194 Summary and discussion Integrating findings – neurobiology on a scale The brain’s reward circuitry plays a decisive role in the pathophysiology of AN. The mesocorticolimbic pathways are critically implicated in the motivational aspects of eating, and extant functional neuroimaging studies denote aberrant processing of both rewarding and aversive food-related stimuli in AN. Additionally, the cortico-striatal-thalamo-cortical circuits are instrumental in governing executive functions, habit formation, and reward processes relevant to eating behavior and eating disorders (4-9). Our empirical investigations corroborate the central involvement of reward circuitry in the pathophysiology of AN through multiple avenues. In our DBS-AN study, we strategically targeted the vALIC, a key node within the reward circuitry. Subsequent clinical assessments indicated a diminution in the rewarding properties ascribed to eating disorder-related pathological behaviors. In a parallel fMRI study, we observed discernible alterations in frontostriatal circuit activity during phases of both reward and loss anticipation in AN patients post-DBS. Moreover, our data suggest that the AN cohort exhibits a differential neural response to DBS treatment compared to a healthy control group. Collectively, these findings support the hypothesis that reward circuitry is integral to the pathogenesis of AN and that DBS holds promise in modulating aberrant neural activity. Our EEG study further substantiates the notion that DBS-induced effects transcend localized stimulation targets. EEG data reveal that the impact of DBS extends to diffuse pathological network activity. After an initial period of neural disorganization, the brain seems to undergo adaptive reorganization, potentially culminating in a more stable, healthier state. These observations align with extant literature on DBS, affirming its capacity to reduce maladaptive neural activity and restore pathological network activity. Our meta-analysis on DBS in AN suggests that the therapeutic potential of this technique may extend across diverse neural targets. This pluralism in target efficacy may indicate multiple avenues for the normalization of aberrant neural activity within comparable brain circuits. This aligns with the emerging concept of connectomic DBS, where various implementation sites are linked to pathophysiologically relevant white matter tracts. The utilization of advanced connectomic methodologies could facilitate the identification of personalized pathological neural networks, thereby enabling more precise target selection tailored to individual patients. Additionally, this suggests the possibility of transdiagnostic benefits, as the positive outcomes appear to extend to other psychiatric disorders where similar neural targets have been employed with therapeutic success. The outcomes of our investigation align closely with extisting research elucidating the mechanisms of action underpinning DBS. DBS implies continuous modulation of neural structures integral to, or associated with, specific brain circuits. Historically, high-frequency stimulation exceeding 100 Hz has been posited to mediate its therapeutic effects by locally attenuating
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