PROJECT SUMMARY: Irritability emerges during infancy as a substrate of psychopathology. However, reliable identification of irritable infants at high risk for clinical progression is challenging, due to substantial individual differences in adaptive or maladaptive outcomes for irritable infants over time. The When to Worry (W2W) study utilizes a neurodevelopmental framework to generate empirically derived, parameters for differentiation of irritability patterns that mark clinical risk. This administrative supplement request supports completion of the 36 month clinical endpoint and imaging sub-sample assessments, delayed due to COVID-19 disruptions. Key innovations are: (1) specification of developmentally atypical patterns of irritability beginning in infancy; (2) joint developmental consideration of irritability, executive function, and prefrontal cortical regions; and (3) transactional focus. We first conduct a cross-sectional survey of a representative sample of 12-36 mos. olds (N=2,000). We then ascertain an independent community cohort (N=356 infants oversampled for irritability), with longitudinal follow-up (12-36). Irritability assessments are: (a) bimonthly parent reports and real-time irritable vocalizations via the LENA; and (b) annual direct observations of irritability with executive function tasks (12-36 mos.) Performance-based assessments of executive function occur annually. The 36 mo. timepoint is the key clinical endpoint, when preschool psychopathology is well validated. Transactional processes are assessed via parent-infant mutual regulation processes. SPECIFIC AIMS: IA. Differentiate developmentally atypical irritability patterns from infancy-early preschool age via population-based parameters cross-sectionally (IAi) and quantitative longitudinal parameters (IAii). IB. Specify longitudinal parameters of irritability to optimize prediction of clinical progression. IIA-B. Map developmentally atypical irritability patterns to disruptions in the maturation of executive function and prefrontal cortical (PFC) regions and test the hypothesis that their joint consideration will enhance predictive clinical utility. Prefrontal cortical maturation will be assessed from infant natural sleep-MRI at 12 & 36 months (n=50-75). We test whether atypical irritability patterns predict slowed executive function development and abnormal PFC anatomy. IIIA-B. Elucidate how transactional processes shape clinical prediction, testing the hypothesis that parent-infant mutual regulation processes modulate clinical progression. Specification of irritability phenotypes in transactional context is key for prevention. The supplement is key for completing data collection to meet critical objectives of the W2W study.

PROJECT NARRATIVE Early irritability is a precursor to most common childhood mental disorders, but identifying “when to worry” is challenging because infants’ regulatory capacities develop so rapidly. The goal of this study is to develop a scientific evidence base beginning in infancy that distinguishes the normative irritability of early childhood from atypical irritability patterns. We will use a neurodevelopmental framework to characterize typical and atypical brain and behavioral patterns longitudinally from infancy to preschool age, including how infant irritability shapes and is shaped by proximal interactions with parents, and link these to dimensional patterns of clinical risk. Generating reliable markers of irritability that identify those infants at highest risk for developmental psychopathology lays the foundation for targeted early intervention at the earliest phase of clinical risk.