Christina E. Wierenga, Ph.D. - US grants

PROJECT SUMMARY/ABSTRACT Common to all eating disorders (ED) are alterations in the motivation to eat , ranging from extreme food restriction and weight loss, to binge eating coupled with compensatory strategies like self-induced vomiting. Despite the traditional emphasis on these physical symptoms, they often overlap, and, along with significant diagnostic crossover (e.g., from anorexia nervosa to bulimia nervosa) over the course of one's illness, suggest shared features that are not well captured by current diagnostic criteria. This novel proposal aims to examine how RDoC-based temperament measures ? behavioral activation/impulsivity, behavioral inhibition, and effortful control ? identify clinically meaningful groups of adolescent ED patients that may reflect core dimensions of ED better than DSM diagnosis and correspond more strongly to brain function and clinical symptoms. These temperaments are thought to play a role in ED behavior because they are linked to altered incentive processing, particularly in the ventral striatum and insula, which guides approach and avoidance motivation via evaluation of anticipated and actual outcomes. For example, in other approach disorders, like addiction, high impulsivity is associated with reduced striatal activity during monetary reward anticipation,8 whereas in avoidance disorders, anxiety and inhibition are linked with an increased insula response to reward anticipation,9 and decreased striatal outcome response.10 We test the novel hypothesis that over- and under- controlled eating behavior reflects aberrant incentive processing stemming from altered evaluation of anticipated and/or actual outcome to induce compensatory consumption (approach) or avoidance behaviors. We will recruit 150 females currently ill with an ED and 50 controls ages 14-17 to investigate how temperaments reflecting greater inhibition, impulsivity, or effortful control correspond to 1) clinical symptoms and 2) the brain's response to anticipation and outcome of appetitive and aversive generalized (monetary wins and losses) and disorder-specific (taste) salient stimuli, and 3) by collecting follow-up clinical data one year later, identify how temperament-based subtypes predict ED symptom change (e.g., clinical prediction). Demonstrating that certain temperament and personality characteristics are directly related to brain response to both money and taste, rather than only disorder-specific food stimuli, and that correspond to clinical symptoms, will provide greater support for the contribution of biological processes underlying incentive processing to ED behavior. We will also explore whether temperament is meaningfully related to white matter structural connectivity and resting state functional connectivity to further characterize brain-behavior relationships in adolescent ED. Resolving these questions is critical to our mechanistic understanding of the neural basis of disordered eating and will move us towards more meaningful characterization and development of more targeted intervention and prevention strategies than subtyping by physical symptoms.

PROJECT SUMMARY/ABSTRACT Anorexia nervosa (AN) is a debilitating, often chronic, and sometimes fatal eating disorder (ED) that typically develops in adolescence. The etiology of AN is likely complex, yet remains unknown, and as a result, current treatments lack sufficient efficacy. Significant symptom heterogeneity exists, yet is not well captured by current diagnostic criteria. Thus, the identification of dimensional constructs underlying ED symptoms and their neural correlates is critical to improve our mechanistic understanding of ED and identify novel therapeutic targets to inform precision medicine. Behavioral symptoms of AN, such as food restriction (AN-R) and binge/purge episodes (AN-BP), arise from maladaptive decision-making. Decision-making is governed by two systems: 1) goal-directed learning reflects flexible and purposeful actions based on anticipated outcome, and 2) habit learning reflects automatic, efficient, and inflexible choices established by previous reinforcement. These learning systems are mediated by separate, yet overlapping, corticostriatal circuits and can be computationally modeled using a two-step sequential decision-making task. Difficulty arbitrating between these systems, resulting in an over-reliance on one strategy over the other, may contribute to divergent AN symptoms. This proposal tests the novel hypothesis that goal-directed and habit learning under conditions of reward and loss differs in AN and is uniquely associated with divergent symptoms and corticostriatal connectivity. Adolescent girls ages 14-17 with AN-R, AN-BP or who are healthy controls will undergo neuroimaging to assess resting state functional connectivity and microstructural integrity of corticostriatal networks, followed by performing the two-step learning task outside the scanner under conditions of reward and loss. For each participant, a weighting factor (?), representing the relative balance between goal-directed and habit learning, will be calculated for gain and loss conditions. After scanning, AN participants will complete a 14-day ecological momentary assessment protocol to evaluate naturalistic, momentary experiences of ED symptoms. Aim 1 will determine the behavioral differences in goal-directed and habit learning under conditions of reward and punishment in individuals with AN- R, AN-BP and healthy controls. Aim 2 will examine the association of goal-directed and habit learning for reward and punishment with symptoms and real-world experiences in AN to determine whether learning differences contribute to divergent symptoms. Aim 3 will determine whether corticostriatal circuits associated with goal- directed and habit learning for reward and punishment differ by group and condition to inform neural mechanisms of altered reinforcement learning in AN. Data will support a future longitudinal R01 application to test a dimensional approach of behavioral phenotyping based on reinforcement learning in a wider spectrum of restricting and binge-type EDs to inform a neurodevelopmental model. Defining meaningful biomarkers in ED would be a major advance in the field, as it would allow the development of new treatment approaches to reduce poor outcome.