Cognitive Training in the Treatment of Alcohol Use Disorders in Older Veterans
Phase: NA
Conditions: Alcohol Use Disorder Cognitive Decline
Sponsor: VA Office of Research and Development

PROJECT DESCRIPTION 
February 7, 2018  
1. Principal Investigator:  Morris Bell, Ph.D.  
2. Project Title: Cognitive Training in the Treatment of Alcohol Use Disorders in Older Veterans 
NCT02664038 
 
 

PROJECT DESCRIPTION 
February 7, 2018  
1. Principal Investigator:  Morris Bell, Ph.D.  
2. Project Title: Cognitive Training in the Treatment of Alcohol Use Disorders in Older Veterans 
3. Purpose: This study aims to determine whether a combined intervention of cognitive remediation therapy 
(CRT) and Individual Drug Counseling (IDC) can benefit older Veterans in the initial phase of alcohol abuse 
treatment by improving abstinence outcomes and neurocognition. Substantial cognitive impairment is 
associated with alcohol use disorders (AUD), 7 and becomes worse with years of use and the aging processes8-
10. In particular, Veterans entering treatment for AUD display cognitive deficits that may reduce their ability to 
benefit from treatment. While there is considerable variety in the severity and types of cognitive impairment 
found in newly recovering patients, problems with attention, learning and memory and executive function are 
common8,21. Since treatment requires that the individual be able to sustain attention, remember what is 
learned, and apply it to recovery, impaired underlying cognitive processes make successful treatment less 
likely. Moreover, problems with executive functioning and other pre-frontal cognitive processes have been 
associated with decreased treatment retention and poorer AUD treatment outcomes7-9. Although cognition can 
improve with sustained abstinence27 it is during the early phase of recovery, when cognition is most impaired, 
that patients receive the most intensive treatment. AUD is a major cause of suffering and functional disability 
for older Veterans and a common co-morbidity with other physical and mental disorders. Finding more effective 
treatments of AUD remains a priority for VA healthcare.  
The purpose of the proposed study is to learn whether CRT plus IDC, an evidence-based outpatient 
AUD treatment56 is more effective than a Game-Play Placebo plus IDC.  Game-Play Placebo has been used to 
provide equipoise between conditions in other CRT studies and in a current CRT study with mTBI Veterans 
funded by DoD being conducted by the PI.  The proposed randomized controlled trial (RCT) will allow us to 
fulfill the following aims and test their related hypotheses: 
Specific Primary Aim # 1: To determine if CRT+IDC is more effective than Game-Play Placebo +IDC in 
decreasing alcohol use in older Veterans during the 3 month active intervention period. 
 
Ho1: CRT+IDC will be more effective than Game-Play Placebo+IDC in reducing heavy drinking days and 
decreasing days of use as measured by Breathalyzer and Timeline Follow-back Method (TLFB) during the 90 
days of active intervention. 
 
 
Secondary Aim #1: To determine if CRT+IDC is more effective than Game-Play Placebo+ IDC in 
sustaining decreased alcohol use in older Veterans at the end of 6 months (3 months after the active 
intervention period).  
 
Ho2: CRT+IDC will be more effective than Game-Play Placebo+IDC in reducing heavy drinking days and 
decreasing days of use as measured by Breathalyzer and Timeline Follow-back Method (TLFB) for the 30 days 
preceding 6 month follow-up. 
 
Secondary Aim #2: To determine if the combination of CRT and IDC is more effective than game play 
placebo and IDC in improving neurocognitive functioning.  
 
Ho3: Veterans receiving CRT+IDC will show greater improvement than Veterans receiving Game-Play 
Placebo+IDC at 3 month follow-up on a global index of neurocognitive function, and on an index of working 
memory and an index of executive function. 
 
Ho4: Differential improvements in neurocognitive function will be sustained at 6 month follow-up  
 
 
4. Background: Alcohol Use Disorders (AUDs) have a significant public health impact, cost billions of dollars 
in the US each year for treatment and lost productivity, and are highly prevalent in Veterans.1-4 Estimated point 
prevalence is 5.5% in returning Veterans, higher than the 3.8% civilian estimate.3 Lifetime prevalence for 
Vietnam Era Veterans was much higher when examined approximately 15 years after the end of the war, at 
almost 40% in men4 as compared to male civilians at 30%.2 Psychosocial behavioral interventions have some 
efficacy, but as revealed in a large VA cooperative multi-site study of a pharmacological augmentation 
(naltrexone), a high proportion in all arms of the study relapsed within one year.5 A recently published study of 
the relative efficacy of mindfulness-based relapse prevention6 in a civilian sample reported that 19% in the 
treatment as usual condition had returned to heavy drinking within 3 months.  AUD is a major cause of 
suffering and functional disability for Veterans and a common co-morbidity with other physical and mental 
disorders. There is, therefore, a critical need to explore ways to improve treatment for AUDs in Veterans. 

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42
44
46
48
50
0
1
2
3
4
5
6
Working Memory Index
Months
Work+Cog
Work Only
Figure 1. Work+Cog Working Memory increases over time. 
Note Simple slopes analyses of rates of change found Working 
Memory slope for Work+Cog was statistically significant (γ = 
.785, se=.314, p = .01). Slope for Work Only was not statistically 
different from zero (γ = -.335, se=.398, p = .264). Difference 
between groups’ baseline scores was not statistically significant  
(γ = 3.445, se=2.627, p = .196). TimeXCondition is statistically 
significant (F = 6 7 p< 01)
 
One possible avenue for improving AUD treatment outcomes may be to address neurocognitive 
impairments especially common in the early phase of recovery but often persisting over years7 that interfere 
with the acquisition of new learning (e.g. attention and memory) and with  better decision making (executive 
functioning).  Indeed, alcohol related brain defects and associated cognitive impairments may contribute to the 
progression of AUD by affecting the individual’s ability to benefit from treatment8 and by impairing their daily 
community functioning, which in turn increases stress and subsequent relapse.9,10 Recent research has 
suggested that cognitive remediation therapy (CRT) may improve attention, memory and executive function in 
schizophrenia and related disorders,11-15 and there is evidence that these improvements are in turn associated 
with better skill acquisition in structured groups.16  Many AUD treatments also require skill acquisition such as 
learning new ways of coping with craving, learning better methods for tolerating distress, being able to 
integrate feedback, and finding more constructive problem-solving strategies; therefore, improving attention, 
working memory and executive functioning could allow patients to get more out of these treatments. 
 There is a small amount of research to suggest that a CRT intervention could improve neurocognition 
for patients with substance abuse disorders (SUDs). In a landmark study, CRT was integrated into the context 
of a residential treatment17, 18 and patients receiving CRT had better SUD outcomes. However, it is a major 
limitation of that research that the CRT was administered in the context of long-term residential treatment 
settings.19 The only other published study of CRT for AUD also found significant improvement in 
neurocognition, well-being and compulsive craving, but it was within the context of an inpatient treatment unit.20 
These residential and inpatient studies provided CRT in a context that ensured that participation in the 
interventions could be tightly controlled and monitored. There were also other non-specific but stimulating 
activities such as a work-focused daily routine in the residential treatment that may have combined 
synergistically with the cognitive treatment. 
Although promising, these findings provide only 
limited support for CRT as a possible 
augmentation to SUD treatment and may not 
generalize to outpatient treatments.  Nevertheless, 
the National Institute on Drug Abuse (NIDA) was 
sufficiently encouraged by these findings as well as 
the large neuroscience literature on the effects of 
SUD’s on cognition to issue an RFA entitled 
“Cognitive Remediation Approaches to Improve 
Drug Abuse Treatment Outcomes (R21)”. Our 
group (PI: Bell) was awarded an R21 pilot grant 
under this mechanism to demonstrate feasibility of 
CRT for outpatients with SUDs and to determine 
effect sizes on neurocognitive and substance 
abuse outcomes.  
In this NIDA funded study, CRT was 
combined with Work Therapy (CRT+WT) and 
compared with WT alone (Cognitive Training and 
Work Therapy in the Initial Phase of Substance 
Abuse Treatment; PI: Bell).  Eighty-seven 
Veterans from substance abuse outpatient services were screened for eligibility within their first 30 days of 
sobriety; 48 were administered baseline assessments and randomized on a 1:1 ratio into CRT+WT (n= 24) or 
WT only (n = 24). They were on average 50.2 years of age, 49.4% Caucasian and most had felony convictions 
(80.5%). Twenty-eight had Alcohol Use Disorder (AUD) and 20 had other SUDs (amphetamine, cocaine, 
opiates). Our analysis of baseline neurocognitive assessments revealed high baseline rates of cognitive 
impairment, with 87.5% showing a clinically meaningful decline (1 SD) from a measure of their pre-morbid IQ 
on at least one cognitive measure. Moreover, 77.1% showed decline on 2 measures or more and the median 
was 3 measures out of 14 possible measures showing such a decline. Interestingly the highest rates of 
significant cognitive decline and impairment were on measures of verbal (50%) and non-verbal (45.8%) 
learning and memory with measures of executive function (41.7%) and working memory (37.5%) commonly 

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45
50
55
60
0
1
2
3
4
5
6
Executive Function Index
Months
Work+Cog
Work Only
Note Simple slopes analyses of rates of change found Executive 
Function slope for Work+Cog was statistically significant (γ = 
2.509, se=.677, p = .001). Slope for Work Only was not 
statistically different from zero (γ = .457, se=.930, p = .478). 
Difference between groups’ baseline scores was not statistically 
significant (γ = 3.067, se=2.263, p = .183). TimeXCondition is 
statistically significant (F = 4 87 p< 03)
Figure 2. Work+Cog Executive Functioning increases over time. 
deteriorated. These findings add justification to focusing our cognitive training on processes that support 
learning, memory and executive function, cognitive functions required to benefit from recovery-oriented 
treatment and to remain abstinent.27,28  
There were also differences noted in the 
R21 between those with a primary diagnosis of 
AUD (n = 28) and other SUDs (n = 20) with 
greater frequency of learning, memory and 
executive function decline and impairment in 
alcohol dependent participants and greater 
frequency of impairment in attention and 
response inhibition for participants with other 
SUDs. These group differences on performance 
measures were also mirrored in a self-report 
measure, the Barratt Impulsivity Scale, with other 
SUD participants scoring more than one 
standard deviation higher scores (more impaired) 
than AUD participants on Attention and Non-
planning subscales. These findings indicate that 
these two groups differ in type of cognitive 
impairment and is a primary reason that we have 
decided to focus on Veterans with AUD for the 
proposed submission.  
We got excellent participation. Those 
randomized to the CRT+WT condition had an 
average of 213 hours of productive activity, performed an average of 39.6 (median =42.8) hours of cognitive 
training and attended on average 10.4 (median = 12) out of 13 weekly groups.  The WT Only group had similar 
total hours of productivity and group attendance. Follow-up rates were also very good, with 44 out of 48 
(95.7%) completing 3 months follow-up and 42 out of 48 (87.5%) completing 6 month follow-up. Thus, this pilot 
demonstrated excellent adherence and study retention, well above what is usually found in SUD research. 
 Neurocognitive outcomes were analyzed by creating 5 composite indices: Visual and Verbal Working 
Memory, Visual and Verbal Learning, Processing Speed, Attention, and Executive Function.  Mixed effects 
model for 3 points in time (Baseline, 3 month and 6 month follow-up) revealed significant Time effects on all 
indices and significant differences (TimeXCondition) favoring CRT+WT on the Visual and Verbal Working 
Memory Index (p < .01; ES Cohen’s d = .84) and on the Executive Function Index (p < .05; ES Cohen’s d = 
.72).  All index trends favored the CRT+WT condition, and a Global Index Composite Score showed a non-
significant trend with an Effect Size of Cohen’s d = .36.  
Subanalyses that examined differential responses to treatment by primary diagnosis (AUD or Other 
Substances) found generally greater gains across indeces for those with AUD.  For example, Verbal Learning 
(HVLT scores) slopes across the 3 learning trials at baseline and at 3 month follow-up were compared for the 
two diagnostic groups by condition.  AUD participants showed significant improvement (p < .01) whereas the 
change in slope was not significant for those with other SUDs. These improvements in HVLT were sustained at 
6 month follow-up. Moreover, the Global Index Composite Score for AUD participants showed a near-
significant trend (p < .07) with an Effect Size of Cohen’s d = .71, almost double the effect size of d = .36 when 
all participants were included. 
Regarding SUD outcomes, CRT+WT had a mean of 87.3/90 (97%) days of abstinence (PDA) in the 
first 90 days, and 28.2 days of abstinence in the 30 days (94%) prior to 6 month follow-up. They also averaged 
23.8/26 (91.5%) weeks of abstinence out of 26 weeks.  However, the WT only condition produced similarly 
impressive SUD outcomes, so there was no differences by condition at either 3 month or 6 month follow-up.  
Results of the R21 study suggest that cognitive training is acceptable to older Veterans with SUD in 
outpatient treatment and leads to significant improvements in cognitive functioning beyond that of normal 
recovery with medium to large effect sizes. Moreover AUD participants may have benefited more from 

CRT+WT than those with other SUDs. In particular, CRT led to recovery of verbal learning for Veterans with 
AUD, a crucial cognitive ability for IDC, which depends upon verbal learning to be effective.   
5. Significance: Alcohol Use Disorders (AUDs) have a significant public health impact and are highly 
prevalent in Veterans. Alcohol related brain effects on neurocognition (attention, memory and executive 
function) reduce ability to benefit from current treatments.  These cognitive impairments are especially 
common in the early phase of recovery, persist over years and get worse with age. Recent research suggests 
that cognitive remediation therapy (CRT) may improve attention, memory and executive function in other 
disorders, and our just completed pilot study with AUD Veterans found significantly greater improvements for 
those receiving CRT.  This study will be the first to examine AUD outcomes and neurocognitive improvements 
when CRT is combined with a standardized alcohol treatment for outpatients with AUD.  Findings will 
determine whether CRT augmentation can benefit Veterans with AUDs.   
6. Research Plan:  
Design: This is a double-blind, intent-to-treat randomized controlled trial (RCT) that will randomize 90 
Veterans with a current and primary DSM-V (APA, 2013) alcohol use disorder (AUD) into two conditions.  
Participants will be within the first 30 days of recovery when consented, and those who meet all inclusion and 
exclusion criteria will be randomly assigned (ratio 1:1) to CRT+IDC or Game-Play Placebo+IDC for 13 weeks 
of active intervention.  All participants will continue to receive their usual alcohol abuse outpatient treatment. 
Psychotropic medications are sometimes prescribed and will be tracked in this study. Primary outcome is days 
of use and number of heavy drinking days (4 or more standard drinks per occasion for women and 5 or more 
for men; NIAAA website). Secondary neurocognitive and community function outcome measures are listed 
below in “Measures” section. Treatment adherence will be assessed. Assessments will be performed at 
baseline, 7 weeks, 13 weeks (end of active intervention) and 26 weeks. 
Participants: We expect to recruit by clinical referral and by flyer postings in clinical settings 
approximately 150 individuals of whom about 110 will pass the phone screening.  Following informed consent 
procedures, these 110 will complete all baseline assessments and we expect that 90 participants will meet 
criteria for a primary alcohol use disorder and all other inclusion and exclusion criteria. Participants will be 
recruited from the VACHS substance abuse program.  All study participants will be part of Dr. Joanna 
Fiszdon’s subject re-contact repository (#0009).  
Inclusion criteria: Males and females at least 21 years of age; fluency in English and a 6th grade or 
higher reading level; meets DSM-V criteria for a current Alcohol Use Disorder; referred for the study within 30 
days of detoxification or last substance use according to medical records; willingness to attend follow-up 
assessments at 13 weeks and 26 weeks; willingness to submit to Breathalyzer screenings and Urine 
Toxicology screenings.   
Exclusion criteria:  Lifetime diagnosis of a psychotic disorder, not induced by drug use; current 
prescribed treatment of opioids or benzodiazepines, which may affect new learning; involvement in a legal 
case that may lead to incarceration during study period; residential plans that would interfere with participation; 
medical illness that may significantly compromise cognition (e.g. Parkinson’s, Alzheimer’s, Huntington’s 
Chorea, Moderate or greater TBI); an uncorrected sensory impairment (hearing or sight) that would seriously 
interfere with cognitive training; pre-morbid IQ estimate below 70; unstable housing or lack of commitment to 
staying within a geographic area that would make follow-up possible); unwillingness to provide contact 
information of someone who can help us contact the participant in the event that we are unable to maintain 
contact directly.  They must be competent to give written informed consent and HIPAA authorization.   
Measures: Primary outcome measures are Heavy Drinking Days and Days of Use for the 90 days of 
active intervention as measured by Time-Line Follow-back (TLFB) Alcohol Use Assessments. This assessment 
asks for days of use and how many drinks and what types of drinks were consumed at each occasion during 
the preceding week. Other drug use is also recorded. TFLB assessment is done weekly along with an alcohol 
urine toxicology test and a Breathalyzer test. If more than one week has passed since the last TFLB 
assessment, the TLFB procedure is used to review the entire lapsed period. For example, if it has been 14 
days since the last TLFB, then going backwards, the interviewer would ask about alcohol use for those 14 
days. Breathalyzer testing and an alcohol urine toxicology test is always performed first, followed by the TFLB.  
This sequence encourages disclosure even though Breathalyzer results only reflect alcohol use during the past 
day.  The alcohol urine toxicology test reflects a window of up to 80 hours of prior use. A positive Breathalyzer 
test and an alcohol urine toxicology test is regarded as definitive evidence of alcohol use and has precedence 
over self-report when the person denies use.  However a negative Breathalyzer test or a negative alcohol urine 

toxicology test is not regarded as evidence of abstinence when the person states that he/she used alcohol. 
Secondary outcomes include Heavy Drinking Days and Days of Use for the 30 days preceding 6 month follow-
up using Breathalyzer and the Time-Line Follow-back procedure.. Changes in Alcohol Craving from baseline at 
3 and 6 month follow-up will be examined. Neurocognitive outcomes at 7 weeks and at 3 month and 6 month 
follow-ups are also secondary outcomes. Measures are presented in the following chart by category. They 
include AUD related assessments and cognitive assessments by domain. These domains include attention, 
working memory, learning and memory, executive function, and processing speed. We also include measures 
of risk taking and impulsivity because they are strongly associated with AUD and may be inhibited by improved 
executive functions. A treatment utilization form is included as a weekly measure of treatments received 
beyond study procedures.  Given space limitations, descriptions are not provided, but references are included. 
From our experience in the R21, which used very similar assessments, Baseline is estimated to be 3-4 hours 
and follow-up evaluations are 2-3 hours. Inter-rater agreements were in the good to excellent range in prior 
studies and in the R21, and agreement drift is checked through consensus meetings. 
Instrument 
Source 
Blinded  Baseline Weekly 
7wks 
13wks 
26wks 
Inclusion/Exclusion 
Chart + 
Interview 
 
 
 
 
 
 
Demographics & M.I.N.I39 
Interview 
 
X 
 
 
 
 
AUD Related Assessments 
 
 
 
 
 
 
 
EtG Urine Tox Screen 
 
 
X 
X 
 
X 
X 
Alcohol Breathalyzer 
 
X 
X 
X 
 
X 
X 
Time-Line Follow-back Alcohol 
Use Calendar40 
Interview 
X 
X 
X 
 
X 
X 
Addiction Severity Index  
modified41 
Interview 
X 
X 
 
 
X 
X 
Drug Urine Tox Screen 
 
 
X 
 
 
X 
X 
Penn Alcohol Craving Scale42  
Self 
 
X 
X 
 
X 
X 
Premorbid-IQ Estimate 
 
 
 
 
 
 
 
Wechsler Test of Adult 
Reading (WTAR)43 
Perform 
X 
X 
 
 
 
 
Attention 
 
 
 
 
 
 
 
Integrated Visual & Auditory 
Continuous Performance  
Test-244 
Perform 
X 
X 
 
X 
X 
X 
Trails A & B45 
Perform 
X 
X 
 
X 
X 
X 
Working Memory 
 
 
 
 
 
 
 
Digit Span46 
Perform 
X 
X 
 
X 
X 
X 
Spatial Span47 
 
X 
X 
 
X 
X 
X 
Learning and Memory 
 
 
 
 
 
 
 
Hopkins Verbal Learning Test 
(multiple forms)48 
Perform 
X 
X 
 
X 
X 
X 
Logical Memory I + II47 
Perform 
X 
X 
 
X 
X 
X 
Brief Visual Motor Test49 
Perform 
X 
X 
 
X 
X 
X 
Babcock Story Recall Test 59 
Perform 
X 
X 
 
X 
X 
X 
Executive Function 
 
 
 
 
 
 
 
Wisconsin Card Sort Test (64 
cards)50 
Perform 
X 
X 
 
X 
X 
X 
D-KEFS Tower Test60 
Perform 
X 
X 
 
X 
X 
X 
D-KEFS Color-Word 
Interference Test61 
Perform 
X 
X 
 
X 
X 
X 
Mazes51 
Perform 
X 
X 
 
X 
X 
X 
Processing Speed 
 
 
 
 
 
 
 
Digit Coding46 
Perform 
X 
X 
 
X 
X 
X 
Symbol Search46 
Perform 
X 
X 
 
X 
X 
X 
Self Assessments 
 
 
 
 
 
 
 
Barrett Impulsivity Scale52 
Self 
 
X 
 
 
 
 
Beck Depression Inventory62 
Self 
 
X 
 
 
X 
X 
Beck Anxiety Inventory63 
Self 
 
X 
 
 
X 
X 
VR-1264 
Self 
 
X 
 
 
X 
X 
Bell Object Relations & 
Self 
 
X 
 
 
 
 

Reality Testing Inventory65 
WHODAS 36 Item Self 
Report66 
Self 
 
X 
 
 
X 
X 
Patients Assessment of Own 
Functioning Inventory 
(PAOFI) 67 
Self 
 
X 
 
 
X 
X 
Treatment Utilization 
 
 
 
 
 
 
 
Treatment Utilization Form 
Chart+ 
Interview 
 
X 
X 
X 
X 
X 
Procedures:  
Informed Consent and HIPAA authorization will be obtained according to procedures approved by the 
VACHS IRB. A certificate of confidentiality will be requested.   
Randomization: Participants will be randomized into CRT+IDC or Game-Play Placebo+IDC conditions.  
Randomization will be stratified by neurocognitive deterioration (Yes/No) based on having 3 or more baseline 
cognitive measures greater than 1 SD below premorbid estimate (3 was the median number of measures 
below expected value in the pilot R21 study described above).  Variable block randomization tables will be 
created based on computer generated blocks using random permuted blocks of 2 to 6 by our statistician from 
Yale Center for Analytic Science. Sealed envelopes containing the randomization by participant entry number 
will be created and opened when a participant’s pre-randomization procedures are completed.  
Assessments Procedures: Measures are listed in the table above. Preliminary screening will be 
performed with a brief interview usually by phone that describes the inclusion and exclusion criteria in simple 
language and asks if the individual believes he/she meets criteria. After informed consent, participants will 
undergo DSM-V diagnostic procedure with the M.I.N.I diagnostic interview adapted to DSM-V.39, the WTAR to 
determine reading level and pre-morbid IQ estimate and a thorough demographic and psychosocial interview 
to determine whether they are eligible for the study according to inclusion and exclusion criteria. Information 
from medical records and referring clinicians are also used. During the active intervention participants will have 
weekly Breathalyzer tests and a weekly TLFB Alcohol Use Calendar. Critical events will also be recorded along 
with on-going process data about participation in procedures and response to cognitive training. Treatment 
utilization will be tracked weekly and at follow-ups by chart review and interview. Baseline assessments will be 
repeated at 3 months and 6 months. A briefer battery of cognitive tests will be performed at 7 weeks. The 
participant time line is shown in the table below: 
Participant Time-Line 
Week 
Procedure 
-1 
Screening to determine eligibility and Informed Consent 
0 
Baseline Assessment, and Randomization  
1-13  
Intervention Condition with Weekly Alcohol Use Assessments & Breathalyzer & 
Alcohol Urine Toxicology Screen 
7 
Cognitive Assessment 
13 
Complete Intervention Condition and Follow-up 1 Assessment 
26 
Complete Follow-up 2 Assessment 
Blinding: This is possible because of our ability to have specialized staff for each purpose. Cognitive 
Remediation/ Individual Drug Counselors (IDCs) are required to be un-blinded in order to provide support for 
participants in their assigned conditions. They will be distinct from the psychometrician doing weekly and 
follow-up assessments.  Blinded Roles: Staff responsible for the administration and scoring of participants’ 
assessments after randomization will remain blinded to participant treatment condition.  To prevent un-blinding, 
the following controls will occur: 1.The treatment condition (CRT+IDC) and the control condition (Game-Play 
Placebo+IDC) will be identified as “Cognitive Training A” and “Cognitive Training B”; 2. Participants will be 
reminded not to discuss details related to treatment with the psychometrician prior to the start or at the 
conclusion of their visit (a sign on the desk reminds the participant of this rule); 3. Research staff will be 
instructed not to discuss details of treatment related to either cognitive training arm during informed consent or 
at any other point throughout the study.  The informed consent accurately describes this study as a 
comparison of two approaches to using challenging computer games to improve cognition. Every effort will be 

made to avoid the implication that one condition is the experimental condition and the other is the control 
condition. 4. Accidental un-blinding of the psychometrician (e.g. through the un-intended viewing of treatment 
sessions) will be avoided. 5. Signs will be posted in appropriate areas reminding staff and participants not to 
discuss treatment details in open locations. 6. Mid-way and at the end of the trial, the psychometrician will be 
asked questions to evaluate the integrity of the blinding procedures employed throughout the trial. The 
psychometrician will complete a rating of degree of blindness (Definite CRT+IDC to Definite Game-Play 
Placebo+IDC) after each assessment. The primary outcome of Heavy Drinking Days and Days of Use is 
relatively immune to bias, particularly since it is informed by chart review and weekly Breathalyzer testing. All 
procedures are already in place and were successfully implemented in the R21. 
Treatment Conditions 
Individual Drug Counseling (IDC): Once randomized to condition, all participants meet individually each 
week with their Individual Drug Counselor, who follows the manualized IDC treatment.  All participants receive 
these procedures during the 13 weeks of active intervention.  IDC has been summarized in a published manual 
for study therapists56.  It is based on the disease model of addiction.  Clients are counseled regarding such 
fundamental concepts of AUD treatment as pointing out when a client is denying the extent and consequences 
of alcohol use, teaching clients to avoid “people, places and things,” and encouraging clients to make a 
personal inventory of qualities to change.  It is practical and behavioral, with a focus on abstinence in the here 
and now.  The manual describes sessions devoted to treatment engagement, early abstinence and 
maintenance of abstinence.  IDC does not prevent clients from getting the treatment-as-usual they have been 
getting prior to enrollment. In addition to standard IDC, several adaptations have been made to IDC for this 
study. These include a) research staff will make phone calls to remind participants of their appointments and to 
coordinate with other clinicians to schedule appointments; b) weekly appointments will be scheduled over 13 
weeks, with rescheduling and drop-in appointments allowed; c) abstinence is presented as desirable but to 
prevent the Abstinence Violation Effect (a slip becoming a full-relapse), relapse prevention and harm reduction 
will be emphasized; and d) participants are encouraged to participate in available AUD treatment groups at 
VACHS, whereas classic IDC more specifically refers to Twelve Step groups.  
CRT and Game-Play Placebo: This study employs two computerized programs for cognitive 
enhancement.  The CRT+IDC condition uses BrainHQ and the Game-Play Placebo uses a set of ordinary 
computer games.  Participants will be asked to use their assigned program for one hour per session, up to five 
sessions per week, over three months (maximum of 65 sessions).  A particular advantage of this training is that 
after participants are trained in how to log on to the training website and are familiar with the training programs, 
they may continue their training on site at the Learning Based Recovery Center (LBRC)’s “Cog Lab” or at 
another quiet location of their choice. If the participant prefers, it is also possible to use the program on their 
own device at home, use a computer available at their residence or a computer at a local library.  The program 
allows participants to change locations as fits their schedule. Usage and progress tracking for both programs is 
completely web-based, allowing participants to move between computers as is convenient for them.  Research 
staff carefully monitor usage and progress each week and use that information in phone call counseling 
sessions regardless of condition assignment.   
Also, while we will encourage participants to complete 5 sessions per week of training, we will also let 
them know that we understand that not every participant will be able to maintain this schedule.  We will let 
them know that if they feel they need to drop to a lower number of sessions per week that they should discuss 
it with their research counselor who will work out a schedule that is feasible in their overall life circumstances. 
There are also circumstances in which the participant may wish to practice more than 5 sessions in a week, 
particularly when they missed some practice days in a previous week.  This is allowable but should be 
discussed with the participant’s research counselor. Participants may also choose to do their computer-based 
training even if they miss a weekly IDC appointment.  The research counselor will contact the participant by 
phone to encourage continued participation and to learn about any alcohol or other substance use during the 
week. If a participant wishes to stop or minimize use of the training program, they will still be encouraged to 
continue their IDC sessions, and contact will be maintained by phone, if possible, even if the participant does 
not regularly come to IDC sessions. Potential reasons for discontinuing might include a change in work 
circumstances, a change in residence, health issues, family/personal issues, relapse or a lack of interest in 
program activities.  However, the participant may want to meet their personal commitment to the basic 
scientific research of the study and will be encouraged to participate in follow-up assessments.   

Brain HQ is a computerized cognitive remediation program consisting of a set of specific cognitive 
exercises and is commercially available on the internet.  To disguise to which condition the participant is 
assigned, Posit Science created a special study log-in site so that a participant encounters the same initial 
screens when entering the system regardless of condition.  This special study website was created for the DoD 
funded mTBI study (BRAVE) currently in progress, and Posit Science has agreed to allow us to use it for the 
this study. To use BrainHQ, a participant opens a standard web browser on a broadband connected computer 
and goes to the study website.  The participant then logs into the website (using a study-provided screen name 
that contains no personally identifiable information).  A game-like experience begins, where the participant is 
encouraged to earn points and in-game rewards to advance.  To do so, the participant selects one of the 
cognitive exercises scheduled for the day, and performs that exercise for fifteen minutes.  After each trial, the 
difficulty of the next trial is updated to ensure that within a session, the participant gets ~85% of trials correct.  
Summary screens including game metrics (points, levels) and exercise metrics (usage, progress) are shown to 
the participant at the end of each session. BrainHQ has multiple cognitive exercises.  The scheduling 
mechanism ensures that the participant progresses through the exercises in a defined order, generally moving 
from simpler (early sensory processing) exercises to more complex (multimodal, cognitive control) exercises 
over the course of the three month experience.  At any point in time, the participant only has access to a 
subset (typically six) of these exercises, four of which are performed per day.  Each exercise has specific 
criteria for completion or plateaued performance, and after those criteria are met, the exercise is removed from 
the active set and the next exercise is added to the active set.  This ensures ongoing novelty and engagement, 
while allowing for smooth progression through the complete set of exercises.  The exercises include many of 
the auditory and visual tasks used in our R21 pilot study that address attention, working memory, processing 
speed, memory and learning, and executive function 
Game-Play Placebo: The active control program is composed of 13 ordinary computer games.  It is 
designed to 1) be a face-valid approach to cognitive remediation to maintain participant blind and match 
BrainHQ in any halo or expectation effect, 2) match BrainHQ in overall program use intensity, requirements for 
attention, delivered rewards, and overall engagement, and 3) provide a comparison group that matches 
BrainHQ with the exception of the specific scientific approach to cognitive remediation embodied by BrainHQ 
to allow the study results to be interpreted in light of that specific approach. The Game-Play Placebo is 
launched in the same manner as BrainHQ.  The participant chooses from a number of ordinary computer 
games (e.g., hangman, boggle, word scramble, chess).  The games are chosen for their face-validity in 
improving cognitive function.  The number, availability, and time spent on each game is managed by the game 
controller to generally match the experience of progress through BrainHQ.  Only games providing face-valid 
cognitive stimulation and that are rated E (for everyone) by the Entertainment Software Rating Board (ESRB) 
will be used. This is the same control condition currently in use in the DoD funded mTBI study (BRAVE). 
Participant Compensation 
 
To encourage participation, small incentives are included in this study to compensate for time and 
inconvenience. Participants will receive $50 for the interview and screening procedures, $25 for the 7 week 
assessment, $75 for 3 month follow-up, and $75 for 6 month follow-up, for a total of $225 for assessments. 
They will receive $10.00 for each individual session of Individual Drug Counseling plus $5.00 for the 
breathalyzer test during 13 weeks for a maximum total of $195.00. They will also receive $5 per hour for time 
spent doing cognitive training for a maximum total of $325 for 65 hours of training.  The maximum total 
compensation for full participation in all procedures over 26 weeks is $745. Payment will be made according to 
current VA procedures.  They may choose to have a check mailed to the address they provide or they may 
choose electronic fund transfer (EFT) if they provide required banking information or they may choose to 
receive gift certificates for use at the VCS canteen (retail store) or VCS cafeteria here at the VA 
Concomitant Treatment and Staff Training 
Approach to Concomitant Treatment: The aim of this study is to determine efficacy in an outpatient 
setting, and there will be wide variability in how much participants utilize concomitant treatment-as-usual.  
Concomitant treatment will be tracked using our Treatment Utilization form to determine whether CRT+IDC 
increases participation in concomitant treatment and if such an increase mediates its effect on AUD outcomes.  
All participants will have access to a VA primary treating clinician.  Primary clinicians will coordinate the 
participant’s access to other available treatments including a prescribing physician, restricted settings 
(inpatient, day hospital and detoxification), residential assistance (supervised housing, group homes, rent 

assistance), outpatient substance abuse treatment, and vocational rehabilitation.  Participants are encouraged 
to remain engaged in outpatient services and to do so throughout the study. Their study condition is meant to 
be an augmentation to their usual treatment at VACHS. Part of the consent process includes permission for 
research staff to speak with their clinician and to convey clinically relevant information at the discretion of the 
PI. Moreover, all participants will have at least monthly notes recorded in their electronic medical record 
relevant to clinically related events that may occur during research activities. This is carefully explained in the 
consent form and is for the medical welfare of the participant. These procedures are to ensure that participants 
experience the study intervention as an augmentation to their on-going AUD treatment.  
Therapist Training to Conduct Individual Drug Counseling:  Training will be overseen by Dr. Rosen and 
will employ multiple modalities: review of the therapy manual, role plays, and group meetings to discuss 
problematic aspects of the therapy.  Digital recordings of IDC delivered as part of Dr. Rosen’s RO1 are 
available from the NIAAA website. Hiring counselors who have an AUD treatment background is important 
because when experienced counselors deliver IDC, it is readily learned and delivered with fidelity57, 58.  In the 
main clinical trial, IDC was the intervention rated as being delivered with the highest fidelity to the manual59.  
 
Therapist Supervision of IDC:  The therapist will be supervised intensively by Dr. Rosen until the 
therapist understands IDC and delivers it effectively, as verified by review of therapy videotapes and therapy 
notes.  Dr. Rosen will not be one of the independent raters of the videotapes for fidelity purposes and thus, will 
be able to review the videotapes in supervision without compromising the ratings’ impartiality.  After the initial 
period, supervision will be phased back to weekly, with as-needed consultation.   
 
Assessment Training. The psychometrician is independent of the research counselors and is kept blind 
to condition. Our assessors have already been trained through our previous research. Dr. Bell monitors the 
procedures and carefully reviews assessment data weekly for any inconsistencies that may suggest errors in 
scoring or data entry. If new staff is added during the course of the proposed study, Dr. Bell takes responsibility 
for training them in these procedures by having them observe assessments, perform assessments under his 
supervision and by determining inter-rater agreement. In the proposed study, the only clinical assessments are 
MINI diagnosis at baseline, the Time Line Follow-back Alcohol Use Calendar, and the ASI. 
Data Management, Sample Size Calculation, and Analysis Plan  
 
Data management will follow procedures established in previous studies Our research team will use 
Teleforms® software to create, clean, and enter quantitative data. Forms are created with barcodes that are 
scanned using Teleforms’ object character recognition software. Data is extracted and automatically inputted to 
an SPSS database. Filters flag data that needs to be re-checked by a person such as unclear characters, out-
of-range variables and logical inconsistencies.  The research assistant will scan files monthly so that errors can 
be readily corrected and consequential differences between treatment types (e.g., different levels of attrition) 
can be monitored closely. SPSS (vers. 21) will be used as the primary analysis software. Baseline 
characteristics will be tested for any significant differences between randomized conditions using parametric 
and non-parametric procedures as required by the nature of the data. Data reduction is a major issue in a 
relatively small N, large-number-of-variables study. We have chosen a primary outcome measure (Heavy 
Drinking Days and Days of Use in the first 90 days) to reduce Type I error. Heavy Drinking Days and Days of 
Use will be determined by Time-Line Follow-back calendar and Breathalyzer results. If a participant cannot 
provide more exact information about days of use for that week, then we will assume continuous use.   
 
Neuropsychological data will be indexed into established domain scores (attention, working memory, 
memory and learning, executive function, processing speed) and a composite index score.  The design is 
intent-to-treat. Distributions of continuous data will be tested for normality and transformed when necessary. 
Randomized conditions will be tested for potential differences on baseline values. We believe that our stratified 
randomization will make it unlikely that significant differences will be found; however, any significant 
differences will be used as covariates in between-group comparisons.  
Sample size: We plan to screen approximately 150 Veterans and recruit 110 Veterans (after telephone 
screen) with a current and primary DSM-V AUD who are within the first 30 days of recovery and expect that 90 
will be eligible for randomization after baseline testing.  We expect better than a 90% retention rate at the 3 
month time point, and thus expect to have more than 80 individuals for the primary analysis.  Assuming equal 
loss-to-follow-up in each of the two treatment arms, we will have at least 40 individuals per group.  Using data 

from our pilot study and the study done by Bowen et al.,6 we estimate mean Days of Alcohol Use in the 
Placebo + IDC arm to be 4 and the number of Heavy Drinking Days to be 3 at 90 days.  Using PASS 12 
(Kaysville, Utah) Poisson regression procedure, and assuming an over-dispersion parameter of 2 for days of 
use and 4 for heavy drinking days, we will be able to detect a 37% reduction in days of use and a 55% 
reduction in days of heavy drinking with 80% power and a type I error rate of 5% for each outcome in the 
CRT+IDC arm compared to the Game-Play Placebo + IDC arm.  Stratification on neurocognitive functioning 
was not factored into the sample size calculations.  In most situations, stratification will increase precision, and 
thus we will have a conservative estimate of the detectable effects.  Given that we expect to lose another 5-
10% of individuals to follow-up, we will have less power to detect the same effect size at 6 month time point.   
Analysis Plan: We will use a Poisson regression model accounting for over-dispersion to compare the 
CRT+IDC arm to the Game-Play Placebo+IDC arm on the primary outcomes: Days of Use and Days of Heavy 
Drinking at 90 days (Ho1). We will use the same model to compare the CRT+IDC arm to the Game-Play 
Placebo+IDC for the 6 month time point, a secondary endpoint (Ho2).  We will conduct sensitivity analysis 
using a negative binomial model and assess any differences in the results compared to the Poisson model with 
over-dispersion60. To evaluate neurocognitive functioning (global index; index of working memory; index of 
executive function, etc..), we will use generalized estimating equations and/or linear mixed models (if the data 
appear normally distributed) to account for the correlation between time points (baseline, 3 months, 6 months) 
for a given individual.  We will test for a significant treatment arm by time interaction to determine whether the 
combination of CRT+IDC is more effective than Game-Play Placebo+IDC in improving neurocognitive 
outcomes (Ho3, Ho4).  We use contrast statements to explore the individual time point effects. In all models, 
we will adjust for neurocognitive functioning (the stratification variable). We will use the Benjamini-Hochberg 
procedure61 to control the false discovery rate for all secondary outcomes keeping the overall level of 
significance at 0.05. However, given the limited sample size in this study, we do not expect to reach statistical 
significance unless there are large effects, especially for the secondary outcomes, and thus plan to use these 
results as hypothesis generating for a larger confirmatory study. 
 
 

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