Bonnie J. Nagel, PhD - US grants

DESCRIPTION (provided by applicant): Studies utilizing modern neuroimaging techniques have provided clear evidence that the adolescent brain is actively developing. This neurodevelopment, particularly in the frontal lobes, coincides with improvements in several areas of higher order cognitive functioning, including working memory abilities. It has been documented that working memory skills are crucial to the intact performance in several other cognitive domains. Deficits in working memory have been demonstrated among a number of neurological and psychiatric conditions that manifest during adolescence. However, the neurobiological substrates of working memory in even normally developing adolescents remain unclear. The current cross-sectional study proposes to integrate neuropsychological, functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) techniques to more clearly explore frontal lobe white matter development as it relates to both verbal and spatial working memory functioning in 90 typically developing adolescents (ages 12 to 17). It is hypothesized that 1) working memory abilities will be positively associated with age, 2) adolescents will show a hemispheric dissociation between the verbal and spatial working memory tasks that will become more pronounced with increasing age, 3) prefrontal white matter integrity will show a significant positive correlation with age and will mediate the positive relationship between age and working memory performance, and 4) prefrontal white matter integrity will be positively associated with nearby cortical fMRI response during the working memory tasks. The applicant is requesting a five-year mentored Career Development Award (K08) in order to develop the skills and expertise necessary for answering these research questions. Career development activities will include training in DTI data collection and analysis, development of expertise in fMRI, training in developmentally-focused longitudinal study design and analytical techniques and continued training in the ethical conduct of scientific research with children and adolescents. The proposed training plan will include structured coursework, seminars, and mentoring by experts in the fields of development and neuroimaging. Together, the implementation of this training and research plan will provide the beginnings of a much-needed framework for understanding the neurobiological substrates of working memory during adolescence and will allow the applicant to transition into an independent investigator specializing in longitudinal examination of adolescent cognition and neurodevelopment.

DESCRIPTION (provided by applicant): Adolescence is a developmental period during which individuals engage in risk-taking behavior and are likely to initiate use of alcohol or other drugs. Past research suggests a strong correlation between early age of onset of alcohol use and a heightened vulnerability to addiction later in life. Adolescence is also a time of considerable neuromaturation, particularly in frontal brain regions thought to subserve higher level cognition, such as decision making and inhibition. Heavy alcohol use during these critical periods of brain development may permanently disrupt the course of maturation, resulting in long-term deficits in these functions and thereby increasing the risk of subsequent substance use behavior. The proposed R01 project is designed to prospectively and longitudinally examine the influence of developmental stage on the effects of alcohol on adolescent cognition, brain functioning, and brain structure, using neuroimaging and neuropsychological testing techniques. This project will examine neuropsychological performance during tests of executive functioning, brain functioning during executive and risk taking fMRI tasks, brain structure in prefrontal and limbic regions, and frontostriatal white matter integrity in 250 at-risk, non-using 12-14-year-old youth (based on family history of alcoholism). We hypothesize that youth who drink in adolescence will show abnormalities on these measures compared to developmentally-matched non-drinking youth, and that youth who initiate heavy drinking earlier in puberty will show greater abnormalities than teens that initiate heavy drinking later in development. This prospective study will answer critical questions about how developmental timing of adolescent heavy alcohol use initiation affects the developing brain. PUBLIC HEALTH RELEVANCE: Studies show that the adolescent brain may be particularly vulnerable to alcohol's neurotoxic effects, and that earlier use is associated with greater subsequent risk of addictive behaviors. Despite this, alcohol use is very common among adolescence. Understanding the impact of early alcohol use on the developing adolescent brain will facilitate the creation of interventions aimed at reducing alcohol drinking behaviors that are targeted at specific age and risk groups.

DESCRIPTION (provided by applicant): This application describes the contribution of the OHSU site to the data collection efforts of the consortium entitled, Tracking Ethanol's Effects on Neurodevelopment (TEEN), and the specific focus of the OHSU site on examining how alcohol impacts functional connectivity in the developing brain and whether connectivity patterns can be used to predict risk for alcoholism. It is well-established that adolescence is a time of dramatic maturation in the brain, paralleled by improvements in executive abilities, social functioning, and emotional regulation. More recently, it has become appreciated that functional network dynamics of the brain, subserving these improvements, also dramatically change over the adolescent years. This period of heightened plasticity coincides with greater vulnerability to neurotoxic alcohol effects, such that heavy alcohol exposure during adolescence may result in disruption to normally occurring maturation of neural circuitry. To examine this question, the approach of the TEEN consortium will be to disproportionately recruit individuals who are at elevated risk for alcohol use, based on personality features. This approach was chosen to ensure sufficient numbers of individuals who will transition from no use to use within the duration of this project, and also ensures sufficient numbers of individuals who are already drinking thereby enabling cross-sectional comparisons to complement the longitudinal studies. Using a sequential cohort design, the TEEN consortium will recruit 750 youth, stratified across three age-ranges: 12-15 years, 15-18 years, and 18-21 years, with each site recruiting and following 150 youth. A standardized set of neuroimaging, cognitive, and clinical assessments will be included and administered at baseline and at three one-year follow-ups. The major aims of the OHSU site proposal are toward understanding the influence of alcohol on adolescent brain circuitry and at delineating risk-related abnormalities in developing adolescent brain networks using multi-modal integration. Understanding the neural phenotypes associated with increased risk for alcoholism and the potentially deleterious impact of alcohol on the neural connections in the adolescent brain could aid in the development of targeted strategies aimed at reducing adolescent alcohol drinking behaviors.

DESCRIPTION (provided by applicant): It is well-established that adolescence is a time of dramatic neuromaturation, paralleled by improvements in cognition, social functioning, and emotional regulation. In addition, cross-sectional studies have demonstrated that rising gonadal hormone levels associated with puberty influence emotional and appetitive processing and limbic brain structure and functioning. Given the rise in psychopathology during adolescence, the hormonal activation of limbic brain regions during puberty, coupled with the immaturity of sexually dimorphic prefrontal regulatory systems, may contribute to heightened adolescent vulnerability for psychopathology in a sex- specific manner; however, little longitudinal work has been done to fully explore this notion. To that end, this study will longitudinally follow 120 healthy, 12-15-year-old male and female adolescents after one year with a rich, multimodal neuroimaging and behavioral characterization. This assessment will include functional neuroimaging during working memory and decision making, resting state functional neuroimaging, diffusion tensor imaging, neurocognitive assessment, mood/behavior/personality assessment, and serum hormone assays. Using a multi-modal longitudinal design, we aim to better understand sex-specific structural and functional neuromaturation of the brain during adolescence and to explore associations with gonadal hormones, cognition, and behavior. Increased understanding of these relationships may help to explain sex- specific vulnerability, better dissociate hormonally influenced developmental pathways from those that are not, elucidate individual characteristics conferring risk and resilience, and may ultimately permit the development of targeted treatment strategies aimed at reducing adolescent psychopathology.

? 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. 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 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, and extensive assessment of substance use patterns and mental health functioning. These comprehensive assessments will occur at 2-year follow-up intervals, with intermediate assessments of functioning and substance use at 6- month intervals. The brain, behavioral, psychological, social, genetic, and environmental data collected 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. Elements Unique to this Site: This hub's Research Project application leverages site-specific expertise to address two aims focused on the identification of risk and resilience factors for adolescent substance use. Using baseline data categorized into distinct domains (Demographic, Cognitive, Mental Health, Personality, Life Stressors, Family History/Genetics, Environmental, and Brain), we will use cutting-edge, multi-stage analytic methods involving data reduction within each domain (e.g., latent variable analyses), identification of etiologically-distinct subgroups (e.g., community detection), and the construction of integrated multi-modal predictive models (e.g., regularized regression). This approach will delineate subgroups characterized by distinct profiles of risk and resilience. This approach is essential for informing outcomes of substance use during adolescence, which will ultimately inform the development of more efficacious interventions and clarify the toxic effects of exposure on adolescent brain, health, and cognition.

Project Summary / Abstract Having a family history of alcohol use disorder (AUD) increases one's likelihood of developing an AUD. The mechanisms underlying this risk are unclear, but familial AUD-related premorbid differences in brain circuitry have been demonstrated. Further, studies comparing the subjective responses to alcohol in family history- positive and family-history negative (FH+/FH-) individuals indicate that FH+ individuals report more stimulation and less sedation than FH- individuals, and these effects are seen across the ascending and descending limbs of the blood alcohol curve (BAC), respectively. These subjective phenotypes are associated with the perpetuation of alcohol use. However, little is known about concurrent alterations in brain circuitry across the BAC and the extent to which these alterations, and differing subjective effects, reflect underlying neurobiological differences in AUD risk. Accordingly, we aim to address this knowledge gap using functional magnetic resonance imaging techniques. We will compare patterns of functional connectivity in FH+ and FH- individuals, matched for drinking history, across the BAC during acute alcohol intoxication. Specifically, functional connectivity magnetic resonance imaging (fcMRI) will be examined in relation to the BAC, using a 90-min scanning protocol in a total of 72 young adults (36 FH+/36 FH-; age 21; groups matched for prior drinking history). Twenty minutes prior to beverage consumption, a pre-beverage assessment will occur and an intravenous (IV) line will be placed to allow repeated blood draws. Next, participants will consume a beverage (0 [placebo], 0.6 g/kg [total alcohol dose]; order counterbalanced between sessions for a within subjects dosing design) and scanning will begin, including 70 minutes of fcMRI across the BAC. Every 10 minutes throughout the fcMRI data collection (at the same times blood samples are taken), subjects will also complete a brief subjective effects questionnaire, so that subjective effects (stimulation, sedation) can be recorded and related to fcMRI between specific brain regions. Comparing functional connectivity underlying response to acute alcohol intake across the BAC in the brains of at-risk, compared to lower risk, individuals will provide useful information about the neurobiology of alcohol's actions and interactive factors associated with abuse liability (subjective response), which may ultimately inform intervention efforts.

? DESCRIPTION (provided by applicant): Adolescence is a time of dramatic development, much of which varies as a function of sex. Also during this time, alcohol use becomes very common. Likely due to heightened plasticity, the adolescent brain is particularly susceptible to the neurotoxic effects of alcohol. While studies have separately documented cross- sectional sex differences in the effects of alcohol on the adolescent brain and hormonal influences on normative adolescent brain development, to fully understand sex-specific adolescent risk and resilience for alcoholism, multimodal prospective longitudinal studies are crucial. To that end, during this funding period, we will assess an additional 120 healthy non-alcohol/drug using 14-16-year-old youth using functional neuroimaging during working memory and decision making, resting state functional neuroimaging, diffusion tensor imaging, neurocognitive assessment, mood/behavior/personality assessment, and serum hormone assays. Together with over 200 youth assessed during the first funding period of the project, all youth will be quarterly monitore for changes in alcohol/drug use, and youth who emerge into heavy alcohol use (as well as a matched non-using control) will be re-assessed at two time points following initiation of heavy drinking behavior. Using a multi-modal longitudinal design, we aim to better understand sex-specific effects of heavy alcohol use on adolescent brain functioning and connectivity, as well as identify premorbid sex-specific neurobiological risk phenotypes that are predictive of problem drinking during adolescence and young adulthood. Further, we will explore moderating variables, such timing and frequency of alcohol and other drug use, as well as the role of gonadal steroids on sex-specific developmental trajectories. Disentangling sex- specific risk for and consequences of alcohol use during adolescence, in relation to normative brain development, and determining which effects may be hormonally influenced, will move the field closer to more personalized prevention and intervention strategies aimed at male and female youth.

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 use2. 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 adolescent alcohol use in adolescence and young adulthood. To achieve this, the OHSU site of NCANDA-2 will continue to follow a cohort of 150 Portland-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 OHSU site will collaborate with the Duke and USCD sites to study recovery of these abnormalities. Specifically, we will examine the degree to which targeted heavy drinking related neurocognitive and brain integrity deficits remit over 4 weeks of monitored abstinence. 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.