102 Chapter 5 INTRODUCTION Anorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Deep brain stimulation (DBS) has been proposed as a promising last-resort treatment option for severe therapy refractory AN-patients (1). A recent meta-analysis showed overall beneficial effects of DBS on weight, eating disorder, depression and anxiety symptoms, as well as quality of life (2). A better understanding of the working mechanisms of DBS in AN would improve our understanding of the pathophysiology AN and enhance DBS therapy by optimizing patient and target selection. Studies on DBS in AN have explored diverse targets including the subcallosal cingulate cortex (SCC), nucleus accumbens (NAcc) and ventral anterior limb of the internal capsule (vALIC) (1, 3-6). Interestingly, different targets have shown comparable clinical effects, suggesting that DBS is effective at different targets and normalizes wider aberrant network activity in the brain. This aligns with the concept of connectomic DBS, where different DBS targets relate to similar pathophysiologically relevant white matter tracts (7). One important circuit that may play a role in the clinical effects of DBS in AN is the reward system which has been proposed as a key brain circuit in the pathophysiology of AN (8-17). The reward circuit encompasses multiple brain regions including the ventral striatum, insula and prefrontal cortex. In AN, the reward system processes the motivation for eating, the hedonic experience of food, and the value of specific food items. Neuroimaging studies have demonstrated dysfunctional activation in structures associated with salience and reward networks related to emotional and reward processing, as well as in a cortical cognitive circuit related to selective attention and planning, in both individuals with AN and those who have recovered from the disorder (17). These brain regions are part of the cortico-striatal-limbic neurocircuit, which is also implicated in other reward related psychiatric disorders such as obsessive-compulsive disorder (OCD) (18, 19). Reward-based neurobiological models suggest that AN is characterized by deficient reward processing and enhanced punishment processing. AN symptoms are thought to be maintained by reward-based learning, where abnormal eating- and weight-related cognitions alter reward processing. One hypothesis is that AN patients have a diminished sense of reward towards food and a decreased motivation for food consumption, (20-22). Additionally, studies have found an exaggerated response to losses in executive and striatal regions using a monetary guessing task (14), as well as increased activation in the insula and cingulate during loss anticipation in a monetary incentive delay task, indicating hypersensitivity to punishment in general (23). It is hypothesized that in AN, cues compatible with the illness (such as weight-loss behaviors, thinness and excessive exercising) become positively associated with reward while healthy cues (such as seeing, tasting and smelling food and foraging behavior) lose their primary rewarding properties,
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