Deep brain stimulation for obesity in the normal non human primate: A preclinical approach.

Abstract Object: Deep brain stimulation (DBS) has become an effective therapy in a variety of brain disorders. Recently, Hypothalamic DBS in cases of chronic intractable cluster headache has revived the interest in this region, which is also well-known to be involved in food intake and energy balance regulation. In the other hand, risks and problems related with implantation in this area has raised several questions regarding the safety of this approach. In this study, the authors proposed an Intraventricular “floating” electrode inserted in the third ventricle adjacent to the ventromedial hypothalamus (VMH) in freely moving Macaca fascicularis to modulate food intake and weight and as a potential treatment of morbid obesity. Methods: Five adults Macaca fascicularis (4 subjects and 1 sham) monkeys were implanted stereotactically in the third ventricle contiguous to the VMH with chronic indwelling 3389 and 3388 Medtronic electrodes used for Deep Brain Stimulation (DBS). The study was divided in two phases: acute tests and chronic 8-weeks trials. In the acute tests, the meal size, eating time and locomotor activity were recorded after short periods of electrical stimulation (ES) in 24 hrs fasting animals at different frequencies and intensities of stimulation, in order to obtain the most effective sets of ES parameters able to reduced food intake (FI) and consequently weight and fat during chronic stimulation. In the chronic trials, three cycles of continuous ES of 8 weeks each were performed at the most effective frequency reducing FI in the acute test (or 80Hz), at 130Hz (considered High Frequency ES and used in Parkinson Disease DBS) , and 30Hz (considered Low frequency ES and used in Pain DBS). Body Mass Index, weight, fat content, subcutaneous skinfolds and hormones were measured during baseline and at the end of each 8 week stimulation trials. Results: Results: During Acute 24 hrs-fasting trials, there was a decrease in FI in all subjects at 80 Hz, (mean 15 ±4.4%). During Chronic 8 weeks stimulation trials, a decrease in weight and BMI was observed in three out four monkeys at 80 HZ (mean 8% ± 4.4%), and slight increase at 130HZ (mean 2% ± 2.5) and at 30HZ (mean 5%±2,93). Fat mass decreased at the end of 80 Hz trials to ratio 0.82±0.08. (18% reduction).Subcutaneous skinfolds were reduced in all four subjects at 80 Hz and slightly increased at 130 Hz. Sham monkey remained stable. FI increased during off stimulation period (washout) following effective weight loss. Glucose also increased during hyperphagic period. Hormones and Leptin did not show significative variations in relation to different frequencies stimulation. No major adverse effects were recorded. Conclusion: We conclude that stimulating the VMH region throughout an Intraventricular approach might modulate acutely food ingestion and induce a sustained decrease in weight and in fat content in normal non obese human primates.