Anorexia nervosa is the third most common chronic illness among adolescent females. The mortality rate is 12-fold higher than with all other combined causes of death for females aged 15 to 24 years.1 The disorder is associated with severe emaciation from self-driven food refusal and a perception of being overweight despite very low body weight. Anorexia nervosa shows a complex interplay between neurobiological, psychological, and environmental factors, and it is a chronic disorder with frequent relapses, high treatment costs, and severe disease burden. Little is known about the pathophysiology or biomarkers that characterize anorexia nervosa brain function, treatment effectiveness is limited, and there are no FDA-approved medications.2
What makes anorexia nervosa so difficult to treat is the seemingly willful food avoidance and self-driven relentless motivation to lose weight. While eating is a very normal behavior for most of us, overcoming the fear of eating and weight gain is extremely difficult for children or adults with anorexia nervosa. Humans have historically evolved to be biologically protected to survive times of food scarcity. The brain circuitry that drives food-seeking has been well defined in basic science models.3
Developing neurobiological models for anorexia nervosa and existing mechanisms that disregard or override hunger signals has been much more difficult. Moreover, there are psychological and social factors involved in anorexia nervosa, including anxious traits and the tendency to worry, and their interaction combined with peer pressure and stress in general affect illness behaviors.4 This has made it difficult to tease apart environmental effects from brain biology that poses a vulnerability for developing or maintaining anorexia nervosa.
Recent brain research in anorexia nervosa has focused on reward pathways, with the hypothesis that these pathways might disturb food approach mechanism in anorexia nervosa. Food is a salient stimulus or natural reward, and reward pathways similar to those of substance abuse are activated when we desire, approach, or eat food.5 Important regions in this circuitry include the ventral striatum, which receives midbrain dopaminergic input and drives motivation and the reward approach; the orbitofrontal cortex responsible for reward valuation; the insula, which processes our taste sensations and provides input to the striatum; and the hypothalamus, which integrates body homeostasis.5,6 The circuitry between those brain regions may adapt to weight loss and instead of driving eating may reinforce food restriction in individuals vulnerable to anorexia nervosa.
A variety of studies in the past applied tasks that either showed food pictures or delivered monetary or taste rewards to stimulate the reward system. The studies repeatedly showed that the insula, orbitofrontal cortex, or striatum activated differently in persons with anorexia nervosa during those tasks compared with healthy controls.
In our laboratory, the aim is to identify chemical targets to develop better treatments for anorexia nervosa. To accomplish this, we applied reward tasks that were closely associated with brain dopamine response to find evidence of dopaminergic involvement in the pathophysiology of anorexia nervosa.
The dopamine neurotransmitter system has been intensively studied and well characterized. Its neurons’ cell bodies lie in the brain stem in the ventral tegmental area and substantia nigra and from there distribute to the cortical and subcortical brain. The basal ganglia and especially the ventral striatum that includes the nucleus accumbens receive dopamine input and have been involved in the drive to reward stimuli. The reward stimuli can be unconditioned or conditioned (learned) stimuli.
Dr Frank is Professor in Residence, University of California, San Diego, Eating Disorder Program for Treatment and Research, and Rady Children’s Hospital, San Diego, CA. He reports that he has received research funding from the NIMH, is on the Scientific Advisory Board of EDCare, and has provided expect testimony for Senter Goldfarb, & Rice.
1. Golden NH. Eating disorders in adolescence and their sequelae. Best Pract Res Clin Obstet Gynaecol. 2003;17:57-73.
2. Attia E. Anorexia nervosa: current status and future directions. Annu Rev Med. 2010;61:425-435.
3. Kessler RM, Hutson PH, Herman BK, Potenza MN. The neurobiological basis of binge-eating disorder. Neurosci Biobehav Rev. 2016;63:223-238.
4. Kaye WH, Wierenga CE, Bailer UF, et al. Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa. Trends Neurosci. 2013;36:110-120.
5. Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. J Neurosci. 2002;22:3306-3311.
6. Haber SN, Behrens TE. The neural network underlying incentive-based learning: implications for interpreting circuit disruptions in psychiatric disorders. Neuron. 2014;83:1019-1039.
7. DeGuzman M, Shott ME, Yang TT, et al. Association of elevated reward prediction error response with weight gain in adolescent anorexia nervosa. Am J Psychiatry. 2017;174:557-565.
8. Frank GK, Reynolds JR, Shott ME, et al. Anorexia nervosa and obesity are associated with opposite brain reward response. Neuropsychopharmacol. 2012;37:2031-2046.
9. Frank GKW, DeGuzman MC, Shott ME, et al. Association of brain reward learning response with harm avoidance, weight gain, and hypothalamic effective connectivity in adolescent anorexia nervosa. JAMA Psychiatry. 2018;75:1071-1080.
10. Abraham AD, Neve KA, Lattal KM. Dopamine and extinction: a convergence of theory with fear and reward circuitry. Neurobiol Learn Mem. 2014;108:65-77.
11. Frank GK, Shott ME, Hagman JO, et al. The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa. Int J Eat Disord. 2017;50:447-450.
12. Lock J, La Via MC, and the AACAP Committee on Quality I. Practice parameter for the assessment and treatment of children and adolescents with eating disorders. J Am Acad Child Adolesc Psychiatry. 2015;54:412-425.
13. Frank GKW, DeGuzman MD, Shott ME. Motivation to eat and not to eat: the psychobiological conflict in anorexia nervosa. Physiol Behav. 2019;206:185-190. ❒