James MacKillop - US grants

DESCRIPTION (provided by applicant): This project has the ultimate goal of improving behavioral treatment for alcohol dependence. Experimental animal and human research demonstrating the prominent influence of associative conditioning in drinking behavior has given rise to cue exposure treatment (CET) for alcohol dependence. This treatment component exposes individuals with alcohol dependence to cues associated with drinking for prolonged periods to extinguish conditioned responding. In turn, CET attempts to facilitate transition beyond treatment by reducing cue reactivity to previous associations and enhancing both coping skills and self-efficacy. Despite generally promising outcomes, CET has been criticized for failing to incorporate contemporary learning research that suggests various factors that may compromise extinction, namely context-dependent leaming. Equally, recent animal learning research has demonstrated approaches to reduce context-dependent learning, such as the use of an extinction reminder or multiple context extinction. This study attempts to extend this latter finding to a human population and evaluate whether multiple context exposure will enhance extinction to alcohol cues, toward ultimately enhancing CET for alcohol dependence.

DESCRIPTION (provided by applicant): This proposal for a K23 Mentored Patient-Oriented Research Career Award is to provide James MacKillop, PhD, with the necessary mentorship and training to conduct high-quality research using behavioral economics to enhance research on pharmacotherapies for alcoholism. A behavioral economic approach may enhance pharmacotherapy research by focusing on medication effects on alcohol self-administration, facilitating mechanistic analyses, and providing greater translational consilience. The Career Development/Training Plan includes training in: 1) neuroscience and psychopharmacology; 2) laboratory methods for alcoholism pharmacotherapy research; 3) clinical methods for alcoholism pharmacotherapy research; 4) advanced training in behavioral economics; 5) professional development; 6) responsible conduct of research. The training will be overseen by a mentorship team comprised of Robert Swift, MD, PhD (Sponsor), Peter Monti, PhD (Co-Sponsor), Jennifer Tidey, PhD (Advisor), and Robert Miranda, Jr., PhD (Advisor). The training plan also proposes an empirical research project using behavioral economics to examine the effects of topiramate (TOP), a promising novel pharmacotherapy. The proposed study will recruit 60 alcohol dependent individuals who are not seeking treatment and study the effects of TOP under neutral conditions and during the ascending limb of the blood alcohol curve, using a 2 (TOP SOOmg/placebo) X 2 (neutral/ascending limb) mixed design. Based on its putative neuropharmacological actions and correlational clinical data, TOP is predicted to reduce alcohol self-administration on two behavioral economic measures. For exploratory purposes, the effects of TOP will also be examined during the descending limb of the blood alcohol curve. In addition to serving as criticial training; this research may have important clinical and methodological implications. RELEVANCE OF THE RESEARCH TO PUBLIC HEALTH: Medications for treating alcoholism have considerable promise and behavioral economics may enhance research in this area. This proposal is an application for a K23 Mentored Patient-Oriented Research Career Award for Dr. James MacKillop to gain the expertise to pursue this prospect, including mentorship, training, and an empirical study using behavioral economics to study topiramate, a promising new medication for alcoholism.

DESCRIPTION (provided by applicant): Extinction-based treatment for alcohol dependence has a strong theoretical and empirical basis, but only modest positive outcomes in clinical trials. Recent basic and human research has revealed that D-cycloserine (DCS) enhances extinction to fear cues and several lines of evidence suggest that DCS may also enhance extinction to alcohol cues. Thus, DCS may be a useful pharmacological adjunct to extinction-based treatment for AUDS. The proposed study is a proof-of-concept test of whether DCS enhances extinction to alcohol cues. Sixty-six alcohol dependent adults will be enrolled in a double-blind placebo-controlled two-group (DCS [50 mg]/placebo) between-subjects human laboratory study. Subjects will undergo an initial test of reactions to alcohol cues, two extinction sessions with acute administration of DCS or placebo, and follow-up alcohol cue reactivity tests one-week and one-month later. We hypothesize that DCS will enhance extinction to alcohol cues, as evidenced by attenuated cue-elicited craving at the second extinction session, the one-week follow- up, and the one-month follow-up. A secondary aim is to investigate whether the effects of DCS on extinction to alcohol cues translate into changes in craving in daily life. Effects of DCS on arousal and affect in response to alcohol cues will also be examined. Affirmation of the proof-of-concept that DCS enhances extinction to alcohol cues will provide the empirical basis for subsequent clinical research on whether DCS enhances extinction- based treatment. Furthermore, the proposed study will employ a translational experimental paradigm that has the potential for investigating additional medications that may enhance extinction to alcohol cues in future studies. PUBLIC HEALTH RELEVANCE: Extinction-based treatment is a promising approach for treating alcohol misuse but has demonstrated only modest positive outcomes in clinical trials. D-Cycloserine has been demonstrated to enhance extinction in animal and human research on anxiety and may also enhance extinction to alcohol cues. The proposed study will empirically test whether D-Cycloserine enhances extinction to alcohol cues toward improving extinction- based treatment for alcohol misuse.

DESCRIPTION (provided by applicant): This is a proposal for a second renewal of travel grant R13AA017107-06. For the last six years, this grant has provided funding to support scientific dissemination and early career investigator (ECI) career development at the annual convention of the American Psychological Association (APA). Psychologists make up a major constituency in the scientific community of alcohol researchers and on topics related to alcohol. The APA is the largest organization of psychologists and their trainees in the US, and its annual convention attracts thousands of attendees. In particular, APA Division 50 (Society for Addiction Psychology) and Division 28 (Psychopharmacology and Substance Abuse) are heavily populated with alcohol researchers, many of whom are recipients of NIAAA funding. This R13 grant partners with APA Division 50 and Division 28 to achieve two goals: 1) To disseminate the state-of-the-art alcohol research to the psychological community. 2) To foster the development of the next generation of alcohol researchers from the psychological community. The first goal will be achieved by supporting state-of-the-art alcohol research within the Division 50 and Division 28 conference programs. This will take the form of travel support for speakers in two symposia that showcase advances and innovations in alcohol research. In addition, these symposia and other alcohol research will be communicated to conference attendees via an Alcohol Research Highlights brochure. The second goal will be achieved by providing 20 travel awards to ECIs (i.e., graduate students, postdoctoral fellows, and junior faculty) and hosting an ECI poster session/social hour. In addition, the R13 will support grantwriting and career development workshops each year. For both, the dissemination goal and the career development goal, the R13 will reach out to women and underrepresented minorities to maximize inclusion. To date, this R13 grant has been highly successful in disseminating advances in alcohol research and nurturing the careers of early career alcohol researchers. The goal for the next segment is to sustain these contributions to the field and to expand the travel award program to support a larger number of ECIs.

PROJECT SUMMARY/ABSTRACT Alcohol misuse remains a major public health problem in emerging adults (age 18-25). Excessive drinking is the largest source of morbidity and mortality in this age group and also predicts subsequent alcohol problems across the lifespan. A large number of cross-sectional studies have found significant associations between alcohol misuse and indices from behavioral economics. Specifically, two novel behavioral economic domains - alcohol demand and proportionate alcohol-related reinforcement - have been consistently associated with alcohol misuse in emerging adults in cross-sectional and laboratory studies. These motivational measures may clarify the development of alcohol misuse, but no longitudinal studies have been conducted to date. The proposed study will use a longitudinal risk design to systematically investigate the relationship between these measures and changes in alcohol misuse in emerging adults. Specifically, the study will leverage these novel risk indicators to predict changes in drinking from age 22 to 25, a time period when many individuals `mature out' of alcohol misuse but others exhibit persistently high levels of problem drinking. To address this question, the study will assess 530 at-risk drinkers (50% male/50% female) every three months from 22 to 25 using in- person and Internet-based assessments. The study has two primary aims. The first primary aim is to predict changes in alcohol misuse in emerging adults using the novel behavioral economic measures - individually, in combination with one another, and in the context of established risk factors. The second primary aim is to examine mediating and moderating relationships. Mediational analyses will test whether the behavioral economic variables causally mediate the development of alcohol misuse over time or, alternatively, whether their influence is mediated by the established mechanisms. Moderator analyses will systematically examine differences based on college status (i.e., college vs. non-college) and other substance use. The study also has a secondary aim to inform future intervention studies. This exploratory aim is to identify the most salient periods of change and the concurrent psychosocial factors that increase or decrease the value of alcohol. Collectively, the study will leverage recent advances in behavioral economics to make major contributions to understanding of alcohol misuse over the transition to adulthood.

FUNDED PROJECT ABSTRACT Alcohol misuse remains a major public health problem in emerging adults (age 18-25). Excessive drinking is the largest source of morbidity and mortality in this age group and also predicts subsequent alcohol problems across the lifespan. A large number of cross-sectional studies have found significant associations between alcohol misuse and indices from behavioral economics. Specifically, two novel behavioral economic domains - alcohol demand and proportionate alcohol-related reinforcement - have been consistently associated with alcohol misuse in emerging adults in cross-sectional and laboratory studies. These motivational measures may clarify the development of alcohol misuse, but no longitudinal studies have been conducted to date. The proposed study will use a longitudinal risk design to systematically investigate the relationship between these measures and changes in alcohol misuse in emerging adults. Specifically, the study will leverage these novel risk indicators to predict changes in drinking from age 22 to 25, a time period when many individuals `mature out' of alcohol misuse but others exhibit persistently high levels of problem drinking. To address this question, the study will assess 530 at-risk drinkers (50% male/50% female) every three months from 22 to 25 using in- person and Internet-based assessments. The study has two primary aims. The first primary aim is to predict changes in alcohol misuse in emerging adults using the novel BE measures - individually, in combination with one another, and in the context of established risk factors. The second primary aim is to examine mediating and moderating relationships. Mediational analyses will test whether the BE variables causally mediate the development of alcohol misuse over time or, alternatively, whether their influence is mediated by the established mechanisms. Moderator analyses will systematically examine differences based on college status (i.e., college vs. non-college) and other substance use. The study also has a secondary aim to inform future intervention studies. This exploratory aim is to identify the most salient periods of change and the concurrent psychosocial factors that increase or decrease the value of alcohol. Collectively, the study will leverage recent advances in behavioral economics to make major contributions to understanding of alcohol misuse over the transition to adulthood. PROPOSED ADMINISTRATIVE SUPPLEMENT ABSTRACT We propose to enrich the parent project with 70 additional African American participants to have sufficient statistical power to conduct subgroup analyses on the trajectories of white participants vs. African American participants. Epidemiological research suggests greater risk of long-term problems from drinking for African American young adults and this enrichment will allow us to directly examine the risk mechanisms in this subgroup.

ABSTRACT Alcoholics Anonymous (AA) is now well-established in its capacity to help individuals recover from alcohol use disorder (AUD), but there are substantial gaps in understanding the mechanisms by which it does so. Recent studies suggest two novel domains of mechanisms: 1) decreases in impulsivity; and 2) increases in salutary social networks. However, these mechanisms have been investigated in only a small number of studies and the extant studies employed low resolution measurement and suboptimal study designs. The proposed study will address these limitations to systematically investigate impulsivity and social network composition as novel mechanisms of behavior change (MOBCs) for AA?s positive effects on AUD recovery. The first primary aim is to examine impulsivity, fractionating the concept into three distinct forms: 1) steep discounting of future rewards (i.e., delay discounting); 2) poor behavioral inhibition (i.e., inability to inhibit a prepotent response); and 3) impulsive personality traits (i.e., self-attributions about regulatory capacity). The second primary aim is to examine social network properties, quantifying participant social relationships via formal egocentric social network composition analysis. The third primary aim is to examine whether these mechanistic relationships systematically differ according to three important moderators: age, sex, and study site. An exploratory secondary aim is to mine the findings from the primary aims to generate specific recommendations and applications for clinical practice. These aims will be executed in a prospective cohort design that is optimized for characterizing lagged dynamic changes in MOBCs. Specifically, the study design will examine these processes in individuals with AUD who are newly engaging in community outpatient AUD treatment. Participants will receive assessments at baseline, 6-weeks, and 3-, 6-, 9- and 12-months. AA involvement will be measured using both the traditional measure of frequency of meeting attendance and a novel measure of AA program engagement. Outcome variables will include percent days abstinent and percent heavy drinking days. The findings will be disseminated using a comprehensive knowledge translation plan. Collectively, the proposed study has the potential to make major contributions to understanding how AA helps people recover from AUD. In turn, the insights from the study have the potential to substantially contribute to the use of AA and other mutual recovery services in clinical practice.

PROJECT SUMMARY/ABSTRACT The novel field of neuroeconomics integrates concepts and methods from psychology, economics, and cognitive neuroscience to understand the neurobiological foundations of decision making, and has been increasingly applied to understanding alcohol use disorder (AUD). A novel focus in neuroeconomics is alcohol demand, or the value of alcohol as measured by cost-benefit preferences. Behaviorally, alcohol demand has been found to be elevated among individuals with higher levels of alcohol misuse and to predict treatment response. In addition, alcohol demand can also be dynamically increased via acute stress. These findings are consistent with theoretical perspectives that emphasize both stable tonic and acute phasic aspects of motivation. The overall goal of the proposed studies is to characterize the neural activity that subserves these established behavioral findings using a novel functional magnetic resonance imaging paradigm. The first aim is to examine how the brain represents the value of alcohol in individuals with AUD compared to a control group. To do so, the first study will use a between-subjects case-control design to identify differences in neural activity associated with elevations in alcohol demand in individuals with AUD (i.e., cases) versus individuals who drink regularly but do not have an AUD and are matched on key variables (i.e., controls). The second aim is to investigate the changes in neural activity associated with stress-elicited increases in the value of alcohol. To do so, a second study will use a within-subjects design, comparing demand-associated neural activity following a neutral induction to neural activity following a stress induction in individuals with AUD. The third aim is to investigate the relationship between patterns of neural activity during alcohol demand decision making and intervention response. To do so, all participants with AUD in Study #1 and Study #2 will receive Motivational Enhancement Therapy, a previously validated four-session manualized motivational interviewing intervention, and neural activity during the alcohol demand paradigm will be used to predict subsequent drinking at 1-month and 6-month follow-up. Collectively, these aims will systematically apply a novel neuroeconomic approach to diverse aspects of AUD across the translational spectrum, from basic differences in neural activity to predictors of intervention response.

PROJECT SUMMARY/ABSTRACT Alcohol misuse remains a major public health problem in emerging adults (age 18-25). Excessive drinking is the largest source of morbidity and mortality in this age group and predicts subsequent alcohol problems across the lifespan. Although most emerging adults ?mature out? of hazardous drinking and transition into moderate use, many continue a developmentally persistent pattern of alcohol misuse, and the predictors of differential trajectories remain largely unknown. A large number of cross-sectional studies have found significant associations between alcohol misuse and indices from behavioral economics, thus we are currently conducting a longitudinal investigation of behavioral economic indicators as processes in regular binge drinkers from their early twenties (21-24) to their mid-twenties (24-27). However, this ?parent? R01 study does not include any measures of biological risk factors, so the proposed R21 study aims to collect neurophysiological measures of reward processing in a subsample at two timepoints spaced 8 months apart during the parent longitudinal study. The neurophysiological measures include two event-related potential (ERP) components that are robustly associated with reward processing: (1) P3, which reflects the incentive salience of alcohol-related vs. alcohol-free stimuli and (2) Reward Positivity (RewP), which will reflect sensitivity to immediate versus delayed reward. These ERP data would permit systematic investigation of the ERPs as biomarkers of persistent alcohol risk, a substantially understudied relationship in the existing literature. To address this question, the study will recruit 355 participants from the existing study to complete additional EEG sessions during already-scheduled study visits. This study has two primary aims. The first aim is to integrate cross-sectional neurophysiological measures into the ongoing longitudinal study to examine the utility of these measures to predict problematic alcohol use individually and in conjunction with behavioral economic indicators. The second aim is to determine correspondence between longitudinal changes in neurophysiological and behavioral economic indices of risk and their relations to alcohol misuse. Longitudinal models will be used to examine if changes in the neurophysiological indicators are responsible for changes in alcohol misuse over time and to disentangle overlapping versus independent influences.

PROJECT SUMMARY/ABSTRACT Alcohol misuse remains a major public health problem in emerging adults (age 18-25). Excessive drinking is the largest source of morbidity and mortality in this age group and also predicts subsequent alcohol problems across the lifespan. A large number of cross-sectional studies have found significant associations between alcohol misuse and indices from behavioral economics. Specifically, two novel behavioral economic domains - alcohol demand and proportionate alcohol-related reinforcement - have been consistently associated with alcohol misuse in emerging adults in cross-sectional and laboratory studies. These motivational measures may clarify the development of alcohol misuse, but no longitudinal studies have been conducted to date. The proposed study will use a longitudinal risk design to systematically investigate the relationship between these measures and changes in alcohol misuse in emerging adults. Specifically, the study will leverage these novel risk indicators to predict changes in drinking from age 22 to 25, a time period when many individuals `mature out' of alcohol misuse but others exhibit persistently high levels of problem drinking. To address this question, the study will assess 530 at-risk drinkers (50% male/50% female) every three months from 22 to 25 using in- person and Internet-based assessments. The study has two primary aims. The first primary aim is to predict changes in alcohol misuse in emerging adults using the novel behavioral economic measures - individually, in combination with one another, and in the context of established risk factors. The second primary aim is to examine mediating and moderating relationships. Mediational analyses will test whether the behavioral economic variables causally mediate the development of alcohol misuse over time or, alternatively, whether their influence is mediated by the established mechanisms. Moderator analyses will systematically examine differences based on college status (i.e., college vs. non-college) and other substance use. The study also has a secondary aim to inform future intervention studies. This exploratory aim is to identify the most salient periods of change and the concurrent psychosocial factors that increase or decrease the value of alcohol. Collectively, the study will leverage recent advances in behavioral economics to make major contributions to understanding of alcohol misuse over the transition to adulthood.