NRSA for Ellen Kessel: A Study of Childhood Irritability: Neural Mechanisms and Development Pathways to Internalizing and Externalizing Psychopathology

Abstract Irritability is the most common reason that children are referred for mental health services9. However, irritability- specific treatments are lacking, in part because little is known about its pathophysiology. It is also a heritable trait1,2 that, even at relatively low levels3,4, increases risk for many common psychiatric disorders. An emerging literature suggests that impairments in cognitive flexibility may be a core mechanism underlying irritability13,14. However, the precise mechanisms that mediate the cognitive rigidity in irritable youth have yet to be identified. In addition, little is known about the mechanisms by which irritability leads to disparate forms of psychopathology. While deficits in cognitive flexibility may be a shared mechanism underlying many forms of irritability, impairments in other domains of executive functioning may influence the development and clinical expression of irritability, leading some youth to develop internalizing, and others externalizing, psychopathology21. The goal of this research proposal is to elucidate the neurocognitive mechanisms mediating irritability, and identify moderators that shape the way in which irritability is expressed clinically over the course of child and early adolescent development. This knowledge is crucial to developing intervention/prevention efforts that jointly target both common and specific liabilities and mechanisms of psychopathology. The proposed study has three specific aims: (1) Developmentally adapt and psychometrically validate a novel Wisconsin Card Sorting Task for use in conjunction with temporally sensitive event-related potentials (ERPs) to isolate and disentangle the role of set-switching, working memory and feedback processing in cognitive flexibility; (2) Relate neural indices of set-switching, working memory and reinforcement learning to irritability in 7-10 year old children (N = 95); and (3) Capitalizing on a large ongoing NIMH-funded longitudinal study (N=609) of 12 year-old children, use cross-lagged path modeling to examine whether the error-related negativity (ERN) at ages 6 and 9 moderates heterotypic continuity of irritability to internalizing and externalizing symptoms from ages 3 to 12. The current training proposal will allow me to integrate training from co-sponsors and consultants who have expertise in running large-scale studies on youth irritability (Drs. Klein and Leibenluft), task development for pediatric populations (Drs. Hajcak and Leibenluft) advanced statistical techniques to conduct longitudinal data analysis (Dr. Kotov), and developmental neuroscience (Dr. Tottenham).