Deep Brain Stimulation of the Nucleus Accumbens in Severe Enduring Anorexia Nervosa: A Pilot Study.

Introduction: Anorexia nervosa (AN) is one of the most debilitating psychiatric disorders, becoming severe and enduring in a third of cases; with few effective treatments. Deep brain stimulation is a reversible, adjustable neurosurgical procedure that has been gaining ground in psychiatry as a treatment for depression and obsessive-compulsive disorder, yet few studies have investigated AN. Abnormal eating behavior and the compulsive pursuit of thinness in AN is, in part, a consequence of dysfunction in reward circuitry and the nucleus accumbens (NAcc) is central to reward processing. Methods: Phase 1 prospective open-label pilot study of seven individuals with severe enduring AN. Electrodes were implanted bilaterally into the NAcc with stimulation at the anterior limb of the internal capsule using rechargeable implantable pulse generators. The protocol of 15 months included 12 months of deep brain stimulation incorporating two consecutive, randomized blind on-off fortnights 9 months after stimulation onset. The primary objectives were to investigate safety and feasibility, together with changes in eating disorder psychopathology. Results: Feasibility and safety was demonstrated with no serious adverse events due to deep brain stimulation. Three patients responded to treatment [defined as > 35% reduction in Eating Disorders Examination (EDE) score at 12 months] and four patients were non-responders. Responders had a statistically significant mean reduction in EDE scores (50.3% reduction; 95% CI 2.6-98.2%), Clinical Impairment Assessment (45.6% reduction; 95% CI 7.4-83.7%). Responders also had a statistically significant mean reduction in Hamilton Depression Scale, Hamilton Anxiety Scale and Snaith-Hamilton pleasure scale. There were no statistically significant changes in Body Mass Index, Yale-Brown-Cornell Eating Disorder Scale, Yale-Brown Obsessive-Compulsive Scale and World Health Organization Quality of Life Psychological subscale. Conclusion: This study provides some preliminary indication that deep brain stimulation to the NAcc. Might potentially improve some key features of enduring AN. In this small study, the three responders had comorbid obsessive-compulsive disorder which predated AN diagnosis. Future studies should aim to further elucidate predictors of outcome. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [Project ID 128658].

Translating the promise of 5HT4 receptor agonists for the treatment of depression.

Animal experimental studies suggest that 5-HT4 receptor activation holds promise as a novel target for the treatment of depression and cognitive impairment. 5-HT4 receptors are post-synaptic receptors that are located in striatal and limbic areas known to be involved in cognition and mood. Consistent with this, 5-HT4 receptor agonists produce rapid antidepressant effects in a number of animal models of depression, and pro-cognitive effects in tasks of learning and memory. These effects are accompanied by molecular changes, such as the increased expression of neuroplasticity-related proteins that are typical of clinically useful antidepressant drugs. Intriguingly, these antidepressant-like effects have a fast onset of their action, raising the possibility that 5-HT4 receptor agonists may be a particularly useful augmentation strategy in the early stages of SSRI treatment. Until recently, the translation of these effects to humans has been challenging. Here, we review the evidence from animal studies that the 5-HT4 receptor is a promising target for the treatment of depression and cognitive disorders, and outline a potential pathway for the efficient and cost-effective translation of these effects into humans and, ultimately, to the clinic.

Study Protocol: Using Deep-Brain Stimulation, Multimodal Neuroimaging and Neuroethics to Understand and Treat Severe Enduring Anorexia Nervosa.

BACKGROUND: Research suggests that altered eating and the pursuit of thinness in anorexia nervosa (AN) are, in part, a consequence of aberrant reward circuitry. The neural circuits involved in reward processing and compulsivity overlap significantly, and this has been suggested as a transdiagnostic factor underpinning obsessive compulsive disorder, addictions and eating disorders. The nucleus accumbens (NAcc) is central to both reward processing and compulsivity. In previous studies, deep-brain stimulation (DBS) to the NAcc has been shown to result in neural and symptomatic improvement in both obsessive compulsive disorder and addictions. Moreover, in rats, DBS to the NAcc medial shell increases food intake. We hypothesise that this treatment may be of benefit in severe and enduring anorexia nervosa (SE-AN), but first, feasibility and ethical standards need to be established. The aims of this study are as follows: (1) to provide feasibility and preliminary efficacy data on DBS to the NAcc as a treatment for SE-AN; (2) to assess any subsequent neural changes and (3) to develop a neuroethical gold standard to guide applications of this treatment. METHOD: This is a longitudinal study of six individuals with SE-AN of >7 years. It includes an integrated neuroethical sub-study. DBS will be applied to the NAcc and we will track the mechanisms underpinning AN using magnetoelectroencephalography, neuropsychological and behavioural measures. Serial measures will be taken on each intensively studied patient, pre- and post-DBS system insertion. This will allow elucidation of the processes involved in symptomatic change over a 15-month period, which includes a double-blind crossover phase of stimulator on/off. DISCUSSION: Novel, empirical treatments for SE-AN are urgently required due to high morbidity and mortality costs. If feasible and effective, DBS to the NAcc could be game-changing in the management of this condition. A neuroethical gold standard is crucial to optimally underpin such treatment development. CLINICAL TRIAL REGISTRATION: The study is ongoing and registered with www.ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01924598, 22 July, 2013. It has full ethical and HRA approval (Project ID 128658).

Differential activation of the frontal pole to high vs low calorie foods: The neural basis of food preference in Anorexia Nervosa?

Neuroimaging studies in anorexia nervosa (AN) suggest that altered food reward processing may result from dysfunction in both limbic reward and cortical control centers of the brain. This fMRI study aimed to index the neural correlates of food reward in a subsample of individuals with restrictive AN: twelve currently ill, fourteen recovered individuals and sixteen healthy controls. Participants were shown pictures of high and low-calorie foods and asked to evaluate how much they wanted to eat each one following a four hour fast. Whole-brain task-activated analysis was followed by psychophysiological interaction analysis (PPI) of the amygdala and caudate. In the AN group, we observed a differential pattern of activation in the lateral frontal pole: increasing following presentation of high-calorie stimuli and decreasing in during presentation of low-calorie food pictures, the opposite of which was seen in the healthy control (HC) group. In addition, decreased activation to food pictures was observed in somatosensory regions in the AN group. PPI analyses suggested hypo-connectivity in reward pathways, and between the caudate and both somatosensory and visual processing regions in the AN group. No significant between-group differences were observed between the recovered group and the currently ill and healthy controls in the PPI analysis. Taken together, these findings further our understanding of the neural processes which may underpin the avoidance of high-calorie foods in those with AN and might exacerbate the development of compulsive weight-loss behavior, despite emaciation.

Enhanced Early Neuronal Processing of Food Pictures in Anorexia Nervosa: A Magnetoencephalography Study.

Neuroimaging studies in Anorexia Nervosa (AN) have shown increased activation in reward and cognitive control regions in response to food, and a behavioral attentional bias (AB) towards food stimuli is reported. This study aimed to further investigate the neural processing of food using magnetoencephalography (MEG). Participants were 13 females with restricting-type AN, 14 females recovered from restricting-type AN, and 15 female healthy controls. MEG data was acquired whilst participants viewed high- and low-calorie food pictures. Attention was assessed with a reaction time task and eye tracking. Time-series analysis suggested increased neural activity in response to both calorie conditions in the AN groups, consistent with an early AB. Increased activity was observed at 150 ms in the current AN group. Neuronal activity at this latency was at normal level in the recovered group; however, this group exhibited enhanced activity at 320 ms after stimulus. Consistent with previous studies, analysis in source space and behavioral data suggested enhanced attention and cognitive control processes in response to food stimuli in AN. This may enable avoidance of salient food stimuli and maintenance of dietary restraint in AN. A later latency of increased activity in the recovered group may reflect a reversal of this avoidance, with source space and behavioral data indicating increased visual and cognitive processing of food stimuli.