Sara J. Nixon - US grants

cognition; psychological models; disease /disorder proneness /risk; adolescence (12-20); alcoholism /alcohol abuse;

Polysubstance abusing alcoholics constitute the majority of alcoholics seeking treatment, yet there is no systematic research examining their cognitive and psychosocial status and the effect that these variables might have on recovery. The current project proposes a systematic consideration of these functions in three subgroups of alcoholics: those who a) regularly abuse no other drug (excluding marijuana); b) abuse "stimulants"; and c) abuse "depressants". A model identifying the underlying processes of access, availability and efficiency is proposed as a means of evaluating initial cognitive function and its recovery over a one year period (M = 14 months). Consistent findings regarding alcohol-related deficits in abstraction and problem-solving have prompted us to limit our investigation to this aspect of cognitive function. Psychosocial status and adaptation will be assessed at both initial testing and retesting with a series of questionnaires shown to be valid and reliable measures of family environment, work environment, and typical coping and general health issues. Specific cognitive tasks previously shown to be related to treatment outcome and relapse will also be administered. Measures of childhood and residual adult attention deficit disorders, family histories of alcoholism or other drugs, and sex differences will also be examined for possible effects on obtained differences in cognitive and/or psychosocial function. The cross-sectional aspects of the project involve a 4 (controls and 3 alcoholic subgroups) by 2 (males and females) factorial design. The longitudinal aspects of the study involve the initial assessment of function at 21-45 days sobriety followed by a reassessment at approximately 14 months (range 12-16 months) posttreatment. The study (N-240) requires the initial testing of 60 control subjects (n=30 females) and 60 alcoholic subjects (n=30 females) in each of the alcohol-drug subgroups. Alcoholic subjects, recruited from area inpatient and outpatient facilities, will meet DSM-IIIR criteria for alcohol abuse/dependence. Controls, recruited from community resources, will indicate no history of drug use of excessive social drinking. All subjects will be screened for any medical or psychiatric condition which might confound results. Subjects will be tested in our laboratories and paid for their participation. Dependent variables for the various cognitive studies include accuracy, response times, types and numbers of errors, and electrophysiological responses associated with semantic processing. Measures pertinent to assessing psychosocial adaptation include reported satisfaction with family and work environment, number and type of coping mechanisms, quality of interpersonal skills, depressive symptomatology, cognitive status and resumption of drinking or use (amount and pattern). The results will contribute to the scientific literature by identifying potential cognitive and psychosocial differences between the alcohol-drug subgroups and determining to what extent variables, as well as subject variables such as sex, family history, and attentional problems, are associated with differential outcome in the groups.

In recent years, a number of studies have addressed the health and mental health needs of American Indian (Al) people. These studies typically reveal a high rate of alcohol-related disorders among Indian people. The application of these findings, however, is limited by several factors. First, most of this work is limited to reservation residing tribes. Thus, virtually nothing is known about these issues among the Indian people who are not reservation residing, e.g., those tribes who were not placed on reservation lands, per se, but have established communities within larger, more integrated communities. Second, most have included predominantly male samples. Women are infrequently included. Third, under-appreciated in the literature is the heterogeneity of drinking practices both between and within tribes. In summary, there are essentially no data relevant to needs assessment, community perception or specific outcomes and consequences among male and female non-reservation residing Indian tribes. Oklahoma is home to approximately 260,000 American Indian people representing approximately 36 tribes dispersed across the state without reservation assignment or housing. Thus, Oklahoma represents an ideal environment for the conduct of programmatic study of non-reservation residing Indians. The overall objectives of this three-year collaborative initiative proposal are to 1) enhance our understanding of alcohol use among non-reservation residing American Indians, 2) facilitate the development of American Indian clinical researchers within our rather large collaborative group, and 3) to empower tribal affiliates and leaders to address problem areas related to alcohol use through the application of current research findings in both applied and basic sciences. To achieve these objectives, we are proposing a multicomponent project which a) involves community networking, educational programming and the conduct of pilot/feasibility studies and b) requires the collaborative efforts of the Cognitive Studies Laboratory (within the Oklahoma Center for Alcohol & Drug-Related Studies), Al academicians, clinicians and administrators across the state, and the Al recovering community.

comorbidity; substance abuse related disorder; nicotine; central nervous system stimulants; tobacco abuse; drug interactions; neuropsychology; psychopharmacology; ethanol; substance abuse related behavior; family; racial /ethnic difference; gender difference; alcoholic beverage consumption; patient oriented research; clinical research; human subject;

[unreadable] DESCRIPTION (provided by applicant): Despite the recognition that the cohort of older adults continues to increase, that older adults remain socially and professionally engaged for longer periods of time and that alcohol may adversely interact with common medications and various functions, systematic research on moderate alcohol use in older populations is remarkably limited. It is restricted by narrow test batteries, the inclusion of largely male samples and/or the failure to recruit representative samples. This revised pilot study was designed to address some of these limitations. Specifically, it would provide critical preliminary data regarding the effects of the acute administration of moderate alcohol and the effects of continued moderate drinking on neurocognitive, neurophysiological, and psychomotor performance as well as psychosocial functioning and adaptation. To complete this initial work, 148 older moderate drinkers between the ages of 56 and 70 will be evaluated. 132/148 will be tested under a double-blind placebo-controlled design. The remaining 16 (8 male/8 female) will comprise a comparison group to be tested under control conditions where alcohol is neither expected nor administered, Because older women are a particularly understudied group, every attempt will be made to recruit equal numbers of male and female drinkers. Data collected from this study will provide critical information regarding the effects of acute, moderate doses of alcohol on older drinkers in a variety of domains and will also provide comparison data with younger substance abusing and community control subjects evaluated in our on-going work. This project, by ensuring appropriate protocol development, training, pilot work and initial data collection, would provide the necessary foundation for the further development of an aging focus in our on-going research program. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): There has been increasing attention directed to the potential benefits of moderate drinking, particularly in middle-aged to older adults. Importantly, most of this work has focused on moderate drinking as a lifestyle, without direct consideration of the acute effects of moderate doses of alcohol on older drinkers (i.e., moderate drinking as an event). Little is known about the effects of moderate doses of acute alcohol on neurocognitive, neurophysiological and performance measures among healthy adults in middle to later adulthood. From a scientific perspective, the absence of these data restrains conclusions regarding the direct effects of alcohol on behavior as well as the compensatory neurobehavioral mechanisms that may impact outcome. From a clinical perspective, the absence of data greatly restrains recommendations regarding the short-term risks associated with bouts of moderate drinking for a growing segment of the population. Pilot work (partial support, NIAAA R03AA14039, Nixon, principal investigator) revealed age effects suggesting that a low dose of alcohol negatively affected performance on the ascending limb to a greater extent than on the descending limb, but only for older (as opposed to younger) participants/subjects (Ss). Interestingly, the older group was also less aware of their deficits. Importantly, age-related differences in pharmacokinetics could not account for these results [40]. Interestingly, visual attention assessed at peak breath alcohol concentration (~.04 percent) was impaired equally for older Ss who received alcohol and those who actually received placebo but believed they had received alcohol [39] [See Section 3]. Unfortunately, representation across the conditions was not sufficient to allow gender- related analyses. These data provide conceptual guidance and reinforce the feasibility of and need for a systematic study that includes a greater dose range, larger samples for gender analyses, and more comprehensive neurobehavioral assessments. Therefore, we propose a double-blind placebo controlled study using a 2 (age: younger (25-35)/older (55-70)) by 2 (gender) by 3 (placebo, low (~.04 percent), and moderate (~. 065 percent)) alcohol dose factorial design to clarify the main and interactive effects of these variables on psychomotor speed, set-shifting abilities, attentional processes, and complex integrated behavior (i.e., driving simulation). To enhance the theoretical import of the work, we bring current models of cognitive aging to bear. The study has significant relevance to basic and applied studies of moderate (i.e., legal) levels of acute alcohol, healthy aging and cognition, and gender differences in sensitivity to the neurobehavioral effects of alcohol administration. PUBLIC HEALTH RELEVANCE: There has been increasing attention to potential cardiovascular and quality of life benefits associated with a moderate drinking lifestyle, particularly in middle aged to older adults. However, little systematic work has focused on the acute effects of these moderate doses on cognitive and performance variables critical to effective higher order functions including decision-making and tracking information. Building on our pilot work, this project compares performance between male and female older and younger moderate drinkers under 3 alcohol conditions designed to achieve zero blood alcohol concentration (placebo (0), a low level (~.04 percent) or a moderate level (~ .065 percent) to examine 1) to what extent and under what low-to-moderate alcohol doses older adults may demonstrate differential sensitivity and 2) whether older drinkers can accurately anticipate alcohol- related deficits. The findings will not only allow us to disentangle age from alcohol effects on neurocognitive tasks, but also shed light on differential risk for injury and negative outcome associated with episodes of moderate drinking among non-problem, older drinkers.

DESCRIPTION (provided by applicant): As detailed in PA-11-047 (Women and sex/gender differences in drug and alcohol abuse/dependence), gender differences in the etiology, progression, and consequences of substance use disorders (SUDs) remain incompletely understood. The current proposal focuses on one important aspect of this gap; consequences. More specifically, it is directed to clarifying how men and women may differentially experience the neurobehavioral consequences of alcohol dependence. It is noteworthy that most research directed to neurobehavioral assessments has focused on traditionally defined neurocognitive/ neuropsychological domains. Another compromised component of neurobehavior and a key aspect of successful adaptation, emotional processing, has been examined primarily in a separate literature. To better understand the breadth of neurobehavioral compromise, concurrently assessing neurocognitive and emotional performance in men and women is required. Furthermore, although studies of community samples typically reveal a female advantage on these tasks, gender differences among alcoholics are infrequently addressed. To enhance interpretation and direct future research, it is imperative that this work be conceptually driven. In response to these issues, we propose to assess cognitive and emotional functions in sufficient samples of male and female detoxified alcoholics (n=100, 50 females) and community controls (n=100, 50 females) to address both main and interaction effects. Guiding this work is a conceptual model which directs testable hypotheses, thereby informing future research and providing clinically relevant information concerning the processes underlying alcohol-related neurobehavioral (i.e., cognitive and emotional) impairment.

? DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period that is associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the University of Michigan and University of Florida is in response to RFA-DA-15-015, as part of the ABCD-USA Consortium (9/13) to prospectively determine the neurodevelopmental and behavioral effects of substance use on children and adolescents. A representative community sample of 975 9-10 year olds with enrichment for high-risk will be recruited as part of this application, contributing to the sample of 11,111 to be collected from 11 total sites across the ABCD-USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, DNA, and extensive assessment of substance use patterns, behavioral, psychological and social functioning. These comprehensive assessments will repeat at 2-year follow-up intervals, with intermediate assessments of functioning and substance use at 6-month intervals. These Consortium-collected data obtained during the course of this project will elucidate: 1) the effects of substance use patterns on the adolescent brain; 2) the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the gateway interactions between use of different substances. This Research Project focuses on risk and protective factors influencing trajectories of substance use and associated behaviors. Our emphasis is on: externalizing and internalizing phenotypes, both as core nonspecific risk factors for problem substance use and as important co-occurring outcomes of substance use; contextual factors (including sociodemographic, family and social influences) as risk and protective influences on the co-development of brain, substance use and psychopathology; and sex as a moderator of these relationships. We use novel methods for linking these factors to brain maturation. We address three aims: 1) At age 9-10, identify the neurofunctional and contextual factors influencing individual differences in externalizing and internalizing phenotypes prior to substance use; 2) Identify baseline neurofunctional predictors and contextual moderators over time of early (before age 14) substance use initiation; and 3) Characterize the developmental relationship between brain maturation, externalizing/ internalizing symptomatology, context, and substance use. This work will uncover neural correlates of distinct etiological pathways underlying adolescent substance use and identify temporal relationships between brain maturation, substance use and psychopathology.

? DESCRIPTION (provided by applicant): The major mediators of nicotine's cognitive and addictive effects are nicotinic acetylcholine receptors (nAChRs). Stimulation of the ?4ß2 receptor subtype is generally considered responsible for many reward- associated properties of nicotine. However, ?7 type nAChRs appear to share control over nicotine-associated dopamine efflux and self-administration behaviors. Furthermore, data indicate that ?7 subunits may underlie the cognitively enhancing effects of nicotine. Taken together, these findings suggest ?7 manipulation may positively affect a number of neurobehavioral endpoints relevant to effective nicotine cessation. Previous work with a novel ?7 partial agonist, GTS-21, has demonstrated it has neurocognitive benefits in other clinical, but non-smoking, populations. To the best of our knowledge, neither its neurocognitive effects, nor its effects on smoking behaviors have been systematically examined in chronic smokers without psychiatric comorbidities. Thus, this Phase 2 study will provide a necessary first step to measure the effects of GTS-21 on smoking, mood, neurocognitive performance, and brain electrophysiology in a small sample of currently healthy, chronic smokers. Because smoking maintenance and cessation are particularly poorly understood among women, every effort will be made to recruit sufficient numbers of women for preliminary sex comparisons. Using a double-blind, placebo controlled parallel group design, 54 (27 women) community smokers who have been screened to exclude those with major psychiatric disorders and/or significant medical disorders and who have a demonstrated readiness to quit, will participate an 7 week active trial (plus screening and 1-week placebo run-in). With the exception that equal numbers of each sex must be assigned to each group, subjects will be randomly assigned to 75 mg/twice a day (BID), 150 mg/BID, or placebo/ BID. Across the study period, participants will undergo repeated neurobehavioral testing, laboratory assessments of cardiovascular and liver function, and provide weekly updates regarding smoking behavior and mood state. Existing studies of persons with major psychiatric disorders reflect the safety of the drug at these doses. Therefore, although safety data will be collected throughout the trial, the primary focus is on providing preliminary efficacy data across smoking-related neurobehavioral domains (i.e., cigarette use, mood/affect, cognition). As a preliminary study, statistical power will be necessarily limited. However, these data will guide future research wherein alternative doses, exposure time, drug alternatives and/or drug combinations would be considered.

Description This small grant application, developed in response to PA-14-037 (Women & Sex/Gender Differences in Drug and Alcohol Abuse/Dependence), integrates the team?s expertise in neurobehavioral assessment and investigation of sex differences with a growing literature regarding the potential efficacy of cognitive retraining in facilitating recovery among persons with substance use disorders (SUDs). As a pilot project, we ask whether cognitive training specifically focused on remediating compromise in top-down control processes underlying selective attention has differential benefits for treatment-seeking men vs. women. We recognize that although neurocognitive improvement during training is desired, of practical import is whether gains are achieved during training transfer to other tasks and settings. Therefore, we propose to examine transfer of training gains to tasks/domains varying in their similarity to training demands. Furthermore, given noted sex differences in emotional processing and the purported role of emotional factors in women?s substance use, we include training that engages emotional processing via the use of affective stimuli (faces and words) as an experimental variable; we posit that both men and women will benefit, but that women may benefit to a greater degree. To interrogate individual differences and inform further treatment development, we will examine associations between/among pre-intervention measures including demographic and substance use histories, family history of SUDs, interpersonal problems, neurocognitive performance and training-related improvements as well as psychosocial adaptation and substance use after discharge; These analyses are enabled by the overlap between the proposed work and the on-going R01 (AA022456, PI Nixon). In the current proposal, we focus on treatment-seekers with alcohol use disorders (AUD) who may or may not meet criteria for other substance use disorders (SUD). To address our objectives/aims, we propose that equal numbers of treatment- seeking men and women (Ss) be randomly assigned to one of two active training interventions (neutral or affective stimuli). Ss will complete baseline and post-intervention testing and will be contacted on a monthly basis for ~ 3 months following discharge to assess substance use and psychosocial adaptation. To control for abstinence-related recovery, a third group of Ss who meet identical selection criteria will complete pre- and post-intervention testing but will not engage in the intervention. The data will inform questions of neurocognitive recovery and sex differences and guide development of more comprehensive initiatives. The feasibility of the work is enhanced by concurrent work addressing parallel questions in the PI?s laboratory.

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA- DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child?s changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.