A central feature of dopamine neuron response is that it is triggered by unexpectancy, ie, a discrepancy between what one expects versus what in fact happens. After receiving an unexpected reward such as food or money, a dopamine surge is elicited in the striatum and midbrain, which is called a positive prediction error response. When receiving this reward becomes a regular occurrence, the dopamine signal is triggered by the conditioned stimulus that predicts the reward. However, the dopamine system does not respond when the actual reward is received (prediction matches the outcome). If the reward is predicted but not received (there is no food or money after expecting it), there is a dip in dopamine activity in the brain, which reflects the negative prediction error (unexpected omission).
This dynamic can be studied in the living human brain with functional brain imaging during the application of a Pavlovian conditioning paradigm: participants learn to associate sugar-taste or monetary stimuli with pictures of colored shapes that become the conditioned stimulus and appear on the screen before money or sweet solution are delivered (Figure 1). Sometimes when the participants expect to get the reward, they will not get it; at other times the reward is delivered unexpectedly.
During these studies, adults and adolescents with anorexia nervosa repeatedly showed elevated response to the unexpected conditions in the insula and striatum, which suggests altered dopamine function.7-9 Basic science found that in the process of food restriction, the dopamine system in the brain gets sensitized to stimulate food seeking. We interpreted this elevated activation as a normal response.
This brain activation does not drive eating as it would in heathy individuals. In fact, it can often be observed in individuals with anorexia nervosa that despite weight loss, fear of weight gain worsens and there is no limit as to how low the weight will drop. In our most recent study, we propose a model of how this drive to lose weight may be perpetuated and how the elevated prediction error response fits into this behavior.9 Our findings indicate that elevated brain response correlated positively with harm avoidance—a measure of trait anxiety—but negatively with weight gain during treatment.
Harm avoidance was positively correlated with drive for thinness and body dissatisfaction. We propose that when a person who develops anorexia nervosa starts to lose weight, the dopamine system quickly gets faster or more strongly involved, ie, sensitized. Weight loss leads to low blood sugar and changes in hormonal and neuropeptide levels, which signal to the hypothalamus that the organism should eat. However, this biological motivation and drive to eat disagrees with conscious motivation to not eat and lose weight, which leads to high levels of anxiety. To avoid weight gain and driven by extreme anxiety, the person with anorexia eats even less, which further reduces weight and triggers more biological drive to eat and further increases anxiety. Thus, setting off a vicious cycle that is difficult to break (Figure 2).
Benefits of understanding the mechanism
Clinically, this has been a useful model to discuss the neurobiology of anorexia nervosa with patients or families. I draw and develop this model in a monthly seminar with parents of children with anorexia nervosa, which helps them understand the typically very difficult to comprehend ongoing drive for food restriction.
Understanding a certain mechanism does not cure the illness, but it provides opportunities to support treatment. In psychotherapy it helps to go from something inexplicable to understanding the connection between an anxious temperament with a predisposition to worry and eating problems. This is also relevant for patients who have recovered but who may be at risk for relapse.
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. ❒