ARTICLES Developmental Trajectories of the Orbitofrontal Cortex and Anhedonia in Middle Childhood and Risk for Substance Use in Adolescence in a Longitudinal Sample of Depressed and Healthy Preschoolers Joan L. Luby, M.D., Arpana Agrawal, Ph.D., Andy Belden, Ph.D., Diana Whalen, Ph.D., Rebecca Tillman, M.S., Deanna M. Barch, Ph.D. Objective: Deficits in reward processing are established in trajectories predicted later alcohol and marijuana use fre- mood and substance use disorders and are known risk fac- quency in adolescence. tors for these disorders. Volume reductions of the orbito- frontal cortex and the striatum, regions that subserve neural Results: The anhedonia-by-age interaction was significant response to reward, have been shown to be related to an- in the multilevel modeling of orbitofrontal cortical but not hedonia in depressive and substance use disorders. The au- striatal volume. Higher anhedonia ratings were significantly thors sought to investigate how structural maturation of associated with steeper decline in orbitofrontal cortical vol- these regions in childhood varies with level of anhedonia and ume with age. Orbitofrontal cortical volume and thickness predicts later substance use. at age 12 and trajectory over time significantly and negatively predicted subsequent alcohol and marijuana use frequency Method: The study employed data from a sample of de- but not depression during adolescence. pressed and healthy preschoolers studied longitudinally that included three waves of neuroimaging from school age to Conclusions: The findings suggest that the development of adolescence. Three years after scan 3, at ages 13–18, par- the orbitofrontal cortex during childhood is strongly linked ticipants underwent a comprehensive behavioral and sub- to experiences of anhedonia and that these growth trajec- stance use assessment. Multilevel modeling was used to tories predict substance use during a developmentally critical investigate the relationship between anhedonia and the period. growth trajectories of the striatum and orbitofrontal cortex. Zero-inflated Poisson regression models were then used to determine whether the intercepts and slopes of these AJP in Advance (doi: 10.1176/appi.ajp.2018.17070777) The ability to experience pleasure during the anticipation and cortex plays a role in processing sensory input and in esti- receipt of reward is a fundamental human experience and mating the value of experiences of reward, including natural is central to the drive to survive and thrive. Deficits in this (e.g., gustatory), monetary, and drug-related incentives (5, 6). domain have been identified in both mood and substance use The striatum drives appetitive behavior by facilitating in- disorders (1, 2). The symptom of anhedonia—the inability to centive salience (e.g., wanting) and reward-related learning enjoy previously pleasurable or rewarding activities—is a (7). While orbitofrontal cortical and striatal volumes show core feature of depressive disorders. Abnormalities in re- normative increases and then decline beginning in early ad- ward processing have been identified from observational, olescence (8), reductions in the volumes of these structures behavioral, and neurobiological studies as a potent risk factor have been identified in adolescent depressive disorders in for the emergence of depression as well as substance use relation to the symptom of anhedonia (9–11). Variations in disorders (3). orbitofrontal cortical and striatal volumes have also been Both human neurobiological studies and experimental linked to substance use and later substance use disorders. animal studies have localized key brain regions involved in Numerous studies have documented decreased gray matter experiences of reward (4). This combined body of data val- volume in the orbitofrontal cortex in substance-using indi- idates the central role of the orbitofrontal cortex and the viduals, including those using alcohol (12, 13) and marijuana striatum in neural responses to reward. The orbitofrontal (14–17). While the role of the striatum in “wanting” is evident ajp in Advance ajp.psychiatryonline.org 1 DEVELOPMENTAL TRAJECTORIES OF ORBITOFRONTAL CORTEX AND ANHEDONIA AND RISK FOR SUBSTANCE USE in reward-related behaviors such as substance use and relate to risk for later substance use, independently of an- substance use disorders, the role of the orbitofrontal cortex hedonia (15), suggesting that independent processes between may be related to the pursuit of goal-directed behaviors, or orbitofrontal cortical volume and adolescent substance use are drive, which may evolve into habitual actions (18, 19), as well also operative. Based on these established brain-behavior re- as learning associations between stimulus and reward (2), lationships, an investigation of the developmental trajectory both highly relevant to risk for substance use disorders. of the striatum and orbitofrontal cortex, as a function of an- Of particular interest, associations between orbitofrontal hedonia in relation to risk for later depression or substance cortical and striatal structure and substance use have been abuse, is of interest. Building on the literature, this study found during the reward-salient period of adolescence. In the aimed to test hypotheses about how behavior and brain in United States, alcohol and marijuana are among the first these domains change together or independently influence substances to be used by Caucasian and African American eachothertopredicttherisktrajectory for later substance youths, respectively, with onsets peaking between ages 15 and use or depression. 17 (20, 21). In addition, epidemiological studies suggest that Utilizing data from a longitudinal neuroimaging study of childhood internalizing problems may modify risk, positively children with early-onset depression and healthy comparison and negatively, for onset of substance use (22). The literature subjects who were followed from preschool into adolescence, thus supports the hypothesis that anhedonia-related changes we examined the developmental trajectory of orbitofrontal in brain maturation may have an impact on the onset of al- cortical and striatal volumes and how they varied as a func- cohol and marijuana use. Both the orbitofrontal cortex and tion of anhedonia ratings. While this study sample was not the ventral striatum have been investigated in the context of specifically designed to investigate risk for substance use adolescent substance use. For marijuana, while most studies and substance use disorder, it provided an ideal opportunity have conceptualized orbitofrontal cortical volumetric alter- to investigate the trajectory of brain change in the context of ations as a consequence of heavy use (23), one longitudinal varying anhedonia and depression across childhood to inform study (15) found that smaller orbitofrontal cortical volume at risk for first onset of substance use disorder in adolescence age 12 was related to onset of marijuana use by age 16. A few and risk for a later recurrence of depression. We hypothesized studies have linked orbitofrontal cortical structure and ad- that orbitofrontal cortical and striatal volumes would decrease olescent alcohol use (e.g., 24). Similar to the marijuana over time as a function of increased anhedonia even when findings, one adolescent co-twin-control study (25) reported other depressive symptoms were controlled for. Based on an an association of lower lateral orbitofrontal cortical volume extensive literature demonstrating the role of the orbitofrontal with alcohol use. However, as no volumetric differences were cortex and ventral striatum in onset of alcohol and marijuana found within pairs of twins with varying levels of alcohol use, use, the first substancestobe used bymost U.S. youths,we then these findings suggest that changes in orbitofrontal cortical sought to explore whether these brain-related volumetric volume may be a preexisting marker of risk and not a con- trajectories predicted later substance use and depression re- sequence of prolonged alcohol exposure. A link between currence as the study sample entered adolescence, which is a structural differences in the striatum and marijuana and key period of risk for onset of substance use and depression. alcohol use is less clearly established, with some studies sug- To examine the role of anhedonia in the associations with sub- gesting that ventral striatal volume increases in users (e.g., 26). stance use, we compared whether volumetric alterations re- These findings suggest that the orbitofrontal cortex and ven- lated to, and independent of, anhedonia were equally predictive tral striatum are key areas involved in adolescent substance of alcohol and marijuana use during adolescence. use and that while they may be vulnerable to the psychoac- tive effects of drugs, variations in their maturation may also METHOD precede and contribute to the onset of substance use. While the key roles of the orbitofrontal cortex and the A total of 305 children (54% white, 33% black, 13% other) ages striatum in reward processing are relatively clear, how struc- 3–6 at baseline, oversampled for symptoms of depression, tural maturation of these regions during childhood relates to were recruited in the St. Louis metropolitan area for par- variation in hedonic tone, experiences of anhedonia and later ticipation in a longitudinal study of preschool-onset de- reward-seeking and substance use, and depression outcomes pression. After a first, behavioral-only study phase, healthy remains unknown. Early deficits