anterior insula (Caria et 
al., 2010), and ACC (Karch et al., 2015). Neurofeedback is also already established as 
feasible in alcohol-using and AUD populations (Karch et al., 2015; Kirsch et al., 
2016), as well as in other patient groups such as depression (Young et al., 2017) and 
stroke (Liew et al., 2016). Feasibility of ROIs selected and patient performance are 
not being investigated in this pilot, since it is already demonstrated. Moreover, 
differential effects of neurofeedback and group effects of neurofeedback are not being 
investigated at this stage of the study.
If following initial piloting, this neurofeedback calculation and display procedure is 
not sensitive to neuromodulation during alcohol cueing, alternative calculation 
procedures will be explored. For example, if we find evidence of increase in neural 
engagement associated with downregulation in some ROIs, we will make the 
following change: prior to calculating the average percent signal change, the sign of 
these “positive” down regulation correlates will be reversed. A post-scan 
questionnaire will ask subjects to rate each stimuli on evoked craving, to rate the 
overall difficulty of self-modulating responses to alcohol and food cues, and to report 
strategies used for down regulation.
Based on initial piloting, a neurofeedback calculation procedure using a support 
vector machine (SVM) machine learning algorithm is more greatly indicated than a 
ROI based approach. SVM compares new data points across the whole brain to the 
brain-states identified in the “functional localizer” step and provides individualized 
feedback based on proximity to “neutral” versus “craving” states. This technique is 
well established (Fede et al., 2020; LaConte, 2011). However, the ROI based 
approach showed more improvement in self-reported craving. Therefore, in Stage 2 
we have utilized the ROI based approach.
Cognitive Assessment: We will administer the following tests: the Continuous 
Performance Test (CPT; following Conners et al., 2000), the Stroop Color and Word Test 
(Golden and Freshwater, 1978), and the Behavior Rating Inventory of Executive 
Function (BRIEF-A; Gioia et al., 2000). We selected these tasks to provide information 
on generalized attention, divided attention, and general executive function, but to 
minimally add to the assessments subjects will undergo. 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
19

The Continuous Performance Test (CPT) will be administered in a neutral 
environment order to assess general attention-related problems in participants. This 
will help us quantify individual differences in attention that are not specifically 
related to response modulation in a biased competition context. It can be administered 
on a computer and typically takes 15 minutes to administer. The CPT will be 
implemented using PsychoPy (Peirce, 2007). 

The Stroop Color Word Test will be administered in both a neutral and an alcohol 
cued environment to assess divided attention. It takes approximately 5 minutes to 
administer. This will help us asses the ability of participants to inhibit attention to 
peripheral stimuli.

The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) will 
be administered in a neutral environment to assess self-reported ability on nine 
executive functioning subscales (Gioia et al., 2000). It will help us asses the baseline 
ability of participants to inhibit, self and task monitor, plan, and control emotional 
response, processes that may be important moderators of socioemotional processing 
or drinking outcomes. This self-report measure has several advantages over a 
traditional full neuropsychologic assessment; it is less time-consuming (15-20 
minutes) and can be administered electronically. 
Self-Report Assessments: A modified version of the Alcohol Craving Questionnaire 
(ACQ; Higley et al., 2011) will be administered pre-and post-scan in an alcohol cued 
environment. Questionnaires designed to identify individual differences and traits related 
to socioemotional processing and drinking behaviors will be also be administered: The 
MacArthur Scale of Subjective Social Status (Adler and Stewart, 2007), the Moral 
Foundations Questionnaire (MFQ; Davies et al., 2014), Interpersonal Reactivity Index 
(IRI; Davis, 1983), the Self-Report Psychopathy (SRP-II) scale (Paulhus et al., 2009), the 
Toronto Alexithymia Scale (TAS; Bagby et al., 1994), and the State General Food 
Craving Questionnaire (GFCQ-S; Nijs et al., 2007). We are aware that honesty on self-
report measures are a limitation of their use; however, these are well validated and the 
ability of participants to fill them out quickly means that the inconvenience for them is 
much lower and their use is more feasible than 2 hour clinical interviews (such as the 
Psychopathy Checklist Revised).

The MacArthur Scale of Subjective Social Status will be used to assess 
socioeconomic status (SES) in addition to objective demographics. This scale shows a 
picture of a ladder and asks individuals to graphically indicate where they are on the 
ladder compared to their community, and then compared to most people in the United 
States.

The Moral Foundations Questionnaire (MFQ) assesses individual differences in 
several domains of moral values including Harm/Care, Fairness/Reciprocity, 
Ingroup/Loyalty, Authority/Respect, and Purity/Sanctity. This scale asks individuals 
to indicate how they evaluate whether something is “right” or “wrong”. This will help 
us identify baseline differences in moral priorities that could moderate socioemotional 
cognition within or between groups.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
20

The Interpersonal Reactivity Index (IRI) assesses individual differences in empathy, 
particularly in four subdomains: perspective taking, fantasy, empathetic concern, and 
personal distress. This will help us identify baseline differences in empathy and 
theory of mind that could moderate socioemotional cognition within or between 
groups.

The Self-Report Psychopathy (SRP-II) scale assesses individual levels of 
psychopathic traits in community, non-criminal samples. Psychopathy is a personality 
disorder made up of affective, interpersonal, antisocial, and lifestyle traits. 
Psychopathy is associated with moral transgressions, so this measure will help us 
identify baseline differences in levels of those traits that could moderate 
socioemotional cognition within or between groups. 

A modified version of the Alcohol Craving Questionnaire (ACQ) as used by Higley 
and colleagues (2011) will be administered in order to assess baseline and post-scan 
alcohol craving in an alcohol-challenge environment. This information will be used 
first to assess whether baseline levels of craving affect socioemotional processing and 
post-scan whether neurofeedback down regulation of craving transfers post-scan.

The State General Food Cravings Questionnaires (G-FCQ-S) assesses current food 
craving in general, particularly the desire to eat, anticipation of positive reinforcement 
from eating, anticipation of reduction in negative states from eating, preoccupation 
with eating, and physiological craving. This questionnaire will be administered at 
baseline and post-scan. This information will be used to assess whether 
neurofeedback down regulation of craving transfers post-scan, and whether baseline 
craving impacts cue reactivity. Time and content of last meal will also be recorded at 
baseline.

The Toronto Alexithymia Scale (TAS) assesses individual levels of alexithymia, 
particularly on three subdomains: difficulty describing feelings, difficulty identifying 
feelings, and externally-oriented thinking. This will help us identify baseline 
differences in emotional processing that could moderate socioemotional cognition 
within or between groups.
Stage 2:
AUD patients will complete two MRI sessions. During session 1, prior to completing their MRI, 
AUD patients will complete the cognitive, craving, and self-report measures described in Stage 
1. After consent but prior to participating in the study, patients will be assigned to active or sham 
condition. A master list, with access restricted to the PI and Lead AI, will contain the random 
assignment for subjects. We will collect baseline information for our outcome measures prior to 
scanning. Following the scan in session 1 and session 2, cognitive and alcohol craving measures 
will be collected again.
Magnetic Resonance Imaging: The first MRI session will occur within one week of admission, 
after active withdrawal (CIWA < 8 ), and will consist of: 1) a localizer, 2) a whole brain 
structural scan, 3) a whole brain resting state BOLD fMRI scan, 4) the whole brain SAAT fMRI 
scan, 5) a functional “craving” locator scan, 6/7) two blocks of rt-fMRI-NF, 8) a post-NF 
functional “craving” locator scan, 9) a post-NF whole brain resting state BOLD fMRI scan, and 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
21
10) post-NF SAAT fMRI scan. The second MRI session will occur within 21-28 days of the first 
MRI session, and will consist of: 1) a localizer, 2) a whole brain structural scan, 3/4) two blocks 
of rt-fMRI-NF, 5) a functional “craving” locator scan, 6) a whole brain resting state BOLD and 
fMRI scan, and 7) whole brain SAAT fMRI scan. We expect that scan order may vary or may 
need to be repeated for technical reasons; the actual order of scans will be recorded.

SAAT task: Three versions of the task will present the stimuli in different orders to be 
used prior to and post the NF scans. Participants will be counterbalanced to receive 
the versions in orders ABC, ACB, BCA, BAC, CAB, or CBA. 

Functional “craving” locator scan: This corresponds to the functional localizer scan 
used in Stage 1, but will also serve as a baseline measurement of the neural correlates 
of craving and as such, will be repeated after NF scans to assess changes. Three 
versions of the task will be used and counterbalanced as in the SAAT task, described 
above.

rt-fMRI-NF: Participants will be randomly assigned to receive either rt-fMRI based 
active or sham neurofeedback. This will be done using a random sorting algorithm to 
balance conditions. This will be a pseudo-double-blind study in that the patients and 
individuals working with patients (except the PI and Lead AI) will be blind to NF 
type. Participants who are assigned to the sham condition will be yoked to an active 
condition participant*. The rt-fMRI-NF protocol will be optimized based on piloting 
from Stage 1; however, the procedure used in Stage 2 will only contain alcohol 
craving cues, not food craving cues. Moreover, participants in Stage 2 will be given 
strategies other participants found useful for neuromodulation.
o
Sham condition: Sham neurofeedback will differ from active feedback only in 
that rather than displaying signal from the patient’s own neural signal, signal 
from his or her yoked active participant will be fed into the receiver and 
displayed to the sham condition patient. The sham condition patient will also 
be compensated at the same level as the active condition participant. The 
procedure will allow us to determine the effect of neurofeedback, regardless 
of perceived performance or monetary earnings.
Other MRI Scan Information. 

Various physiological measures such as heart rate, skin conductance, blood flow, and eye 
position may be recorded during the practice and fMRI scan sessions.

We are conducting the MRI scans using FDA-approved 3T along with approved head coils, pulse 
sequences and software in the NMR Research Center. The scanners used for this protocol is a 
Siemens Magnetom Prisma.

Participants will complete a resting-state fMRI scan at each session to assess changes in 
intrinsic network connectivity. 

Participants will get a whole-brain structural MRI scan. 

All study participants will be accompanied at the NMR Center by study team members 
and/or medically responsible staff. All study team members have completed CPR 
Training, NMR Center Safety Training, and the NMR Center Emergency Preparedness 
Training, including standard emergency procedures to be followed in the event of a fire 
(code red) or if a participant is in respiratory and/or cardiac arrest (code blue). These 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
22
procedures include removing and evacuating the participant from the scanner, contacting 
the appropriate emergency response teams as well as the MAI of the study, and being 
aware of the locations of emergency items such as the emergency drug box, crash cart, 
AED, and fire extinguisher.
General Procedures.

Urinalysis and Breath Alcohol Testing: Urinalysis and Breath Alcohol Testing: 
Participants will be required to provide a urine sample for a qualitative urine drug test at 
the beginning of all study visits. The Qualitative (DLM) tests for cocaine, 
methamphetamines, benzodiazepines (except for inpatients) and opiates must be negative 
for all participants. Tests for THC will be carried out and recorded for data purposes but 
will not be exclusionary. In addition, they will have to complete and pass a breath alcohol 
test at the beginning of each study visit in order to participate. To pass, they must not 
have a positive BrAC value (greater than 0.00 g/dL). Individuals capable of becoming 
pregnant also must have a negative pregnancy test before they can participate in the 
study.

Portions of this study (cognitive assessments) will be conducted in an alcohol-cued “bar-
like” environment. This space is a bar-like room at the CRC. This room includes bar-like 
furniture and décor, liquor bottles (filled with water), as well as a chair and a table. The 
room is also equipped with a two-way intercom system and a closed-circuit camera (no 
sound) through which participants may be monitored for signs of craving-related distress 
by study staff in another room. The use of a bar-like room has never been associated with 
an increased risk of drinking after the experiment. Alcohol cue-reactivity experiments are 
performed on a regular basis at NIAAA. However, increased craving and distress may 
appear during the exposure to the bar-like environment. Should clinically significant 
symptoms appear, participants will have immediate access to licensed health care 
professionals. 
E. STUDY POPULATION

Stage 1:
We plan to study up to 30 individuals with moderate to severe AUD and 30 non-
alcohol naive healthy control volunteers (HCVs). 
Individuals with AUD will be recruited from the surrounding community. Individuals 
may or may not be treatment seeking, but must meet diagnostic criteria for AUD. 
Male healthy volunteers must, on average, drink 14 or less standard drinks and female 
healthy volunteers must, on average, drink 7 or less standard drinks per week in order 
to be considered for this study based on most recent Timeline Followback (TLFB) 
within the last 90 days. AUD participants will not undergo any long-term follow-up 
for the Stage 1 of this study.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
23

Stage 2:
We plan to study up to 56 inpatients with AUD. Over the past two years, there have 
been just over 90 inpatients per year, with the vast majority being between 30 and 60 
years of age, with about a 3:1 male:female ratio, and with about 55% African 
American, 40% Caucasian, 5 % other races. We plan our inpatient recruitment to be 
within these general guidelines. 
The inpatient individuals with AUD will be recruited from alcohol treatment 
conducted at the NIAAA inpatient unit within the first week of treatment. All 
inpatients go through similar treatment regimens, take similar medications, and have 
similar opportunities to participate in research. The impact of these factors is 
expected to differ between neurofeedback conditions only at random, and is not 
expected to impact the research outcome.

Randomization:
The second stage of this study uses randomized group assignment. Patients will be 
assigned to active or sham condition using a random number generator, with 
balanced probability across conditions. A master list, with access restricted to the PI 
and Lead AI, will contain the random assignment for subjects.
E.1: INCLUSION AND EXCLUSION CRITERIA
Stage 1:
A. Inclusion Criteria
1. 21 to 65 years old
3. Healthy volunteers only: Consuming on average 7 or less standard drinks/week 
if female; 14 or less standard drinks/week if male (as determined by the most 
recent measurement within the past 90 days Alcohol Timeline Followback)
4. AUD participants only: Diagnosed with current moderate to severe alcohol use 
disorder according to most recent  SCID 5 diagnosis
B. Exclusion Criteria
1. Significant history of head trauma or cranial surgery
2. History of neurological disease based on self-report and neuromotor physical 
exam, conducted by a health care provider, that would interfere with 
neuroimaging research. Posthoc, clinical MRI scans done according to NIH 
Clinical Center policy may be reviewed and if there is evidence from that scan 
of past or current neuroabnormalities that, in the PI or MAI’s expert opinion, 
interfere with research neuroimaging data, the subject may be excluded from 
data analysis.
3. Physical health concern that would significantly impair or increase the risk of 
study participation.
4. Healthy volunteers only: Have fulfilled DSM-5 criteria for a current substance 
or alcohol use disorder
5. Female participants only: Currently pregnant

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
24
6. Presence of any ferromagnetic objects in the body that may be aversively 
affected by or contraindicated for MRI as determined by the NIAAA MRI 
Safety Screening Questionnaire
7. Any flag on the NIAAA MRI Safety Screening Questionnaire, unless cleared 
by medically responsible staff (MD/NP)
8. History of non-substance related psychosis
9. Lack of experience with alcohol (defined as less than 3 lifetime drinks 
reported in history and physical or on Lifetime Drinking History)
Stage 2*: 
A. Inclusion Criteria
1. 21 to 65 years old
3.  Inpatient currently seeking treatment for alcohol use disorder
B. Exclusion Criteria
1. Significant history of head trauma or cranial surgery,
2. History of neurological disease based on self-report and neuromotor physical 
exam, conducted by a health care provider, that would interfere with 
neuroimaging research.
3. Physical health concern that would significantly impair or increase the risk of 
study participation.
4. Presence of any ferromagnetic objects in the body that may be aversively 
affected by or contraindicated for MRI as determined by the NIAAA MRI 
Safety Screening Questionnaire
5. Any flag on the NIAAA MRI Safety Screening Questionnaire, unless cleared 
by medically responsible staff (MD/NP)
6. History of non-substance related psychosis
7. Female participants only: Currently pregnant
* Inpatients who have been admitted into the behavioral unit at the Clinical Center for AUD 
treatment, maybe considered for this study. Upon completion of consenting procedure, any 
data necessary (but not readily available) to determine eligibility maybe collected under this 
study. However, to avoid undue discomfort, burden, and inconvenience, this information, if 
available, can be gathered from routine clinical care or other NIAAA clinical studies and data 
up to 30 days prior to the consenting date. Participants who do not satisfy any of the above 
criteria will not participate in the study procedures at the time. They may be re-scheduled for 
a future date(s) when they fulfill all inclusion/exclusionary criteria.
We will utilize SCID diagnoses (from other studies such as 14-AA-0181) to determine AUD 
diagnosis and any potential Axis I disorders. However, for inpatients, since the nursing 
practice is initially focused on patient detoxification and treatment, the SCID diagnoses 
might not always take place within the first week of the patient admission to the alcohol unit. 
This could seriously hamper the subject recruitment in the second stage of this study. We will 
conduct the MR scan of eligible participants (based on the above inclusion/exclusion 
criterion) according to study timeline regardless of the availability of SCID diagnoses. 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
25
Inpatients are admitted based on the clinical opinion of medical staff that the individual has a 
pattern of alcohol use disorder. We will enroll inpatients with this opinion but the SCID 
diagnoses will be completed in order to have consistent research data on symptomology and 
severity,  and to use any potential Axis I disorder as a study confound. Additionally, we will 
collect information on medications being taken by patients currently or within the last month, 
including dose, schedule, and timeline. This will be used as a covariate in the statistical 
design to control for variation associated with these medications.
E.2: Clinical and Laboratory Methods
All primary procedures will be conducted for research purposes. Clinical procedures will be 
collected prior to participation primarily for eligibility determination. Participants will be 
required to provide a urine sample for a qualitative urine drug test at the beginning of all study 
visits. Females also must have a negative pregnancy test before they can have a MRI scan. 
In coordination with this study, participants may have a clinical MRI scan under any other 
NIAAA protocol. As part of NIH Clinical Center policy, this MRI may only be done on subjects 
who have qualified for and will participate in an NIAAA study that requires MRI or fMRI scans 
and also have not received a clinical MRI scan at the NIH in the past 12 months. A clinical MRI 
of the brain is a minimal risk procedure that allows the diagnosis of brain damage. This MRI 
scan may include any standard clinical MR sequence.
E.3: Inclusion of Vulnerable Populations
This study does not involve vulnerable populations. NIH employees will be eligible to participate 
as subjects; while NIH employees are not technically a vulnerable population under federal 
regulation, they will be recruited consistent with NIH Manual Chapter 3014-404-Research 
Involving NIH Staff as Subjects (https://policymanual.nih.gov/3014-404)
Employees of the NIAAA will not be enrolled in this study, since their participation and 
potential knowledge of the research study may influence research outcomes. 
Justification for exclusion of vulnerable populations
Children : The inpatient alcohol use disorder treatment clinic from which patients will be 
recruited in stage 2 is an adult sample; stage 1 recruitment is planned to recruit comparable 
adults from the community. Moreover, since in the United States, it is illegal for children under 
the age of 21 to drink alcohol, inclusion of children in this study is an ethical concern. The 
problem of adolescent alcohol drinking is important, but outside the scope of this study. So, 
children under 21 will not be included in this study.
Pregnant Women, Human Fetuses, Neonates : It is not known if it is safe for a developing fetus 
to be in the MRI environment. Since this study’s primary outcome and its primary manipulation 
require patients to be in an MRI environment, this would present an unnecessary risk for 
pregnant women. So, pregnant women will not be included in this study.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
26
Prisoners: The inpatient alcohol use disorder treatment clinic from which patients will be 
recruited in stage 2 does not include individuals who are prisoners, since inpatient treatment 
requires a stay at the clinic; prisoners are not able to leave custody for such a treatment program. 
Stage 1 recruitment is planned to recruit comparable adults from the community. Moreover, 
inclusion of prisoners would require supervised transport from a controlled facility to the 
hospital for a MRI; this would entail procedures for the prisoner that are an unnecessary 
discomfort. Finally, given that prisoners are in a controlled environment, their drinking habits 
would not be representative of their drinking behaviors or disorder status in the community. This 
may be comparable to a treatment seeking population; we are recruiting non-treatment seeking 
individuals from the community. In fact, prisoners may be receiving substance use counseling 
while incarcerated.  So, prisoners will not be included in this study.
Adults Who Are or May be Unable to Consent: Adults who are unable to consent will not be 
included in this study. If individuals do not have the communication or mental capacity to 
provide informed consent, they will likely also be unable to complete study procedures (e.g., 
filling out questionnaires). Since this study does not provide a known direct benefit to the 
participants, exclusion of this vulnerable population will not differentially prevent them from 
obtaining a benefit. If the inability to consent is temporary (i.e., acute intoxication), the 
individual may be eligible to consent on a different occasion.
E.4: Strategies for Recruitment and Retention
Rationale for subject selection based on a review of gender/ethnic/race categories at risk for the 
disease/condition being studied: 
Subjects will be selected equitably based on the population demographics of the greater 
Washington, D.C. and Baltimore metropolitan regions
Healthy control volunteers (HCV) and individuals with AUD will be recruited from the protocol 
14-AA-0181: “NIAAA Natural History Protocol.” Subjects will be recruited from a pool of 
previous participants or through advertisements placed in electronic and non-electronic local and 
social media and bulletin boards or announcement areas. Subjects will be recruited through the 
following methods:

Advertisements placed in electronic and non-electronic local and social media, 
bulletin boards, or displays, or given out as flyers or cards. Advertisements may also 
be used in the form of radio or newspaper ads, or as banners. Advertisements may be 
posted on NIH’s campus as well as in community locations and businesses. 

The participants enrolled in the protocol 14-AA-0181.

The subject’s eligibility requirements are completed after consenting and enrolling 
into this protocol. No study sessions will commence until eligibility is reviewed by 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
27
the PI or an AI (designated by the PI to obtain consent) together with the physician or 
nurse practitioner involved in the evaluation of the participant, and their concurrence 
of the participant’s eligibility is documented on the eligibility checklist form. Further, 
a third signature by an independent clinician or quality assurance monitor will be 
obtained following their verification of the participant’s eligibility for the study. All 
signatures will be obtained prior to obtaining consent of the participant.

See appendixes and attachments for recruitment materials 
Costs: It is possible that the study procedures will reveal previously undiagnosed abnormalities 
(e.g., the potential finding of a tumor from the brain MRI studies). If this happens it may result in 
stress and time and financial costs to the study participant and their family. The investigators are 
not assuming responsibility for such potential consequences, but will make every effort to help 
such families to deal with whatever findings arise. 
Compensation: Participants will be compensated for research-related time dedicated, discomfort, 
and inconveniences in accord with NIH guidelines. Participants will be compensated for the parts 
that they complete. 
Activity
Time (+ inconvenience units) Cost
Stage 1 Visit
Behavioral Assessments
1.5 hours (1)
40.00
MRI Session
2 hours (3)
80.00
Earnings from rt-fMRI task
----
    0.00-60.00
Post-NF Assessments
.5 hour (1)
20.00
Total
      $140.00 – $200.00
Screening Procedures*
Blood work / UDS
0.5 hours (1)
$20.00
Clinical exam (e.g., H&P)
0.5 hours (1)
$20.00
Timeline Followback (TLFB)
0.5 hours (1)
$20.00
Psychopathology assessment (e.g., SCID)
2 hours (1)
$50.00
Total
          $0.00 - $110.00
Stage 2 Session 1
Baseline Behavioral Assessments
1.5 hours (1)
40.00
MRI Session
2 hours (3)
80.00

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
28
Earnings from rt-fMRI task
----
    0.00-60.00
Post-NF Assessments
1 hour (1)
30.00
Total
      $150.00 - $210.00
Stage 2 Session 2
MRI Session
2 hours (3)
80.00
Earnings from rt-fMRI task
----
    0.00-60.00
Post-NF Assessments
1 hour (1)
30.00
Total
      $110.00 - $170.00
Follow up 1
Behavioral Assessments
1 hours (1)
35.00
Total
         $35.00
Follow up 2
Behavioral Assessments
1 hours (1)
50.00
Total
         $50.00
Follow up 3
Behavioral Assessments
1 hours (1)
65.00
Total
         $65.00 
Total Compensation Range: 
      $140-$530
* This procedure is performed only if screening this data is not available from NIAAA natural 
history or other study or the participant has not had a clinical MRI at the NIH within the last 12 
months.
F. PARTICIPANT DISCONTINUATION/ WITHDRAWAL
Participants are free to withdraw from participation in the study at any time upon request.
Additionally, subjects may be discontinued or withdrawn from the study at any time if the 
investigators or the medical staff feel that further participation would pose a risk for the subject 
or for study staff, if they have reason to believe the integrity of the data collected from the 
subject is in question, or if the subject is unwilling or unable to complete study procedures.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
29
 
G. STUDY ASSESSMENTS AND PROCEDURES
G.1: Screening:
As mentioned before, inpatients who have been admitted into the behavioral unit at the Clinical 
Center for AUD treatment, maybe considered for this study. To avoid undue discomfort, burden, 
and inconvenience, any information necessary to determine participant’s eligibility, if available, 
can be gathered from routine clinical care or other NIAAA clinical studies such as 14-AA-0181 
up to 30 days prior to the consenting date. The eligibility of a potential participant may be 
determined any time before or after consenting in this study. Therefore, we have requested a pre-
eligibility consent waiver for this part of the study prior to consenting for the procedures outlined 
in this study. This research involves no more than minimal risk to the subjects. The research 
cannot be carried out unless we are able to brief the participant, verify their age and participation 
in other NIAAA studies, and gather information regarding their handedness, pregnancy status, 
and presence of non-removable metal in their body before consenting them in this study. This 
waiver will not adversely affect the rights and welfare of the subjects. We will not collect and 
store any information from these individuals once their qualification is found implausible or they 
express lack of desire to participate in the study.
The subject’s eligibility is evaluated prior to first study session in this protocol. The eligibility is 
reviewed by the PI or an AI (designated by the PI to obtain consent) together with the physician 
or nurse practitioner involved in the screening and/or evaluation of the participant, and their 
concurrence of the participant’s eligibility is documented on the eligibility checklist form. 
Further, a third signature by an independent clinician or quality assurance monitor will be 
obtained following their verification of the participant’s eligibility for the study. All signatures 
will be obtained prior to obtaining consent of the participant. 
As part of NIH Clinical Center policy, a clinical MRI scan must be done on subjects who will 
undergo any research involving MRI within 12 months prior to the study. If at the time of this 
study such scan is not available, we will conduct the clinical scan within this study session as 
well. A clinical MRI of the brain is a minimal risk procedure that allows the diagnosis of brain 
damage. This MRI scan may include any standard clinical MR sequence.
Withdrawal Assessment: Under this study, outpatient AUD participants will be assessed for 
withdrawal symptoms during screening procedures and prior to study session. As part of 
inpatient treatment, AUD participants are monitored and treated for withdrawal. The Clinical 
Institute Withdrawal Assessment (CIWA-Ar) for alcohol will be used. The study session will not 
commence for AUD participants with most recent CIWA score of 8 or greater.
Urinalysis and Breath Alcohol Testing: Participants will be required to provide a urine sample 
for a qualitative urine drug test at the beginning of all study visits. The Qualitative (DLM) tests 
for cocaine, methamphetamines, and opiates must be negative for all participants. Tests for THC 
and benzodiazapines will be carried out and recorded for data purposes but will not be 
exclusionary. This is because benzodiazapines are often prescribed for withdrawal symptoms 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
30
(Mayo-Smith, 1997) or anxiety (Kushner et al., 2000), which is comorbid with AUD with 
cannabis use as a comorbidity as well (Degenhardt et al., 2001). In addition, they will have to 
complete and pass a breath alcohol test at the beginning of each study visit in order to participate. 
To pass, they must not have a positive BrAC value (greater than 0.00 g/dL). For MRI sessions 
only, females also must have a negative pregnancy test before they can participate in the study.
G.2: Assessments:
Interviews and Questionnaires. 

Outcome Measures (Stage 2 only): Inpatient AUD subjects will be contacted 
approximately 1 month, 3 months, and 6 months post-release from inpatient treatment. 
Treatment release date is part of patient files and will be accessed to determine these time 
points. Follow-up sessions will be conducted via the phone and/or through self-
administered secure online data collection (e.g., through Qualtrics) unless the subject 
prefers to come to the NIH Clinical Center for in-person follow up. Participants will be 
asked for follow-up contact information at baseline, including people for whom we have 
permission to contact to try to reach the patient, and permission to search public records 
for related information (e.g., incarceration). Participants will be asked about behaviors in 
the last month including: 1) alcohol and substance use and craving; 2) contacts with the 
legal system; 3) employment; 4) negative drinking consequences like DUIs, fighting 
while drunk, and blackouts; 5) intimate partner aggression, and 6) fulfillment of social 
responsibilities. These measures will also be given at the first in-person session to 
establish a baseline for each participant. Given the sensitive nature of many of these 
measures, participants will be reminded about the availability of resources for counseling 
and the parameters of confidentiality conferred by the Certificate of Confidentiality.
o
Alcohol Use Outcomes: The Alcohol Timeline Followback (administered initially 
as part of the standard NIAAA Office of the Clinical Director screening session) 
will be conducted to identify patterns of drinking alcohol since release from 
treatment, including amount, variability, relapse and drinking days (Sobell and 
Sobell, 1992). Patients will use a calendar to aid them in specific day by day 
recall of drinking activities. The Alcohol Craving Questionnaire will also be 
administered at follow-ups.
o
Community Functioning Outcomes: The Drinker Inventory of Consequences 
(DrInC) will be administered to assess drinking-related behaviors and outcomes 
including: acute and chronic health problems, personal feeling states, fulfillment 
of social responsibilities, relationship health, and impulsive/risky behaviors 
(Miller et al., 1995). Participants will also be asked for employment status 
information, including hours worked.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
31
o
Aggression, victimization, and antisocial behavior outcomes: The Revised 
Conflict Tactics Scales (CTS2) will be administered to assess intimate partner 
aggression, including type, severity, and regularity of behavior (Straus et al., 
1996). Participants will also be asked to self-report contacts with the police, 
convictions, and other alcohol-related criminal behaviors (such as driving under 
the influence of alcohol, disorderly conduct, and probation violations). Offenses 
will be categorized into one of 27 common categories, following the procedure in 
Aharoni et al., 2013 (Aharoni et al., 2013).
o
Other Measures: Patients will complete the self-report measures of individual 
differences at their first study visit prior to scanning. Patients will complete the 
cognitive assessments and ACQ before and after the first neurofeedback scan, and 
after the second neurofeedback scan.
General Procedures

Portions of this study will be conducted in an alcohol-cued environment (priming 
procedures and the second Stroop Test). This space is a bar-like room at the CRC. This 
room includes bar-like furniture and décor, liquor bottles (filled with water), as well as a 
chair and a table. The room is also equipped with a two-way intercom system and a 
closed-circuit camera (no sound) through which participants may be monitored for signs 
of craving-related distress by study staff in another room. The use of a bar-like room has 
never been associated with an increased risk of drinking after the experiment. Alcohol 
cue-reactivity experiments are performed on a regular basis at NIAAA. However, 
increased craving and distress may appear during the exposure to the bar-like 
environment. Should clinically significant symptoms appear, participants will have 
immediate access to licensed health care professionals. Participants will not be exposed 
to any alcohol.

Any data collected via online surveys will be hosted on Qualtrics, which offers a platform 
that can securely collect participant data while protecting sensitive information. The data 
collected will be linked to the participant by a subject ID code; names, birthdates, and 
similar PII will not be hosted on Qualtrics. The Qualtrics platform has security and 
privacy controls that are consistent with NIH data security requirements, and the platform 
has been approved by the NIAAA ISSO. Qualtrics provides several metrics of the survey 
implementation, including completion times, which will be tracked as a measure of 
compliance. Qualtrics will be used within NIAAA ISSO approved parameters. 
MRI-Scan Portion: Prior to entering the scanner, participants will complete a training protocol 
designed to eliminate the need for practice in the MR environment. This may consist of verbal 
and/or written instructions, and/or examples of what they will see on the screen when they are in 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
32
the scanner. Participants will be given the opportunity to ask questions until an understanding of 
the task is established.
All study participants will be accompanied at the NMR Center by the study team members. All 
study team members have completed CPR Training, NMR Center Safety Training, and the NMR 
Center Emergency Preparedness Training, including standard emergency procedures to be 
followed in the event of a fire (code red) or if a participant is in respiratory and/or cardiac arrest 
(code blue). These procedures include removing and evacuating the participant from the scanner, 
contacting the appropriate emergency response teams as well as the MAI of the study, and being 
aware of the locations of emergency items such as the emergency drug box, crash cart, AED, and 
fire extinguisher. The presence of a healthcare professional will not be required in the MR 
sessions for any participants in this study.
Study Agents/Interventions
No research drugs or devices will be used in this study. rt-fMRI-NF will be investigated as an 
intervention for alcohol cue salience/ response modulation atypicalities related to alcohol use 
disorder
G.3: Adverse Event Reporting:
Adverse events, protocol deviations, unanticipated problems (UP), Unanticipated Adverse 
Device Effects (UADEs), serious adverse events, sponsor and serious, are defined as described in 
NIH HRPP SOP 16 (“Reporting Requirements for Unanticipated Problems, Adverse Events and 
Protocol Deviations.”) or as required by subsequent NIH HRPP SOPs. All adverse events 
occurring during the study, including those observed by or reported to the research team, will be 
recorded. Reportable events will be tracked and submitted to the IRB as outlined in Policy 801. 
Serious unanticipated problems, Unanticipated Adverse Device Effects and serious protocol 
deviations, will be reported to the IRB and CD as soon as possible but not more than 7 days after 
the PI first learns of the event. Not-serious adverse events will be reported to the IRB and CD as 
soon as possible but not more than 7 days after the PI first learns of the event. 
Serious Adverse Events
The study investigator will immediately report to the IRB any serious adverse event, whether or 
not considered study intervention related, including those listed in the protocol and must include 
an assessment of whether there is a reasonable possibility that the study caused the event. 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting 
documentation of the event may be requested by the Data Coordinating Center (DCC)/study 
sponsor and should be provided as soon as possible.
Unexpected fatal or life-threatening suspected adverse reactions will be reported to the Clinical 
Director as soon as possible, but in no case later than 7 calendar days after the PI first learns of 
the event.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
33
Reporting of Pregnancy
We will test for pregnancy at each study visit in individuals capable of becoming pregnant. If a 
subject finds out after participating that they may have been pregnant during study procedures 
(i.e., drinking alcohol), and the study staff becomes aware of this, the participant will be 
discontinued and it will be reported to IRB and the Clinical Director. 
G.4: Unanticipated Problems:
Definition of Unanticipated Problems (UP)
Any incident, experience, or outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; and
•
Related or possibly related to participation in the research (“possibly related” means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and
•
Suggests that the research places participants or others (which many include research 
staff, family members or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) than 
was previously known or expected.
Unanticipated Problem Reporting
The investigator will report unanticipated problems (UPs) to the NIH Institutional Review Board 
(IRB) as per Policy 801. Not-serious unanticipated problems will be reported to the IRB and CD 
as soon as possible but not more than 14 days after the PI first learns of the event.
H. STATISTICAL CONSIDERATIONS
H.1: Statistical Analysis Plan: 
Stage 1:
1. To address primary objective 1, data analysis of neural response during the SAAT 
task will be conducted using AFNI (Cox, 1996). Six conditions of interest will be 
modeled based on stimuli onset time: socioemotional-alcohol, socioemotional-
neutral, not socioemotional-alcohol, not socioemotional-neutral, neutral-alcohol, 
and neutral-neutral. A 3 [cue type] x 2 [distractor type] x 2 [group] mixed-
factorial multivariate model will then be run. The primary comparison of interest 
is the group effect on the contrast of the socioemotional-alcohol > 
socioemotional-neutral conditions.
2. To address primary objective 1, eye tracking and attention task data will also be 
examined using this analysis procedure, conducted in R using the lme4 package 
(Bates et al., 2014; R Core Team, 2017) and other relevant statistical packages.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
34
3. To pilot the rt-fMRI-NF training procedure, we will evaluate performance of the 
task based on a) whether neural response during downregulation is less than 
neural response during functional localization and b) what percentage of trials 
participants are successfully able to hit down-regulation targets (target 
percentage: 50%). The protocol will also be optimized based on post-scan 
questionnaire responses. Benchmark (a) will be evaluated offline post-scan using 
AFNI and other established neuroimaging analysis tools, modeling neural 
responses from the functional locator and from the down regulation trails in a 
within-subject design. Benchmark (b) will be evaluated offline post-scan using R 
to calculate the average behavioral performance by group. Modifications will be 
made to the task as required.
Stage 2:
1. To address primary objective 1, we will analyze neural response during the SAAT 
task by modeling conditions using the procedure described in Stage 1, Step 1. A 3 
[cue type] x 2 [distractor type] x 2 [neurofeedback condition] x 3 [time point] 
mixed-factorial multivariate model will then be run. The primary comparison of 
interest is the neurofeedback condition x time point effect on the contrast of the 
socioemotional-alcohol > socioemotional-neutral conditions.
2. To address primary objectives 1 and 2, eye tracking, craving, and attention task 
data will also be examined using this analysis procedure, conducted in R using the 
lme4 package (Bates et al., 2014; R Core Team, 2017) and other relevant 
statistical packages.
3. To address primary objectives 1 and 2, and secondary objective 1, we will 
examine negative drinking consequences and drinking behaviors following 
release from inpatient treatment as usual with or without rt-fMRI-NF training 
using a mixed-factorial 2 [NF condition: active/sham] x 4 [time point: baseline, 
1/3/6 months post] multivariate model design. The comparison of interest is the 
neurofeedback condition x time point effect on 1) alcohol use outcomes, 2) 
community functioning outcomes, and 3) legal contact and problem behavior 
outcomes. We will also conduct a mediation analysis using the mediation package 
in R (Tingley et al., 2014). Specifically, we will examine whether the association 
between neurofeedback and outcomes is mediated by the change in neural 
engagement corresponding to socioemotional-alcohol > socioemotional-neutral 
conditions before and after neurofeedback.
Secondary Objectives:
1.
To address secondary objective 2, we will use a data-driven independent 
components analysis approach to investigate whole brain network connectivity 
using the GIFT package to analyze BOLD resting state fMRI scan data 
(Calhoun, 2004). Our analysis of interest is the neurofeedback condition x time 
point effect on resting state BOLD dynamics.
2.
To address secondary objective 3, we will conduct a modification of Stage 1, 
analysis 1. Within individuals with mild to severe AUD, continuous measures of 
alcohol use severity, such as the Lifetime Drinking History, Alcohol Timeline 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
35
Followback, and Alcohol Use Disorders Identification Test (maybe collected as 
part of this or any other NIAAA procedure) will be modeled as quantitative 
variables of interest within the 3 [cue type] x 2 [distractor type] mixed-factorial 
multivariate model. The primary comparison of interest is the alcohol use 
severity effect on the contrast of the socioemotional-alcohol > socioemotional-
neutral conditions. Baseline SAAT task data from Stage 2 may also be included 
in this analysis.
3.
To address secondary objective 4, we will conduct modifications of the Stage 1 
and Stage 2, part 1 planned analyses. Data from the IRI, MFQ, and SRP-II will 
be used as quantitative variables of interest within the 3 [cue type] x 2 [distractor 
type] mixed-factorial multivariate model, where the comparisons of interest are 
the empathy, moral foundations, and psychopathy effects on the contrast of the 
socioemotional-alcohol > socioemotional-neutral conditions. Similar analyses 
will be carried out using demographic variables (age, IQ, sex) and attentional 
task performance.
General Analysis Procedures:
1. ALL BOLD fMRI scans will be preprocessed using a standard pipeline in AFNI: 
despiking, temporal alignment, coregistration, smoothing, and motion correction 
(Cox, 1996).
2. Where relevant, appropriate whole brain false positive rate control for the 
neuroimaging analyses will be implemented through 3dClustStim based on the 
updated procedure using autocorrelation functions (ACF) and as recommended by 
Cox and colleagues (2016). Cluster-size thresholds will be set based on a per-
voxel p-value threshold of p = .001 and whole-mask threshold of α = .05.
3. Preprocessing of the data will take place as the collection of data for each session 
is completed.
4. In order to optimize the study and minimize subjecting the patients to undue MR 
procedures, we will conduct group analysis after every 10 subjects in each group. 
Upon determining statistically significant outcomes the study may be terminated.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
36
Power Analysis:
Stage 1:
In order to detect differences in 
socioemotional processing in the 
presence of alcohol cues between 
individuals with AUD and healthy 
controls, we conducted a power 
analysis based on reported effect sizes 
from studies of moral processing and 
substance use and emotional processing 
in the presence of alcohol cues or under 
the influence of alcohol (Table 1). 
Power analysis was conducted using 
the pwr package in R (Champely, 2009; 
Champely et al., 2017). The analyses 
were conducted with an estimated 
average effect size d = 1.235, α = .001, 
power = 0.8. An estimated sample of n 
= 25 per group (total N = 50) is required to detect group effects. 
Stage 2:
In order to detect rt-fMRI-NF related effects, we conducted a power analysis based on 
studies of rt-fMRI neurofeedback. The analyses were conducted with the average effect 
size estimated at d = 2.403. With α = .001, and an estimated power of 0.8, an estimated 
sample of n = 8 per group (total N = 16) is required to detect condition effects of 
neurofeedback. However, given that we are also interested in sustained transfer effects of 
neurofeedback, we ran power analysis with an estimated transfer effect size of 
neurofeedback from Young et al., 2017 of d = .80, α = .05, and an estimated power of 
0.8. An estimated sample of n = 23 per group (total N = 46) would be required to detect 
those group effects. For neuroimaging power analysis, α was estimated at the more 
conservative .001 to account for multiple correction significance thresholds; this is not 
required for hypothesis driven behavioral analysis. We selected the larger subject 
recruitment numbers to be able to address our primary objectives completely.
Study
Effect Size (d) Description
Caldwell et al., 2015
0.58
Implicit moral processing in 
cocaine users versus non 
cocaine users
Fede et al., 2016
0.67
Explicit moral processing in 
stimulant users versus non 
stimulant users
Padula et al., 2011
1.85
Emotional face decoding in 
alcohol administration versus 
placebo
Gilman & Hommer, 2008
1.84
Emotional processing in the 
presence of alcohol cues
Average
1.235
Note: Cohen's d effect size values were estimated based on reported 
significant t-values in referenced publications
Table 1. Effect Sizes for Stage 1 Power Analysis

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
37
Following power analysis, we added 20% to our planned recruitment numbers to account 
for attrition, data collection issues, and variability in effect strength. For both stages, we 
expect some participants may not complete a session due to unanticipated logistical 
challenges (e.g., urinalysis results are 
delayed from the laboratory), 
uncomfortable or excessive 
movement in the MRI, or personal 
reasons. For Stage 2, we expect that 
some participants will not complete 
the planned sessions due to leaving 
treatment early, or schedule problems. 
We also anticipate that some 
participants may not be locatable for 
some or all follow-ups post-treatment 
release. The resulting planned 
recruitment for Stage 1 is N = 60 (per 
group n = 30) and for Stage 2 is N = 
56 (per group n = 28). 
I. REGULATORY AND OPERATIONAL CONSIDERATIONS
I.1: Informed Consent.
Any investigator obtaining informed consent will complete the NIMH Human Subject Protection 
Unit’s “Informed Consent” training, or an equivalent NIH approved informed consent training. 
The informed consent document describes each of the procedures and their risks and benefits in 
layman’s terms. The consent process will take place in a private setting where adequate 
opportunity will be afforded to all subjects to ask any questions they may have, and these will be 
addressed to their satisfaction prior to completing the informed consent process. The consent 
procedure is not in any way binding. Participants will be informed of the following:
1. They have the choice to participate or not in this study.
2. All subjects will be asked to participate in the following assessments:
a) Complete tests of attention/executive function, personality/individual 
differences, craving, and baseline problem behaviors prior to scanning. 
Total testing time will be approximately 70 minutes. 
b) Complete a baseline magnetic resonance imaging protocol, including 
the SAAT task described previously (approximately 35 minutes)
3. Some subjects may also be asked to participate in some of the following 
additional assessments:
a) Complete post scan questionnaires rating pictures used in the scanning 
task (approximately 15 minutes).
b) rt-fMRI-NF training protocol (sham or active) for made up of two 13 
minute blocks (approximately 26 minutes) 
Study
Effect Size (d) Description
Young et al., 2017
0.80
Neurofeedback intervention 
for depression
Kirsch et al., 2016
1.54
Neurofeedback modulation 
of alcohol cue reactivity in 
the striatum
Karch et al., 2015
3.71
Neurofeedback modulation 
of craving related brain 
responses
Robineau et al., 2017
3.56
Increase in neuromodulation 
of visual cortex over two 
sessions of neurofeedback
Average
2.403
Table 2. Effect Sizes for Stage 2 Power Analysis
Note: Cohen's d effect size values were estimated based on reported 
significant t-values or F values in referenced publications

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
38
c) Complete tests of attention and craving after scanning. Total testing 
time will be approximately 25 minutes.
d) Complete post NF magnetic resonance imaging protocol, including a 
different version of the SAAT task (approximately 35 minutes)
e) Complete a second MRI scan visit approximately 3 weeks after the 
first scan, including the SAAT task, the neurofeedback task, craving 
measures, and attentional tests. 
f)
Study staff may attempt to contact participants by phone, mail, or 
email approximately 1 month, 3 months, and 6 months after they leave 
or complete treatment; a phone or in person interview will then be 
scheduled to collect follow up information and about drinking, 
problem behaviors, and community functioning. All or some questions 
may be asked in the form of a secure online survey, rather than verbal 
interview when appropriate.
4. All subjects will be exposed to pictures of alcohol in the scanner and will be 
asked to complete tasks in a controlled environment where alcohol is present.
5. Some subjects who have received active neurofeedback brain activity training 
will have their anonymous feedback displayed to another participant as a 
placebo neurofeedback signal.
6. Some subjects will be randomly assigned to a placebo version of brain activity 
training, in which case their option to earn extra money through performance 
would be tied to the performance of another participant; however, subjects 
will not be informed of whether or not they are in the placebo or active group.  
I.2: Confidentiality and Privacy.
Participant confidentiality and privacy is strictly held in trust by the participating investigators 
and their staff. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval. 
There are two types of stored data resulting from this protocol: (1) cognitive and brain imaging 
data which are stored electronically in secure, password-protected NIAAA computers located in 
the labs of the Clinical NeuroImaging Research Core in the NIH Clinical Center; (2) paper 
questionnaires and evaluation forms stored in locked file cabinets in locked rooms assigned to 
the Clinical NeuroImaging Research Core in the NIH Clinical Center. Access to all the study 
data will be restricted to authorized personnel
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. Data from participants will be maintained by having data coded to mask 
participants’ identities. Further, files containing participant names and the master list of 
participants will be kept in a locked file under the supervision of the Principal Investigator. 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
39
Access to all the study data will be restricted to authorized personnel via an Active Directory 
user account. Each authorized staff member will have a unique logon ID and password. All 
project staff with access to data will be trained on procedures for protecting the confidentiality 
and security of sensitive information.
All research activities will be conducted in as private a setting as possible.
The study monitor, representatives of the Institutional Review Board (IRB), and/or regulatory 
agencies may inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records 
for the participants in this study. The clinical study site will permit access to such records.
Following study completion, study participant research data, which is for purposes of statistical 
analysis and scientific reporting, will be submitted to NIAAA Repository Protocol (PI: Melanie 
Schwandt, Ph.D.), and any future research will be conducted, following appropriate agreements 
and IRB review, under that protocol. Any data transmitted outside of the NIH will not include 
the participant’s contact or identifying information. Rather, individual participants and their 
research data will be identified by a unique study identification number. The study data entry and 
study management systems used by clinical sites and by collaborating research staff will be 
secured and password protected.
Study investigators funded by the National Institutes of Health are automatically granted a 
Certificate of Confidentiality (CoC) issued by the NIH, U.S. Department of Health and Human 
Services (US:DHHS), per NIH policy NOT-OD-17-109 as of October 1st, 2017. A CoC prevents 
the Investigators from being forced to tell people who are not connected with this study about 
subjects’ participation in this research, even under a subpoena.  Disclosure will be necessary, 
however, upon request by DHHS, for the purpose of audit or evaluation, and is limited only to 
DHHS employees involved in the review. The protection offered by the CoC does not stop study 
investigators from voluntarily reporting information about suspected or known sexual, physical, 
or other abuse of a child or older person, or a subject’s threats of violence to self or others. If any 
member of the research team is given such information, he or she will make a report to the 
appropriate authorities. Even with this CoC in place, the consent attached to this study explains 
to participants that they and their family members must still continue to actively protect the 
participant’s privacy. If a participant voluntarily gives their written consent to anyone to receive 
information about their participation in the research, then we may not use the CoC to withhold 
this information.
I.3: Collection and Storage of Human Specimens or Data 
This study will be conducted in accordance with the following publication and data sharing 
policies and regulations:

National Institutes of Health (NIH) Public Access Policy, which ensures that the public 
has access to the published results of NIH funded research. It requires scientists to submit 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
40
final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive 
PubMed Central upon acceptance for publication.

This trial will be registered at ClinicalTrials.gov, and results information from this trial 
will be submitted to ClinicalTrials.gov

In addition, every attempt will be made to publish results in peer-reviewed journals. Data 
from this study may be requested from other researchers after the completion of the 
primary endpoint by contacting the PI; some journals may require de-identified data to be 
uploaded directly alongside publications as possible. Every effort will be made to comply 
with these regulations where doing so does not threaten to identify an individual research 
participant. 
Intended Use of the Samples: No human specimens/samples will be stored as part of this 
study. There are two types of stored data resulting from this protocol: (1) cognitive and 
brain imaging data, which are stored electronically in secure, password-protected NIAAA 
computers located in the labs of the Clinical NeuroImaging Research Core in the NIH 
Clinical Center; (2) paper questionnaires and evaluation forms stored in locked file 
cabinets in locked rooms assigned to the Clinical NeuroImaging Research Core in the NIH 
Clinical Center. The purpose of storing this data is to conduct group statistical analysis 
following completion of data collection in order to address the study aims. We may also 
use this stored data to answer additional research questions. The proposed research will 
include data from participants recruited through the NIAAA natural history protocol, 14-
AA-0181 and screening. The final dataset might include self-reported demographic, 
behavioral, and MR scan data from participants
The proposed research will include data from up to 116 participants and the final dataset 
will consist of behavioral, clinical, and neuroimaging data, including laboratory results. 
Data will be stored securely in the NIAAA intramural clinical database that is available to 
the investigators and collaborators named in the protocol for the research specified in the 
protocol. Data from other NIAAA protocols may also be shared with this protocol for 
assessment of eligibility as well as for data analysis. Data may also be shared with other 
NIAAA protocols to allow for greater power to detect otherwise small effect size analyses. 
Current and future collaborators within and outside of the NIH Intramural Research 
Program may be provided with de-identified data for the purposes of scientifically 
motivated analysis to answer additional research questions. We will make the data and 
associated documentation available to additional users only under a specific data-sharing 
agreement that provides for: (1) a commitment to using the data only for research 
purposes and not to identify any individual participant, (2) a commitment to securing the 
data using appropriate computer technology. 
Future collaborators within and outside of the NIH Intramural Research Program may be 
provided with this data under appropriate agreements. The agreements will include a 
commitment to use the data only for research purposes, to secure the data using 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
41
appropriate computer technology, and to destroy the data after analyses are completed, as 
appropriate. Data will be transferred using secure file transfer protocols. 
I.4: Data Handling and Record Keeping.
All data from the participants will be maintained by having data coded to mask participants’ 
identities. Further, files containing participant names and the master list of participants will be 
kept in a locked file under the supervision of the Principal Investigator. There are two types of 
stored data resulting from this protocol: (1) cognitive and brain imaging data which are stored 
electronically in secure, password-protected NIAAA computers located in the labs of the Clinical 
NeuroImaging Research Core in the NIH Clinical Center; (2) paper questionnaires and 
evaluation forms stored in locked file cabinets in locked rooms assigned to the Clinical 
NeuroImaging Research Core in the NIH Clinical Center.
1) Data Storage: Data from participants will be maintained by having data coded to mask 
participants’ identities. Further, files containing participant names and the master list of 
participants will be kept in a locked file under the supervision of the Principal 
Investigator. Access to all the study data will be restricted to authorized personnel via an 
Active Directory user account. Each authorized staff member will have a unique logon ID 
and password. All project staff with access to data will be trained on procedures for 
protecting the confidentiality and security of sensitive information.
2) Data Tracking: All attempts to access files containing confidential data will be logged and 
periodically reviewed to ensure that only authorized staff is accessing the data. Hard 
copies of data will be signed in and out, under the supervision of the QA monitor. 
Trackers will also be maintained through Filemaker for data tracking. 
3) Data following study completion: Following completion of the study, the data will be 
submitted to NIAAA Repository Protocol (PI: Melanie Schwandt, Ph.D.), and any future 
research will be conducted, following appropriate agreements and IRB review, under that 
protocol.
4) IRB reporting: . We will be collecting identifiable information. Even though the final 
dataset will be stripped of identifiers prior to release for sharing, we believe that there 
remains the possibility of deductive disclosure of subjects with unusual characteristics, 
particularly the participants with alcohol use disorder. In the event of breach of data 
security measures or evidence of loss or destruction of personally identifiable data the PI 
will inform the IRB. 
No human specimens/samples will be stored as part of this study. 
I.5: Monitoring and Quality Assurance
The Principal Investigator and the Medical Advisory Investigator (MAI), along with key 
research staff will be monitoring data collection and the study on an ongoing basis.
1) Monitoring Mechanism: This protocol will be monitored by the PI and MAI. 
Participant flowsheets will be reviewed by Investigators for completeness and 
compliance with study procedures. Adverse events will be evaluated by the MAI. 

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42
Event reporting will be done following the procedure outlined in the previous 
section. 
2) Frequency: QA monitoring will be done after the first participant has completed 
the study, and then following every 5 participants who have completed the study, 
or after six months (whichever occurs first). Investigators will review participant 
eligibility, accrual, and study progress at weekly staff meetings. Participant 
flowsheets will be reviewed by section staff at least monthly.
3) Stop or Change Rules for Study: In case of serious adverse event the study will be 
suspended until determination about cause of such an event is made. If following 
interim analyses, described in the statistical analysis section, the study has robust 
results, the PI may elect to terminate the study early to avoid unnecessary burden 
to additional patients. 
4) Advanced Plans: Interim analyses will be run every 10 subjects, or as needed, to 
evaluate need for continuation of patient accrual or issues in study procedure that 
might need modification in order to avoid unnecessary patient accrual. 
5) Information to be Monitored: 
a.
Overall study progress, including participant eligibility, accrual, and 
completion as well as data quality and timeliness of processes and procedures.
b. Adverse event data and outcomes will be reviewed at the time of annual 
review reporting for IRB. 
c.
Any external factors or relevant published information that might impact the 
safe and ethical conduct of the study at the time of annual review reporting for 
IRB, or whenever such information emerges.
6) Communication: The monitors will produce reports after each evaluation that will 
be sent to the PI and research team. The Investigators and research staff have 
daily interactions and communications regarding the study, as well as at weekly 
staff meetings. Adverse events, unanticipated problems (UP), protocol deviations, 
and non-compliance will be reported to the NIAAA Office of the Clinical 
Director and IRB. 
Data and Safety Monitoring
The Principal Investigator and the Medical Advisory Investigator (MAI), along with key 
research staff will be monitoring data collection and the study on an ongoing basis. Quality 
assurance (QA), including monitoring of Compliance with Good Clinical Practice standards, will 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
43
be performed by PI, MAI or a designated staff after the enrollment of every 5 participants or 
every six months (whichever occurs first) . 
1) Mechanism: 
i. The QA monitor will review participant flowsheets and establish their 
agreement with relevant source documents, as well as review the study 
Regulatory Binder for completeness to confirm compliance with all regulatory 
requirements.
2) Information Being Monitored:
a) Eligibility checklist
Filled out completely
b) NIAAA or NMR Center MRI safety screening questionnaire
Filled out- signed by physician if needed
c) Signed and dated protocol consent
d) Consent quiz administered and number of needed responses correct
e) Initial Breath alcohol (Stage 1 only)
f)
Study-specific items checked:
i. Flow sheets completely filled out
ii. Questionnaires completely filled out
iii. MRI scans or tasks documented as done
3) Communication: The monitors will produce reports after each evaluation that will be 
sent to the PI and research team.
Medical Safety Monitor
This is a minimal risk study; as such no Medical Safety Monitor is required. The Principal 
Investigator and Medical Advisory Investigator will be responsible for noting and reporting 
any problem or adverse event, specifically focusing on a change to the subject’s risk/benefit 
ratio. 
I.6: Protocol Deviations
It is the responsibility of the investigator to use continuous vigilance to identify and report 
deviations to the NIH Institutional Review Board as per Policy 801. All deviations must be 
addressed in study source documents and reported to the NIAAA program. The investigator is 
responsible for knowing and adhering to the reviewing IRB requirements. 
NIH Definition of Protocol Deviation
A protocol deviation is any changed, divergence, or departure from the IRB-approved research 
protocol. 

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
44
o
Major deviations: Deviations from the IRB approved protocol that have, or may 
have the potential to, negatively impact the rights, welfare or safety of the subject, 
or to substantially negatively impact the scientific integrity or validity of the 
study.
o
Minor deviations: Deviations that do not have the potential to negatively impact 
the rights, safety or welfare of subjects or others, or the scientific integrity or 
validity of the study. 
I.7: Responsibilities of Investigators
In regard to human subjects’ protection, the primary role of the investigators will be to 
ensure that proper consent procedures are being followed and that all subjects are 
protected from the risks associated with this study. The subject’s eligibility is evaluated 
prior to consenting and enrolling into this protocol. Consent will not be obtained until 
eligibility is reviewed by the PI or AI (designated by the PI to obtain consent) together 
with the physician or nurse practitioner involved in the screening evaluation of the 
participant, and their concurrence of the participant’s eligibility is documented on the 
eligibility checklist form. Further, a third signature by an independent clinician or quality 
assurance monitor will be obtained following their verification of the participant’s 
eligibility for the study. This third review and signature will be obtained prior to 
obtaining consent of the participant. 
The investigators will also contribute to study design and ensure that the design continues 
to meet the goals of the study without altering the subjects’ risk/benefit ratio. 
Investigators and Post-doctoral fellows will also be responsible for data analysis and 
manuscript preparation. The MAI will be responsible for medical oversight on all 
subjects. In addition, staff physicians and nurse practitioners will contribute to the 
medical safety of the subjects. Post-baccalaureate Intramural Research Training 
Awardees (IRTAs) will be responsible for day-to-day study procedures, such as 
recruiting, conducting scans, and administering cognitive tests.

Abbreviated Title: Socioemotional Processing in Alcohol Use Disorder
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