DESCRIPTION (provided by applicant): Eating disorders are heterogeneous illnesses characterized by aberrant behaviors of extreme dietary restriction, binge eating, and purging. The course often involves adolescent onset, and in more than half of individuals, transition from predominantly restrictive to binge/purge behaviors. The pathophysiology of low- weight eating disorders and mechanisms that underlie restricting vs. binge/purge phenotypes are almost entirely unknown. A critical knowledge gap is the neurobiology underlying the developmental trajectory of these illnesses (e.g. transition from primary restriction to binge eating or purging) Our preliminary data argue for a key role of food motivation pathways involving altered Regulatory (homeostatic) and Positive Valence (reward) systems in low-weight eating disorders. Consistent with the Research Domain Criteria (RDoC) initiative, the current study leverages the complementary skills of Multiple-PIs, Dr. Misra from Pediatrics, Dr. Lawson from the Neuroendocrine Unit and Dr. Eddy from Psychiatry to address this knowledge gap through examination of homeostatic and hedonic food motivation pathways that we hypothesize underlie the longitudinal course of these key eating disorder behaviors. We hypothesize that (i) adolescents who successfully restrict to maintain low weight will have lower homeostatic and hedonic appetite, fMRI hypoactivation of food motivation pathways, and higher postprandial PYY, oxytocin and CCK secretion; (ii) those most vulnerable to binge eating behavior will have greater hedonic appetite, fMRI hyperactivation of reward regions, higher postprandial ghrelin and lower postprandial leptin and CCK secretion; and (iii) those who develop or persist in purging behavior will exhibit increased postprandial fullness, fMRI hyperactivation of satiety regions, and higher postprandial BDNF. We will test this model by characterizing adolescents with low-weight eating disorders across multiple units of analysis within an RDoC framework using an fMRI paradigm, neuroendocrine assays, behavioral paradigms, and self-report measures. We will then follow these individuals for a year to assess who switches to a binge/purge illness and who maintains restriction. Building on our pilot data in adults with low-weight restrictive eating disorders, we will use a novel food motivation paradigm developed and validated by our team. Mapping the relationship between hallmark eating disorder behaviors (dietary restriction, binge eating, purging) and food motivation pathways across the overarching domains of the Regulatory and Positive Valence Systems in a longitudinal cohort of adolescents with low-weight eating disorders will enable us to understand mechanisms whereby dysregulated homeostatic and hedonic food motivation lead to development of these behaviors. Characterizing the neural circuitry, neuroendocrine, and behavioral features associated with eating disorder behaviors will (i) provide insight into mechanisms underlying the pathogenesis of these high-mortality illnesses and (ii) allow for identification of future therapeutic targets that impact behavior at a time when eating behaviors are evolving and when intervention may change disease course.

PUBLIC HEALTH RELEVANCE: Adolescence is a common time for the onset of low-weight eating disorders, and predictors of eating disorder psychopathology and long-term determinants of outcome are not known. This proposal will explore whether alterations in food motivation pathways in specific brain regions underlie restricting, bingeing, and purging in girls with low-weight eating disorders, and whether these alterations are associated with long-term outcomes.