Neural mechanisms of risk and resilience in early childhood irritability

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PROJECT SUMMARY/ABSTRACT Irritability, defined as lowered threshold for anger when experiencing the RDoC construct frustrative non-reward, i.e., failing to receive expected rewards, is one of the most common reasons for pediatric psychiatric evaluation. Our work shows that early detection is critical: If irritability in preschool-age (3-6 years, before 1st grade) continues into school-age (after 1st grade), as it does for approximately 50% of preschool-age irritable children, such persistent irritability puts children on the path to mental disorder across the lifespan. Thus, identifying the neural mechanisms by which children persist vs. remit in irritability is paramount to intervene in the earliest phase of the clinical cascade. 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 inhibition in irritability trajectories is unknown. Investigating longitudinal changes in neural circuitry during this developmental period is important because the reward- and inhibition-related neural networks undergo substantial change and may be most malleable to early intervention. Our overall goal is to identify reward- and inhibition-related neural pathways that characterize persistence vs. remission of early childhood irritability. To this end, the proposed project will longitudinally characterize the neural and symptom trajectories of preschool-age children into school-age. We will collect measures of reward- and inhibitory control-related brain function at baseline and 24-month follow-up from 215 5-6-year-old children prior to 1st grade, alongside assessments of child irritability and inhibition at each 6-month follow-up. A comprehensive assessment of child (cognition, temperament, psychopathology), parent (psychopathology) and contextual factors (e.g., parenting, stressors) will also be assessed at baseline and 24-month assessments. Our central hypothesis is that young children with reward- and inhibition-related neural deficits are more likely to persist in irritability compared to those who remit. Specific aims are to identify (1) concurrent contributions of reward- and inhibition-related neural function to irritability at each age (preschool-age, school-age); (2) developmental changes in reward- and inhibition-related neural mechanisms of irritability trajectories from early to middle childhood; (3) early childhood reward- and inhibition-related neural predictors of irritability trajectories and future psychopathology; and (4) the moderating role of child sex, parent psychopathology, parenting, and life stress on these brain-behavior associations. This proposal will advance the field by revealing the neural circuitry of irritability risk and resilience. Innovative aspects include focusing on a key age range (5-6 years) to prevent later disorders, multiple time point imaging, and machine learning methodology. Our project is significant because it will pave the way for precision medicine for irritability: providing the right treatment (based on neural mechanisms) to the right people (children who will persist in irritability), at the right time (preschool age, before irritability problems worsen).