Neural mechanisms of risk for irritability across the transition to adolescence

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PROJECT SUMMARY/ABSTRACT Irritability—exaggerated anger in response to non-reward—is among the most common psychiatric complaints. Because irritability in late childhood and adolescence predicts mental disorders across the lifespan, identifying the neural mechanisms involved in irritability across the transition to adolescence is paramount to intervene before youth irritability problems harden into entrenched psychiatric disorders in later adolescence and adulthood. Irritability is linked with abnormalities in reward processing, which may lead to greater frustration when rewards are not received. Such reward processing vulnerabilities may be ameliorated by better inhibitory control, which normatively increases with maturation. However, the interplay between reward processing and inhibitory control in irritability is unknown. Investigating longitudinal changes in neural circuitry is important because reward- and inhibition-related neural networks undergo substantial change from childhood through adolescence. Our overall goal is to identify reward- and inhibition-related neural pathways that characterize changes in irritability over the transition to adolescence. To this end, the proposal leverages data from the Adolescent Brain Cognitive Development (ABCD) Study, a large, national longitudinal sample of preadolescents assessed annually (N=~8,312 with usable datasets; baseline age=9-10; 1-Year Follow-Up [1-YRFU] age=10-11; 2-YRFU age=11-12). At baseline and 2-YRFU, youth complete monetary incentive delay and stop-signal tasks during fMRI acquisition that assess neural responses to reward and inhibitory control, respectively. Across all waves, youth irritability and co-occurring psychopathology are assessed using clinical interviews and parent- and youth-report measures, and multiple behavioral and parent- and youth-reported measures of youth reward processing and inhibitory control are collected. Our central hypothesis is that preadolescents with both reward- and inhibition-related neural deficits are more likely to show persistently high or increasing irritability across the transition to adolescence, whereas preadolescents with reward-related brain deficits, but better inhibition, will demonstrate decreases in irritability. Specific aims are to identify (1) separate and (2) interactive contributions of reward- and inhibition-related neural function to concurrent irritability; to identify (3a) preadolescent reward- and inhibition-related neural predictors and (3b) developmental changes in reward and inhibition neural mechanisms, of irritability trajectories and future psychopathology across the transition to adolescence; and to explore (4) the moderating role of developmental-biological-contextual factors (sex, puberty, race/ethnicity, SES, familial characteristics) on these brain-behavior relationships. This proposal will advance the field by revealing the neural circuitry of irritability. Innovative aspects include focusing on a key age range (transition to adolescence) to prevent adult disorders, multiple time point imaging, formulation of a novel and comprehensive reward-based model of irritability, machine learning methodology, and replication analyses. Our project is significant because it will be a catalyst for a research program to inform precision medicine for irritability.