New research in JAMA Psychiatry provides evidence that prediction error brain responses may have a central role in anorexia nervosa.

“Anorexia nervosa is the deadliest disorder in psychiatry, and up until recently, we had little understanding about brain function in anorexia nervosa,” said study author Guido Frank, an associate professor of psychiatry and neuroscience at the University of Colorado School of Medicine.

“Over the past 2 decades neuroscience — aided by new technology — has made significant progress in developing models of how the brain works. Those models can now be used to study psychiatric disorders.”

“The available treatments for anorexia nervosa are few and effectiveness is limited. I am a clinician and clinical researcher, and my goal is it to develop a treatment that improves recovery and reduces relapse rate,” Frank said.

The researchers compared the brain activity of 56 female adolescent and young adults with anorexia nervosa to 52 healthy control participants of the same age.

The participants learned to associate colored shapes with either getting or not getting a sugary solution. Sometimes when they expected sugar they got nothing, and sometimes when they didn’t expect sugar they received it.

Those with anorexia nervosa tended to have a stronger prediction error brain response. In other words, they had heightened brain activity in response to the unexpected getting or not getting of sugar water.

“The prediction error model is a neuroscience-based model that we can use for human brain imaging. The model provides information about brain reward function, and we can make inferences about the dopamine system,” Frank explained.

The heightened prediction error brain responses were detected in the caudate, nucleus accumbens, and insula.

Stronger prediction error brain responses were related to higher anxiety and less weight gain for those being treated for anorexia nervosa.

“Our results suggest the following model for why it is so difficult to recover from anorexia nervosa: The brain adapts to food restriction in anorexia nervosa and sends the message ‘feed me.’ However, that message is in conflict with the desire to lose weight, creating internal conflict. The person with anorexia nervosa then ‘solves’ the conflict by not eating and reducing anxiety. That, however, increases the body’s signal to eat and a vicious cycle begins,” Frank told PsyPost.

Those who are already worried about shape and weight become even more concerned. And a strong response that says “feed me” might be overwhelming and trigger more food restriction instead of eating.

The study — like all research — includes some limitations.

“We have not directly answered questions such as what specific neurotransmitters are involved in this mechanism. This will be key to identifying medication that could help in the process of recovery. We also need to understand further how habit formation plays into the long-term effects of the illness on the brain,” Frank said.

“This study provides data for a mechanistic model in anorexia nervosa, and I am excited to follow up on this work and also expand to bulimia nervosa, binge eating disorder, etc. I would like to thank all the participants in the studies that we have done and I am grateful to my dedicated lab members.”

The study, “Association of Brain Reward Learning Response With Harm Avoidance, Weight Gain, and Hypothalamic Effective Connectivity in Adolescent Anorexia Nervosa“, was authored by Guido K.W. Frank, Marisa C. DeGuzman, Megan E. Shott, Mark L. Laudenslager, Brogan Rossi, and Tamara Pryor.