DESCRIPTION (provided by applicant): The overall goal of the proposed study is to elucidate etiological mechanisms of adolescent substance use and abuse through the integration of developmental and genetic research designs. Previous studies have substantially advanced our understanding of adolescent brain development and the neural basis for impulsive and risk-taking behaviors. An influential neurodevelopmental model posits that accelerated development of reward-related brain regions combined with relative immaturity of the cognitive control regions predisposes adolescents to impulsive behavior and substance abuse. However, the majority of functional magnetic resonance imaging (fMRI) studies have relied on small samples and cross-sectional designs, precluding a direct test of the "maturational asynchrony" hypothesis. Furthermore, cross-sectional correlational studies are unable to delineate pre-existing determinants of substance misuse and its consequences for the brain. Another significant gap in knowledge is the lack of fMRI heritability studies of neural systems underlying reward-related behaviors and inhibitory control, precluding the identification and validation of endophenotypic markers of risk for addictions. A better understanding of the interplay between etiological factors and pathways to addiction and their dynamic changes across adolescent development requires an integration of genetic and developmental research, but so far this approach has been implemented only using electrophysiological markers of brain function (EEG, ERP) that provide limited insight into the underlying functional neuroanatomy of reward processing and cognitive control. These gaps in knowledge create critical barriers to further progress in understanding the etiology of addictive disorders. To address them, we propose a longitudinal (age 13 to 18) study of a large sample (n=320) of adolescent MZ and DZ twins involving multilevel, interdisciplinary, theory- driven assessments of the brain and behavior. The proposed integrative approach capitalizes on the availability of a unique recruitment resource (state-wide twin registry), top-notch imaging methods, and our prior success of recruiting a large sample of adolescent twins into a laboratory-based longitudinal study. The following Specific Aims will be pursued: 1) To examine developmental trajectories of two brain networks implicated in pathophysiology of addiction: the reward network (RN) and the cognitive control network (CCN) across adolescence, and to determine whether substance use interferes with normal brain development; 2) To estimate the heritability of fMRI markers of RN and CCN functioning throughout adolescence and overlap of genetic influences on RN and CCN across development; 3) To determine whether heritable individual differences in RN and CCN functioning and their relative maturation rates prospectively predict impulsivity, substance misuse, and a broader spectrum of externalizing problems. The achievement of these aims will substantially advance our understanding of the determinants and consequences of adolescent substance misuse and comorbid psychopathology.

PUBLIC HEALTH RELEVANCE: A better understanding of the causes for substance misuse in adolescents and its consequences for the brain, cognitive functions, and behavior is essential to the development of more efficient prevention, intervention, and treatment methods. This study will assess adolescent using brain imaging and behavioral tests before the onset of substance use and follow them up for a period of four years. This design will allow us to separate causes and consequences of substance misuse. Because the study will include twins, we will be able to determine the role of genetics and environment on brain function and behavior. Knowledge gained from this study can increase our ability to predict which adolescents are most likely to initiate substance use and progress to abuse and who might benefit the most from prevention and intervention efforts.