Anorexia nervosa (AN) is the third most common chronic illness among adolescents, and its mortality rate is 12 times higher than the death rate associated with all causes of death for females 15-24 years old. AN is characterized by severe weight loss and refusal to eat, suggesting altered brain processing of food rewards. In this application we will study in adolescents with AN brain reward pathways, and how those circuits are affected by malnutrition and re-feeding, as well as stress hormones that are frequently altered in AN. Our long term goal is to characterize pathologic brain circuits in AN that are biomarkers for the disorder, link those alterations to specific neurotransmitter mechanisms, and identify potential treatment targets for adolescent AN.
In Aim 1. we test the hypothesis that adolescent AN is characterized by an increased response of dopamine related brain reward pathways. The proposed results will suggest that malnutrition in adolescent AN is associated with heightened brain reward sensitivity.
In Aim 2. We test the hypothesis that weight recovered adolescent AN will have improved brain reward sensitivity compared to AN who did not restore weight, but will still show an exaggerated brain response compared to control adolescents. This will indicate long lasting alterations in brain reward function in adolescent AN beyond weight recovery.
In Aim 3. We will test the hypothesis that the stress, feeding and reward related hormones cortisol, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S), will be associated with increased reward sensitivity in adolescent AN. This will indicate potential mechanisms that contribute to altered reward processing in adolescent AN. We will study adolescents with restricting type AN, ages 12-17 years old, when underweight at the begin of treatment, as well as after either successful weight restoration or failure to restore weight. Results will be compared to age and education matched healthy adolescents. We will use taste and monetary reward stimuli and tasks that are related to brain dopamine function, together with functional magnetic resonance brain imaging (fMRI). We will examine adolescent AN brain response to reward stimulus expectation, as well as unexpected and expected receipt of reward stimuli. Those brain processes have important implications on reward learning and conditioning. We will further apply on the brain imaging results computational models that simulate brain dopamine action, and this will help getting insight into dopamine related brain function in adolescent AN. Those models will also help identify the larger brain reward circuitry that involves the effects of cognition and emotion on brain reward function in adolescent AN and healthy controls. The stress hormones cortisol, DHEA and DHEA-S have implications on feeding and brain dopamine function and show alterations in AN. We will analyze those neurosteroid hormones in saliva and test their affect on brain reward function in adolescent AN.

Public Health Relevance

Anorexia nervosa is the third most common chronic illness among adolescents and associated with high mortality and food avoidance. This project will study in adolescents with anorexia nervosa the functionality of brain reward circuits, pathways that affect the motivation to eat and that have been associated with the neurotransmitter dopamine. The identification of specific dopamine related brain alterations in adolescent anorexia nervosa will point toward novel treatment approaches and will therefore have important public health implications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH096777-03
Application #
8675950
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Garvey, Marjorie A
Project Start
2012-07-26
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
DeGuzman, Marisa; Shott, Megan E; Yang, Tony T et al. (2017) Association of Elevated Reward Prediction Error Response With Weight Gain in Adolescent Anorexia Nervosa. Am J Psychiatry 174:557-565
Frank, Guido K W; Shott, Megan E; Hagman, Jennifer O et al. (2017) The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa. Int J Eat Disord 50:447-450
Shott, Megan E; Pryor, Tamara L; Yang, Tony T et al. (2016) Greater Insula White Matter Fiber Connectivity in Women Recovered from Anorexia Nervosa. Neuropsychopharmacology 41:498-507
Frank, Guido K W (2016) Brain Reward Processing in Eating Disorders: Opportunities to Build Upon? J Am Acad Child Adolesc Psychiatry 55:929-930
Frank, Guido K W; Collier, Shaleise; Shott, Megan E et al. (2016) Prediction error and somatosensory insula activation in women recovered from anorexia nervosa. J Psychiatry Neurosci 41:304-11
Frank, G K W; Shott, M E; Riederer, J et al. (2016) Altered structural and effective connectivity in anorexia and bulimia nervosa in circuits that regulate energy and reward homeostasis. Transl Psychiatry 6:e932
Frank, Guido K W; Shott, Megan E (2016) The Role of Psychotropic Medications in the Management of Anorexia Nervosa: Rationale, Evidence and Future Prospects. CNS Drugs 30:419-42
Frank, Guido K W; Shott, Megan E; Keffler, Carrie et al. (2016) Extremes of eating are associated with reduced neural taste discrimination. Int J Eat Disord 49:603-12
Shott, M E; Cornier, M-A; Mittal, V A et al. (2015) Orbitofrontal cortex volume and brain reward response in obesity. Int J Obes (Lond) 39:214-21
Frank, Guido K W (2015) Recent advances in neuroimaging to model eating disorder neurobiology. Curr Psychiatry Rep 17:559

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