ABSTRACT Avoidant/restrictive food intake disorder (ARFID) affects 1-4% of adults and is associated with weight loss, nutritional deficiencies, suicidality, and psychosocial impairment. ARFID is heterogeneous, with poor intake characterized by extreme fear of choking, vomiting, or allergic reaction (ARFID-fear of aversive consequences); lack of interest in eating (ARFID-lack of interest); and/or extreme food selectivity (ARFID- sensory sensitivity). Very little is known about the pathophysiology of this serious mental health condition, particularly among adults whose illness has followed a chronic course. Our study will leverage unique and complementary contributions of a multidisciplinary team with expertise in clinical psychology, neuroendocrinology, and neuroscience to investigate the pathophysiology of ARFID in adults. We will establish a cohort of adults age 18-45 years with ARFID (n=150) and healthy controls (n=50) matched for sex and age to investigate how, across units of analysis, RDoC constructs contribute to ARFID phenotypes. First, we hypothesize that Negative Valence (acute threat/fear) hyperactivity (hormones: cortisol in response to a meal; circuitry: amygdala, anterior cingulate cortex, and orbitofrontal cortex activation during a validated food-cue paradigm) will correlate with severity of ARFID-fear of aversive consequences. Second, we hypothesize that Arousal/Regulatory (homeostasis) dysfunction (hormones: CKK, ghrelin in response to a meal; circuitry: hypothalamus activation during a validated food-cue paradigm) will correlate with severity of ARFID-lack of interest. Third, we hypothesize that Cognitive Systems (somatosensory perception) over- sensitivity (hormones: oxytocin in response to a meal; circuitry: activation in the somatosensory cortex and supplemental motor cortex during a validated food-cue paradigm) will correlate with severity of ARFID- sensory sensitivity. We also expect each ARFID phenotype to have greater dysfunction in the corresponding RDoC construct than controls. This study will be innovative and unique by providing an empirical investigation of an understudied clinical presentation and by investigating—for the first time—ARFID pathophysiology in adults. In sum, conceptualizing ARFID within an RDoC framework that integrates both endocrine signaling and neural circuitry has strong potential to advance precision medicine in ARFID by identifying mechanistic targets that could be intervened upon (e.g., through neuromodulation and/or hormone agonists/antagonists) to reduce the burden of ARFID across the lifespan.

PROJECT NARRATIVE Avoidant/restrictive food intake disorder (ARFID)—which affects 1-4% of adults—is a severe mental illness that causes people to eat an insufficient volume or variety of food and puts them at risk for nutritional deficiencies, low weight, psychiatric comorbidity, and suicidality. This multidisciplinary study offers an important opportunity to examine how underlying abnormalities in endocrine signalling and neural circuitry contribute to phenotypic presentations in adults. This innovative project has significant potential to reduce the public health burden of ARFID by informing pathophysiology and identifying mechanistic treatment targets hormonal agonist/antagonist medications and for brain stimulation therapies.