85 Efficacy and safety of deep brain stimulation for treatment-refractory anorexia nervosa: a systematic review and meta-analysis The present meta-analysis showed statistically large effects of DBS in treatment-refractory AN for weight gain, whereas effect sizes otherwise found in literature for pharmacological and psychological treatment seem to be respectively moderate (35, 36) and low (37). The effects of DBS in AN are in line with effects of DBS in other psychiatric disorders including depression and OCD (38). The beneficial clinical effects of DBS in this meta-analyses may also improve insight in the pathophysiology of AN. It is hypothesised that DBS creates a reversible lesion to the stimulated area (6, 39). However, recent evidence suggests that DBS modulates widespread brain network activity, e.g. normalizing neuronal firing in reward circuitry. Due to the uncertainties in the pathophysiology of AN and the working mechanisms of DBS, included trials used diverse stimulation sites, including the NAcc, SCC, and vALIC. However, the effects of the studies were comparable with low heterogeneity. This shows that DBS may be effective at diverse targets, potentially suggesting diverse inroads to normalize aberrant activity in comparable brain circuits. This is in line with the concept of connectomic DBS, where different implementation targets all relate to similar pathophysiologically relevant white matter tracts (40). Moreover, these effects may be shared with other psychiatric disorders, where similar targets resulted in transdiagnostic beneficial effects (34, 41). Literature on the biological effects of DBS in AN is sparse. Zhang et al. used FDG-PET to image glucose metabolism in the brain after DBS to the NAcc to identify which brain regions would be affected by DBS in AN (42), and noted a reduction of (hyper)metabolism in the lentiform nucleus, hippocampus, and frontal lobe. Further evidence comes from research other disorders. DBS to the NAcc in treatment-resistant depression showed metabolic decreases in prefrontal subregions, subgenual cingulate region, posterior cingulate cortex, thalamus and caudate nucleus. DBS of the anterior limb of the internal capsule in patients suffering from OCD, resulted in long-term changes in metabolic activity (43). A decrease of frontal metabolism is a fundamental component of NAcc-DBS mechanism (44). Moreover, Fridgeirsson et al. found an association in OCD between improvement in mood and anxiety with decreased functional connectivity between the amygdala and insula due to DBS (45). These circuitries are also involved in AN, presumably, though the precise mechanisms of action of DBS remains to be determined. Limitations and strengths The main limitation of this study was the inability to rule out the presence of a placebo effect. The nature of DBS and particularly AN make it difficult to apply a double-blind study design. Nevertheless, effects, including on the objective outcome BMI, in this severe and extremely treatment-refractory population maintained over a study follow-up of up to 24 months, which argues for consistency and durability.
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