Duncan B. Clark - US grants

Adolescents with alcohol related problems are increasingly being recognized as a heterogeneous population, with multiple developmental trajectories leading to alcohol use disorders. Psychologically traumatic experiences are among the environmental factors often postulated to contribute to the development of adolescent alcohol use disorders. In our current investigation, a substantially higher proportion of adolescents with alcohol use disorders than community controls have experienced trauma and posttraumatic stress disorder (PTSD). This study s designed to test the hypothesis that PTSD symptoms and abnormalities in biological stress response systems comprise the mechanisms through which trauma adversely influences the development and course of alcohol use disorders. This hypothesis will be tested through three integrated studies; (1) a cross- sectional stud utilizing a neuroendocrine laboratory assessment and structured equation modeling to examine the relationships among trauma, indices of catecholamine system and hypothalamic-pituitary-adrenal axis activities, pTSD symptoms, and alcohol related problems; (2) a prospective study determining the impact of trauma and PTSD symptoms on short-term and long-term outcome for adolescents with alcohol use disorders; and, (3) a prospective study examining whether or not trauma and PTSD symptoms predict alcohol-related problems in adolescents without alcohol use disorders at baseline. The results of this study will determine the mechanisms governing the impact of trauma on alcohol use disorders in adolescents, will identify specific areas important for relapse prevention and will lead to the development of specific methods for identifying adolescents at high risk for alcohol use disorders for preventative interventions.

mental disorder diagnosis; patient /disease registry; adolescence (12-20); biomedical facility; medical outreach /case finding; alcoholism /alcohol abuse; longitudinal human study; clinical research; human subject; intelligence tests;

This study proposes to obtain pilot data on the effects of chronic and alcohol consumption on benzodiazepine receptor (BZR) distribution and density in adolescent onset alcohol dependence using [11C] flumazenil binding visualized by PET. Alterations in the gamma-aminobutyric acid (GABA) neurotransmitter system induced by chronic alcohol consumption represent the mostly likely neurochemical substrate of alcohol dependence. Subjects with adolescent-onset alcohol use disorders, compared with controls, will show reduced binding of [11C]-flumazenil in the cingulate cortex.

This application is submitted in response to RFA AA-94-08 for renewal of support for the Pittsburgh Adolescent Alcohol Research Center (PAARC), located within the Department of Psychiatry of the University of Pittsburgh School of Medicine. PAARC is the only alcohol research center supported by the National Institute on Alcohol Abuse and Alcoholism that focuses on diagnosed alcohol abuse and dependence among adolescents aged 12 through 18 hears of age. The overarching goal of the Pittsburgh Adolescent Alcohol Research Center is to enhance understanding of the structure, development, and consequences of adolescent alcohol use disorders through cross-sectional and longitudinal investigations of clinical and community samples of adolescents (N=500). Specific goals of the projects for the next 5-year period are to: (1) Develop a new and more appropriate adolescent taxonomy of alcohol use disorders/ (2) Determine the impact of alcohol use disorders on the developmental transitions during adolescence and young adulthood; (3) Elucidate brain-behavior covariation among impulsive/aggressive alcohol abusing or dependent adolescents; (4) Clarify the psychobiological mechanisms pertaining to stress and trauma that may underlie the linkage between PTSD and adolescent alcohol use disorders; and, (5) Identify the precipitants of lapse and relapse in adolescents. Excessive alcohol consumption and its consequences comprise a prevalent and serious public health problem among American adolescents. our finding thus far reflect far greater clinical heterogeneity and severity than has been commonly assumed in this population. Furthermore, and most importantly, the biomedical and psychosocial findings from our comprehensive database emphasize that adolescents exhibiting alcohol use disorders cannot be assumed to be merely younger versions of adult alcoholics. The enhancement of understanding of the particular nature of alcohol problems in adolescence is a necessary prerequisite to the development of effective prevention and treatment methodologies for this population.

DESCRIPTION (provided by applicant): This K02 competitive continuation application proposes to advance understanding of adolescent alcohol use disorders (AUDs) through examination of adult outcomes with innovative statistical techniques for longitudinal data. In Years 6 through 10, the program focus evolves from statistical techniques for categorical variables to techniques based on finite mixture models. The programmatic focus shifts from relationships among adolescent characteristics to adult outcomes. The project will emphasize person-centered statistical strategies to predict adult outcomes among adolescents characterized by substance involvement trajectories, psychopathology latent classes, childhood maltreatment histories, and treatment participation. With NIAAA and NIDA support, the Pittsburgh Adolescent Alcohol Research Center (PAARC) is completing adult follow-up assessments in adolescents with AUDs and a reference group. The hypotheses consider the confluence of behavioral, cognitive, and affective dysregulation in predicting AUD course, complications, and outcomes. Adult outcomes examined include AUDs, other substance use disorders, psychopathology,) personality disorders, academic achievement, work performance, family status, somatic symptoms, liver injury, and sexually transmitted diseases. Complementary data from the Center for Education and Drug Abuse Research (NIDA P50: PI Tarter, Co-PI Clark), a study of children at risk for alcohol and drug use disorders followed through adolescence into adulthood, will also be utilized. Incorporating categorical variables pertinent to symptom and diagnostic categories, the statistical strategies applied will include multivariate survival analysis, general growth mixture models, and Bayesian instance-based machine learning. These methods will be specifically optimized to construct clinically relevant models applicable to individual patients, serving as the basis for more thorough phenotype description, more effective prevention programs, and individually tailored treatment interventions.

disease /disorder etiology; substance abuse related disorder; child psychology; mental disorders; substance abuse related behavior; antisocial personality; disease /disorder proneness /risk; child behavior disorders; mood disorders; behavioral /social science research tag; human subject; adolescence (12-20); clinical research;

The study will examine the influence of two neglect dimensions, supervisory neglect and emotional neglect, on the onset, course and treatment outcomes of alcohol use disorders (AUDs) during adolescence and young adulthood. Applying concepts derived from attachment theory, neglect is hypothesized to influence AUD and other adverse outcomes through low parental attachment, behavioral undercontrol, negative affectivity, and deviant peer influence. Through secondary data analyses, neglect sales will be empirically derived from adolescent and parent indicators and validated for late childhood and middle adolescence. Scores on these indicators will be used to identify adolescents classified as experiencing supervisory neglect and/or emotional neglect. Models for the influences of neglect on adolescent and young adult outcomes will include consideration of parental substance use disorders and psychopathology, the subject's history of physical abuse and sexual abuse, parent-adolescent attachment, peer relationships, and neighborhood characteristics. Outcomes will include AUD's, other substance use disorders, psychopathology, and suicide attempts examined by repeated assessments. Two complementary datasets will be utilized. The Pittsburgh Adolescent Alcohol Research Center (PAARC) assesses the adolescent and the mother, obtains information about other family members, peers and neighborhood characteristic. The PAARC sample includes a subgroup of adolescents (n=110) participating in treatment for AUD's and assessed monthly for 12 months to study relapse predictors. The Center for Education and Drug Abuse Disorders (CEDAR) family study (n=750 families) includes high-risk children of parents with substance use disorders and low risk children of control parents. CEDAR assesses father, mother, index case (child 10-12 years old), and siblings. The outcomes of PAARC and CEDAR subjects are assessed every 1-3 years into young adulthood. Since data collection, data entry, and variable analyses will be completed prior to the requested funding start date, the proposed studies will be carried out over a one-year period. These analyses will determine the incremental predictive utility of supervisory neglect and emotional neglect outcomes considered in the context of other risk variables. By focusing on the clinically relevant risks and outcomes, these heuristic findings will inform clinical practice with neglected adolescents and guide future prevention and treatment research.

DESCRIPTION: (provided by the applicant) The transition from drug use to drug addiction typically occurs between adolescence and young adulthood, highlighting the importance of this developmental period to identifying factors influencing the onset and course of substance dependence. The project's primary goal is to determine predictors of the transition from adolescent substance use to dependence in a sample of adolescents (age 12-18) who were recruited through the Pittsburgh Adolescent Alcohol Research Center from addictions treatment (n=385) and community sources (n=163) who have been assessed with an extensive battery of baseline measures. The proposed award will support collection and analysis of adult (age 25 plus/minus 1) substance use and psychosocial outcomes, complementing on-going 1-, 3-, and 5-year follow-ups of the sample. The project will address three objectives described in the RFA. First, changes in drug use patterns in the transition to addiction will be characterized using growth mixture modeling. We hypothesize that trajectory classes differing in drug dependence severity and chronicity (e.g., developmentally-limited and persistent) represent identifiable developmental phenotypes. Second, the influence of co-occurring psychopathology, particularly conduct disorder, major depression, and posttraumatic stress disorder, on drug addiction transitions will be examined. We will examine common and reciprocal influence hypotheses to explain high rates of comorbidity between substance use disorders and psychopathology. Third, behavioral, psychosocial, and environmental factors will be examined as predictors of the transition from drug use to addiction by examining influences on the course of adolescent-onset substance use and related problems through adulthood. Use of a previously ascertained and well characterized sample of clinical and community adolescents represents a cost-effective approach to the identification of developmental phenotypes of adolescent-onset substance users that has with significant implications for prevention, genetics, and addictions treatment research.

The overarching goal of the Developmental Psychopathology Module is to elucidate the ontogeny of psychopathology in relation to substance use disorder (SUD) liability and outcome. During the proposed funding period, the hypotheses to be tested focus on psychopathology and SUD outcomes between late adolescence and early adulthood (ages 19-22). In addition, research will be condcuted to examine the association between psychopathology and precursor as well as contemporaneous psychological traits, particularly cognitive, affective and behavioral dysregulation. These latter traits are hypothesized to be integral to SUD liability (see Scientific Core section 2.4.6) and have been shown to antedate psychopathology. Consistent with CEDAR's epigenetic framework, psychological dysregulation is hypothesized to predispose to psychopathology which in turn predispose to alcohol, tobacco and other drug (ATOD) use and consequently lead to SUD. Studies of children at high risk for SUD, as well as adolescents qualifying for SUD, including CEDAR findings, have reported the predominance of two domains of psychopathology: (1) disruptive behavior disorders (saliently reflecting behavioral dysregulation); and, (2) negative affect disorders (saliently reflecting emotional dysregulation). The Developmental Psychopathology Module proposes to prospectively examine psychopathological characteristics from childhood through early adulthood. Using CEDAR's prospective paradigm, this module will determine the extent to which psychopathology predicts initiation and acceleration of ATOD involvement culminating in SUD. In conjunction with the Center's other modules, the influence and interaction of psychopathology on SUD liability and outcome will be examined in the context of maturational and environmental characteristics. In this context, psychopathology is both an outcome of psychological dysregulation (see Figure 1) and a precursor of subsequent outcomes, specifically SUD.

DESCRIPTION (provided by applicant): This R21 exploratory project will examine frontal white matter, executive functioning and treatment outcomes in adolescents with alcohol use disorders (AUDs). The project will specifically focus on the measurement and integration of constructs from three domains: (1) frontal white matter organization determined by diffusion tensor imaging (DTI), (2) executive functioning, measured by neuropsychological tests and functional assessments, and (3) alcohol and other substance involvement assessed monthly over a one-year period. Utilizing the resources of an on-going project on the substance involvement outcomes of adolescents in treatment for AUDs compared to a community control group (i.e., Recovery Project; R01AA014357; PI: Chung), the project will recruit 75 subjects (50 with AUDs, 25 controls) to participate in neuropsychological and neuroanatomical assessments at treatment initiation and a one-year follow-up. The Recovery Project conducts monthly substance use assessments, yielding an exceptionally detailed description of substance use trajectories in the intervening year. The neurodevelopmental assessment will include neuropsychological tests and neuroanatomical characterization by both conventional morphometric magnetic resonance imaging (MRI) and DTI. We anticipate that one-year outcome data will identify AUD subjects essentially achieving abstinence, AUD subjects relapsing to substantial continued alcohol involvement, and control subjects with minimal alcohol use. The hypothesized model specifies that alcohol abstinence will predict increases in white matter organization in frontal white matter tracts and correlated improvements in executive functioning. The R21 project will determine feasibility, provide estimates for statistical power and sample size calculations and initiate a collaboration between our programs in Pittsburgh and Minnesota. The study will thus determine the feasibility of demonstrating improvements in white matter integrity among adolescents with AUDs successfully completing treatment utilizing a prospective design and a contrasting relapsing AUD group and a community control group.

[unreadable] DESCRIPTION (provided by applicant): Primary health care providers in rural settings can play a vital role in the identification, management, and referral of adolescents with problematic alcohol involvement. This application proposes a cooperative agreement to develop the research capacity of primary health care systems in rural northwestern Pennsylvania for addressing alcohol use and related problems in this age group. The Northwest Pennsylvania Adolescent Alcohol Research Cooperative (NPAARC) will include members from the Pittsburgh Adolescent Alcohol Research Center, the Center for Rural Health Practice at the University of Pittsburgh - Bradford campus and the Kinzua Regional Health Alliance. The Kinzua Alliance includes primary health care organizations serving rural northwestern Pennsylvania. These organizations provide complimentary expertise and resources for conducting the proposed research. NPAARC will assess the extent of underage drinking in the served communities through local high school participation in the Pennsylvania Youth Survey, as well as the evaluation of patients visiting primary care practices. To identify and involve all area practitioners serving this population, a survey and focus groups will be conducted. In collaboration with practitioners, adolescents and parents, an adolescent version of the NIAAA Clinician's Guide and a computer-assisted alcohol assessment and clinical decision support tool will be developed. The computer-assisted decision support system will be tested in five practices. Before their health care visit, adolescents (12-20 years old) will be assessed on alcohol use and problems, including the AUDIT and a computer-administered diagnostic assessment. To determine the influence of this decision support system, practitioner assessment and referral practices and adolescent adherence to recommendations will be compared during two implementation stages: (1) an assessment only control condition and (2) a full implementation including PCP feedback, interpretation of assessments, intervention suggestions, and a tailored print-out provided to the patient. The study will evaluate the influence of the computer-assisted decision support system on practitioner assessment and referral patterns, patient adherence to referral recommendations over a one-month follow-up period and adolescent alcohol consumption. With this project, NPAARC will initiate a long-term partnership among rural health care providers, the Center for Rural Health Care Practice, and the Pittsburgh Adolescent Alcohol Research Center. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This R21 exploratory project will examine frontal white matter, executive functioning and treatment outcomes in adolescents with alcohol use disorders (AUDs). The project will specifically focus on the measurement and integration of constructs from three domains: (1) frontal white matter organization determined by diffusion tensor imaging (DTI), (2) executive functioning, measured by neuropsychological tests and functional assessments, and (3) alcohol and other substance involvement assessed monthly over a one-year period. Utilizing the resources of an on-going project on the substance involvement outcomes of adolescents in treatment for AUDs compared to a community control group (i.e., Recovery Project; R01AA014357; PI: Chung), the project will recruit 75 subjects (50 with AUDs, 25 controls) to participate in neuropsychological and neuroanatomical assessments at treatment initiation and a one-year follow-up. The Recovery Project conducts monthly substance use assessments, yielding an exceptionally detailed description of substance use trajectories in the intervening year. The neurodevelopmental assessment will include neuropsychological tests and neuroanatomical characterization by both conventional morphometric magnetic resonance imaging (MRI) and DTI. We anticipate that one-year outcome data will identify AUD subjects essentially achieving abstinence, AUD subjects relapsing to substantial continued alcohol involvement, and control subjects with minimal alcohol use. The hypothesized model specifies that alcohol abstinence will predict increases in white matter organization in frontal white matter tracts and correlated improvements in executive functioning. The R21 project will determine feasibility, provide estimates for statistical power and sample size calculations and initiate a collaboration between our programs in Pittsburgh and Minnesota. The study will thus determine the feasibility of demonstrating improvements in white matter integrity among adolescents with AUDs successfully completing treatment utilizing a prospective design and a contrasting relapsing AUD group and a community control group.

[unreadable] DESCRIPTION (provided by applicant): This R21 application, in response to RFA-AA-07-006, proposes to initiate a project to determine the effects of alcohol exposure on the developing brain during adolescence. The study examines brain areas that are actively developing during adolescence, involved in psychological regulation, response to rewards, thought to be vulnerable to dysmaturation by alcohol exposure, and evaluate with contemporary neuroimaging techniques. An accelerated longitudinal design will be utilized. A representative community sample will be identified, recruited and screened, and a stratified sample of 160 adolescents ages 12 through 15 years old will be selected. Subject stratification will be based on age, gender and race. A substantial proportion of the sample will be recruited prior to the initiation of alcohol use, and our prior longitudinal study using similar methods indicates that the sample will show sufficient variability in alcohol use trajectories for the study aims to be fulfilled. The neurodevelopmental evaluation will focus on structures and circuits subserving psychological regulation and responses to rewards, including the prefrontal cortex, amygdala, hippocampus and ventral striatum, as well as associated white mater. The project will specifically examine the organization of white matter areas serving the frontal cortex by diffusion tensor imaging (DTI), prefrontal and amygdalar activation by functional magnetic resonance imaging (fMRI) during tasks involving emotional responses to affectively-laden faces, regional activation to a task requiring inhibition of pre-potent oculomotor responses in an anti-saccade task, and responses to systematically varied reward contingencies. Psychological dysregulation constructs measured will include behavioral undercontrol, negative emotionality, and executive cognitive functioning. We hypothesize that neurodevelopmental maturation indicators will be systematically and significantly correlated to behavioral indicators of psychological dysregulation and parental alcohol use disorders. Anticipating the utilization of these data in a larger study, we predict that the maturation of these neural structures and circuits will be adversely affected by adolescent alcohol exposure. The study will also consider environmental and genetic factors. In addition to demographic characteristics, environmental influences considered will include parent involvement, traumatic experiences, and neighborhood context. The project will collect DNA for studies of genetic polymorphisms associated with neurobiological endophenotypes and alcohol involvement trajectories. The R21 data collection will provide sufficient data to determine relationships among neurodevelopmental maturation in early adolescence, psychological dysregulaiton and AUD risk. In addition to providing the initial cohorts for a definitive study on the effects of alcohol exposure on adolescent brain development, the R21 project will facilitate the refinement of recruitment procedures and will collect data needed for statistical power calculations and sample size estimates. [unreadable] [unreadable] Project Narrative: This R21 project will initiate a study to determine the effects of alcohol exposure on adolescent brain development. The study will involve a representative sample of 160 adolescents in an accelerated longitudinal design examining ages 12 through 18 years. Neural circuits known to be involved in psychological regulation and reward responses are hypothesized to be particularly vulnerable to alcohol effects and will be assessed with innovative neuroimaging methods. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Rural primary health care providers can play a vital role in the identification, management, and referral of underage drinkers. This application proposes to continue a program that has successfully engaged 30 rural primary health care providers in the development of a collaborative network for conducting research addressing underage drinking. The Northwest Pennsylvania Adolescent Alcohol Research Cooperative (NPAARC) includes members from the Pittsburgh Adolescent Alcohol Research Center, the Center for Rural Health Practice at the University of Pittsburgh - Bradford campus and primary care practitioners in a rural eight county area. In Phase I, rural practitioners serving underage drinkers participated in a survey on their alcohol-related clinical practices and attitudes. A subset of these practitioners, along with teens and parents, participated in focus groups that explored facilitating and hindering factors influencing alcohol-related screening, brief intervention and referral for treatment. Our Computer Assisted Decision Support for Underage Drinkers (CADSUD) was developed, the assessment component was tested with over 225 adolescents in two practices, and the intervention component will soon be implemented in these practices. With two additional practices scheduled to become involved in 2009, we anticipate that four practices and 800 adolescents will have participated in CADSUD testing during Phase I. in Phase II, CADSUD will be tested in six additional practices with 1200 adolescents. Before their health care visit, these adolescents (12-20 years old) will be assessed via CADSUD on alcohol use and related disorders. To determine the influence of CADSUD, practitioner and adolescent outcomes will be compared during two implementation stages: (1) an assessment only control condition and (2) a full implementation condition including PCP feedback, interpretation of assessments, intervention suggestions, and tailored written materials provided for the patient. Outcomes assessed will include practitioner assessment and referral patterns, patient adherence to referral recommendations, and adolescent alcohol use determined by 2-month and 12-month follow-up assessments. PCPs will be encouraged to utilize CADSUD in community venues and will be provided with related technical support. NPAARC will thus develop, test, and implement a method to address rural underage drinking through primary care practices. PUBLIC HEALTH RELEVANCE: NPAARC will provide clinical tools to practitioners while serving as the platform for intervention research. CADSUD addresses barriers to primary care screening and brief intervention by providing a computer- assisted pre-visit assessment, developmentally appropriate web-based post-visit interventions, and referral suggestions. CADSUD requires limited practitioner training and, if proven effective, could be readily disseminated.

The overarching goal of the Developmental Psychopathology Module is to elucidate the psychopathological precursors and concomitants of substance use disorder (SUD) and their ontogenetic connections. Building on extensive research conducted to date, we propose in the next 5 years to prospectively examine the influences on developmentally specific manifestations of psychological dysregulation and adulthood SUD outcomes. Among characteristics manifested as psychopathology in childhood and adolescence, disruptive behavior disorders have been demonstrated most clearly to predispose to illicit drug use and SUD. Using contemporary psychometric methods, the project will develop a construct indicated by childhood disruptive behavior disorder symptoms, termed Behavioral Undercontrol (BU). This construct is conceptualized as reflecting a persistent trait with developmentally specific manifestations. The indicators of this dimension are collected from parents as well as offspring, and transmission of BU from parent to child will be studied. The research will identify psychopathological precursors of SUD in late childhood and adolescence, and will determine the mediating and moderating influences in the transition from adolescence to adulthood that portend SUD diagnoses resulting from illicit drug use. The Module will determine the influences of BU, in the context of parenting practices and peer selection, on adolescent substance use trajectories and SUDs. In young adulthood, we will examine frontal white matter organization as a neuromaturation outcome indicator. We will examine the influence of frontal white matter organization on laboratory indicators of decision-making competence. We hypothesize that childhood BU and adolescent substance use will predict white matter dysmaturation and associated deficits in decision-making competence in young adulthood, leading to severe and persistent SUDs consequent to illicit drugs.

DESCRIPTION (provided by applicant): In response to RFA-AA-12-006, this application proposes the Pittsburgh Research Component of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA: Pittsburgh) to determine the effects of alcohol use on the developing adolescent brain. Recruited at ages 12 through 21, a high risk enhanced community sample of 170 Pittsburgh subjects (N=680 from all sites) will complete a baseline assessment and undergo three annual follow-up assessments in an accelerated longitudinal design. At each visit, a multimodal magnetic resonance imaging (MRI) protocol, comprehensive neuropsychological battery, and assessments of alcohol and other substance use and related problems, mental health symptomatology, and substance use disorder risk factors will be measured. Brain imaging includes state-of-the-art high resolution structural MRI (sMRI), diffusion tensor imaging (DTI), and resting state MRI (rsMRI). The examination of alcohol consequences will focus on structural and functional maturation of brain areas that are actively developing during adolescence, involved in psychological regulation, responsive to rewards, and thought to be vulnerable to toxic alcohol effects. In addition, NCANDA: Pittsburgh will collaborate on two supplemental studies. We will collaborate with NCANDA: Duke in a study utilizing functional MRI to examine cerebral activation during a reward modulated anti-saccade task to study alcohol effects on reward responding and behavioral inhibition. We will also collaborate with NCANDA: SRI in a laboratory sleep study to examine the effects of alcohol on adolescent sleep architecture. Studied in the context of risks and baseline brain characteristics, we will determine both the effects of alcohol exposure on the developmental trajectory of the adolescent human brain, and identify preexisting psychobiological vulnerabilities that may put an adolescent at elevated risk for an alcohol use disorder. PUBLIC HEALTH RELEVANCE: The National Consortium on Alcohol and Neurodevelopment in Adolescence (N-CANDA) will use multimodal brain imaging, neuropsychological testing and clinical assessments in a large adolescents sample followed over four years to determine neurodevelopmental risks for problematic alcohol use and alcohol effects on adolescent brain development. In addition to contributing to this goal, N-CANDA: Pittsburgh will also determine the effects of adolescent alcohol use on sleep architecture and the neurobiological foundations of behavioral inhibition. This information may be used to advance the prevention and treatment of adolescent alcohol use disorders.

DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period that is associated with dramatic increases in rates of substance use. Identifying predictors of substance use and its effects on child and adolescent development is critically important, as substance-related decrements incurred during ongoing maturation could have long- lasting effects on brain functioning and behavioral, health, and psychological outcomes. In response to RFA- DA-15-015, this application proposes the University of Pittsburgh Research Project Site component [12/13] of the Adolescent Brain Cognitive Development (ABCD)-USA consortium to prospectively determine the neurodevelopmental and behavioral effects of substance on children and adolescents. In Pittsburgh, a representative community sample of 550 9-10 year old substance-naïve children will be recruited (total ABCD- USA n=11,111 from 11 total sites) and will undergo a baseline assessment and two to three follow-ups over a five year period. At each assessment period, participants will undergo state-of-the-art brain imaging, comprehensive neuropsychological testing, and extensive assessment of substance use patterns and mental health functioning. The brain, behavioral, psychological, social, genetic, and environmental data collected during the course of this project will elucidate: 1) the effects o 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. Elements Unique to This Site: In addition, ABCD-USA Pittsburgh will provide a unique focus determining how the cognitive dimensions of working memory and inhibitory control and the maturation of corticostriatal systems can inform our understanding of the risks for and effects of early adolescent marijuana use. Working memory and inhibitory control improve during adolescence in parallel with maturation of underlying corticostriatal neurocircuitry. An understanding of these areas of adolescent brain and cognitive development provide critical information in models determining vulnerabilities for and consequences of marijuana and other substance use. In Y03, Pittsburgh will focus on analyses examining working memory and inhibitory control phenotypes and neurodevelopmental characteristics prior to substance use. In Y04-Y05, these neurocognitive characteristics will be examined as risks for early adolescent marijuana use trajectories and, in Y10, accelerated adolescent marijuana use trajectories. Machine Learning will be applied to integrating cognitive and neuroimaging features to characterize a model of risks for early adolescent marijuana use.

PROJECT SUMMARY During young adulthood, drinking dramatically increases, with binge-level drinking peaking at age 22 and nearly half of individuals reporting binge-level alcohol use. Frequent binge alcohol use during the protracted neuromaturation spanning into the mid-20s may result in greater brain and cognitive effects than similar alcohol use in later adulthood. In response to RFA-AA-17-003, this application proposes a Research Project Site of the National Consortium on Alcohol and Neurodevelopment in Adolescence second phase (NCANDA-2) to determine the predictors and effects of heavy alcohol use in adolescence and young adulthood. To achieve this, the Pittsburgh site of NCANDA-2 will continue to follow a cohort of 125 Pittsburgh-area (n=831 across all 5 sites) participants (ages 12-21 at baseline first visit) to acquire the necessary data to advance our understanding of adolescent development and the effects of alcohol use during adolescence on the adult brain. NCANDA-2 will use multimodal neuroimaging, cognitive testing, behavioral assessment, biospecimen collection, and ecological momentary assessment. The examination of alcohol consequences will focus on structural and functional maturation of brain areas that actively develop during adolescence, are involved in psychological regulation, respond to rewards, and appear vulnerable to neurotoxic effects of alcohol. In addition, the Pittsburgh site will collaborate with the SRI sites to study sleep-related predictors and effects of alcohol use in a subgroup of adolescents. Pittsburgh will also collaborate with the Duke site to collect the Rewarded Antisaccade fMRI task to evaluate changes in the reward and cognitive control systems in relationship to alcohol use. Sex differences in development, alcohol use patterns, impact of alcohol use on the brain, and sex-differentiating psychosocial factors (e.g., depression symptoms) will be considered in analyses. With the additional longitudinal data provided by this renewal, we will determine the effects of alcohol exposure on the developmental trajectory of the adolescent human brain, and identify preexisting psychobiological vulnerabilities that may put an adolescent or young adult at elevated risk for an alcohol use disorder.

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.

PROJECT SUMMARY The Center for Adolescent Rhythms, Reward, and Sleep (CARRS) Phenotyping and Biobanking Core (Core B) supports the research projects through the acquisition of research subjects with specific phenotypic characteristics required by the human and animal projects. Our central hypothesis is that late sleep timing, short sleep duration, and circadian misalignment adversely impact cortico-limbic function in adolescents, further enhancing reward sensitivity, impairing cognitive control, and increasing substance use risk. The coordinated and deliberate procedures for assuring analogous phenotypic characteristics in humans and animals provide the foundation for this translational scientific program. For human studies (Projects 1 and 2), Core B will conduct systematic recruitment and screening of adolescents ages 13 through 15 years old to provide participants systematically varied in sleep timing. For rodent studies, Core B will establish a breeding and phenotyping pipeline to provide the animals required for Projects 3, 4 and 5. Core B will also provide biobanking services, including the collection, management, and banking of specimens from adolescent humans and adolescent HS rats to measure molecular rhythm phenotypes and to provide a high-quality repository for future mechanistic studies. Core B contributes to this innovative translational research program by collaboratively developing and implementing plans for assuring analogous phenotypes for CARRS human adolescent and adolescent rodent model studies.