76 Chapter 4 INTRODUCTION Anorexia nervosa (AN) has an alarming mortality rate (1-3). About 20% of AN patients remain treatment-refractory to psychotherapy and pharmacological treatment aimed at weight restoration (4). To ameliorate this grim perspective, there is an urgent need for novel treatment options. One promising new treatment is deep brain stimulation (DBS). DBS is neuromodulation therapy involving implantation of electrodes at targeted brain areas, which conduct electrical impulses to the brain tissue. These electrical impulses are controlled by a neurostimulator, a device similar to a pacemaker (5). DBS is already established as an effective treatment for Parkinson’s disease (PD), essential tremor, idiopathic dystonia, epilepsy, and obsessive-compulsive disorder (OCD) (6, 7). The idea of treating AN with DBS came from serendipitous positive effects that were noted in earlier DBS studies for other indications. In these case reports, patients were being treated with DBS for major depressive disorder (MDD) (8, 9) or OCD (10, 11), while they simultaneously suffered from comorbid AN. Follow-up showed not only a decrease of the MDD or OCD symptoms, but also an improvement of the AN symptoms, including cognitive and emotional symptoms. Patients presented significant improvement in BMI and decreased anxiety and distress in relation to weight gain (8-11). DBS also holds promise for understanding AN from a pathophysiological perspective. The reward system has been proposed as a key brain circuit in AN (12). This system regulates motivation and hedonic experience of food intake and provides feedback on the value of a specific food. Several lines of evidence show disturbances in the reward system in AN-patients, including failure to connect appropriate responses to stimuli (13), and limited awareness of intero- and exteroceptive homoeostatic triggers (14, 15). Moreover, these disturbances in the reward system are linked to formation of habits (16), reflected in repetitive anorectic behaviours and associated altered activation of striatal brain areas (13, 17). DBS has been shown to directly influence the reward and habit brain circuits, normalizing the aberrant activity associated with psychiatric disorders (18). Based on these serendipitous clinical observations and pathophysiological insights, pioneering studies tested the effects of DBS in patients with AN. In 2013, Lipsman et al. hypothesized the subcallosal cingulate cortex (SCC) and the nucleus accumbens (NAcc) to be effective DBS targets for AN because they met the following criteria; (1) prominent afferent and efferent connection with the anterior insula, (2) involved in reward-processing, (3) involved in AN-related provocation and imaging studies, and (4) involved in anxiety and dysphoric mood (14). Indeed, studies observed positive effects of both NAcc and SCC DBS on AN symptoms (6, 9). Moreover, based on effectiveness in psychiatric disorders phenomenologically related to AN, including treatment-refractory OCD and depression, other targets such as the ventral anterior limb of the internal capsule (vALIC) have been successfully tested in AN (15, 19, 20). Despite promising trial results, to our knowledge, a meta-analysis on the effects of DBS in AN had yet to be performed. In order to provide an estimate on the overall effect of DBS in AN, we
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