There is an urgent need to develop novel therapies for patients with anorexia nervosa (AN). A condition that is heterogeneous, highly resistant to treatment, and associated with striking rates of morbidity and mortality, few therapeutic advances specifically for AN have been made in the past 150 years. A re-orientation in the last two decades toward neuroscientific explanations for AN offers hope that an increased understanding of the illness’ neural roots will lead to better treatments (Kaye et al, 2009).

Deep brain stimulation (DBS) is a neurosurgical procedure that targets critical nodes in dysfunctional neural circuits driving pathological behaviors (Lozano and Lipsman, 2013; Mayberg et al, 2005). DBS’ efficacy in disorders like Parkinson’s Disease has driven its investigation in other circuit-based conditions, including major depression (Lozano and Lipsman, 2013). Several factors led us to consider DBS in refractory AN. First, the primarily limbic structures implicated in the disorder, largely by functional neuroimaging, are consistent with the clinical observations that AN is predominantly a disorder of emotional processing. Further, the ability of DBS to safely and effectively access limbic nodes in mood- and anxiety-related circuits suggested that it could be applied to AN, a disorder marked by high rates of depressed mood and affective dysregulation.

The subcallosal cingulate (SCC) has a key role in modulating emotional states and projects cortically, to medial- and orbitofrontal cortex, as well as subcortically to nucleus accumbens. Our group has also shown that SCC neurons participate directly in emotion processing, responding preferentially to affective-laden stimuli and decisions (Lipsman et al, 2013a). The SCC is thus both structurally and functionally integrated into emotion pathways, and its activity linked to disorders of emotion.

Our initial experience in a small group of treatment-refractory patients (N=6; average age: 38 years; average illness duration: 18 years) showed DBS to be reasonably safe in AN, and associated with improvements in comorbid mood and anxiety symptoms (Lipsman et al, 2013b). These results were maintained during 6 months of clinical follow-up, with significant reductions in depressed mood and anxiety translating, over time, into increases in BMI (Figure 1). Although time spent on eating- and weight-related preoccupations and rituals did decrease (Lipsman et al, 2013b), we believe the primary effect of DBS was an improved utilization of conventional AN treatment as a result of improved mood and affective regulation.

Figure 1
figure 1

Mean (N=6) percentage changes from baseline, of weight and depression ratings, at each study time point (1 month, 3 months, and 6 months). At 6 months post-DBS, the cohort experienced a mean 12% increase in BMI and a 40% reduction in depression ratings. BMI, body mass index; HAMD, Hamilton Depression Rating Scale.

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The influence of focal stimulation on global cerebral metabolism can be investigated with functional imaging, such as positron emission tomography (PET; Figure 2). PET studies in both AN and depression patients have shown significant network-wide changes in glucose utilization with DBS of the SCC. For example, after 6 months of DBS, both patient groups see significant activity reductions in the SCC and insula, as well as significant activity increases in the parietal lobe (Lipsman et al, 2013b; Mayberg et al, 2005). In AN, this change in parietal activity constitutes an effective reversal of known baseline parietal hypometabolism seen in acutely ill AN patients (Delvenne et al, 1996). These results confirm that although DBS is a focal, targeted therapy, it can influence metabolism in remote regions, and that AN-relevant structures, such as those governing mood, emotion regulation, and body perception, can be modulated by SCC stimulation.

Figure 2
figure 2

Three-dimensional rendering of composite cerebral metabolic changes in six patients who underwent deep brain stimulation of subcallosal cingulum for anorexia nervosa. Red indicates areas of increased activity following 6 months of stimulation compared with baseline, and blue indicates areas of decreased activity compared with baseline. Parietal regions, which are hypometabolic in AN patients, saw significant activity increases with chronic stimulation, and prefrontal areas, including the subcallosal cingulate, saw activity decreases.

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Determining the potential role of DBS in the AN treatment algorithm will await the results of larger, sham-stimulation trials. It is clear, however, that the condition’s physical and emotional symptoms are inextricably linked, and novel treatment strategies will need to address both in equal measure, to offer patients hope for a meaningful and enduring recovery.

FUNDING AND DISCLOSURE

NL declares no conflict of interest. AML is a consultant for St Jude Medical, Medtronic and Boston Scientific, and holds intellectual property related to brain stimulation for depression.