Reward and Relapse: Resolving the Riddles of Bulimia Nervosa - Behavioral and Neural Response to Catecholamine Depletion in Remitted Bulimic and Healthy Participants: Relation to Reward Processing and Relapse

Bulimia nervosa is a severe psychiatric disorder defined by recurrent binge eating episodes, which are followed by inappropriate compensatory behavior to prevent weight gain. Bulimia nervosa has been associated with dysregulations of central catecholaminergic systems by various types of evidence. In previous studies, dopamine and norepinephrine concentration was found to be reduced in cerebral spinal fluid, blood and urine, and eating disorders have been associated with abnormal binding potentials of dopaminergic receptors. In functional magnetic resonance imaging (fMRI) studies, dopamine-rich brain regions were reduced activated in bulimia nervosa. In addition, dopamine is involved in reward processing, which was found to be dysfunctional in bulimia nervosa. Based on these findings, we were interested in the role of catecholamines in the pathophysiology of bulimia nervosa. By inducing catecholamine depletion, it is possible to directly investigate the effect of reduced catecholamine availability on eating disorder and mood symptoms, cerebral blood flow (CBF), and reward processing and risk-taking behavior. With this study, we aimed to showed that catecholamine depletion can induce eating disorder and depressive symptoms in participants remitted from bulimia nervosa. In addition, we aimed to identify differential effect of catecholamine depletion on CBF in remitted bulimia and healthy participants which may have predictive value for relapse or maintenance of remission. Next, we investigated the behavioral and neural responses to catecholamine depletion during reward processing, and risky decision making. In a randomized crossover study design, catecholamine depletion was achieved by oral administering of alpha-methyl-paratyrosine (AMPT) to participants remitted from bulimia nervosa and healthy participants. We assessed AMPT-induced changes in eating disorder and mood symptoms with various questionnaires. CBF changes were measured using a pseudo continuous arterial spin labeling (pCASL) sequence. During fMRI, participants performed the Monetary Incentive Delay (MID) task that assesses reward anticipation and reward-effort integration on a behavioral and neural level. Risk propensity was measured with a sequential risk-taking task. In the first paper, we present the differential effect of catecholamine depletion on CBF and mood symptoms and their potential relationship to relapse. In remitted bulimic participants, catecholamine depletion reduced vigor, and decreased CBF in the pallidum, whereas CBF in this region was unchanged in healthy participants. Reporting a bulimic relapse in a follow-up interview was associated with more AMPT-induced depressive symptoms and AMPT-induced reduction of CBF in the hippocampus/parahippocampal gyrus. An increased CBF in this region predicted remaining in remission. These findings indicate that catecholamine depletion is a suitable method to determine biomarkers for relapse and remission maintenance. The second paper describes the effect of catecholamine depletion on reward-effort integration. Catecholamine depletion reduced the ability to effectively integrate reward magnitudes and effort costs in healthy participants, whereas in remitted bulimic participants, reward-effort integration was already reduced in the sham condition and not affected by catecholamine depletion. In healthy participants, the reduced reward-effort integration after catecholamine depletion was significantly associated with the reduction of neural activation in the anteroventral striatum. This finding is in line with the hypothesis of a desensitized dopaminergic system in bulimia nervosa. In the third paper, we present the impact of catecholamine depletion on risk taking behavior. Catecholamine depletion reduced risk-taking behavior in both groups. The catechol-O-methyltransferase (COMT) val158met polymorphism had an impact on risk-taking behavior only in remitted bulimic participants: Carriers of at least one met158 allele showed higher risk-prone behavior than remitted bulimic participants with a val/val genotype. In sum, our results indicate that dopamine and/or norepinephrine play a crucial role in the pathophysiology of bulimia nervosa. With our findings, we encourage future studies to investigate the functional role of the hippocampus or other catecholamine-related biomarkers in relapse, the effectiveness of dopaminergic and noradrenergic drugs in the treatment of bulimia nervosa, and new psychotherapeutic interventions based on our findings regarding dysfunctional reward processing