Effects of vagal neuromodulation on feeding behavior

Abstract

Implanted vagus nerve stimulation (VNS) for obesity was recently approved by the FDA. However, its efficacy and mechanisms of action remain unclear. Herein, we synthesize clinical and preclinical effects of VNS on feeding behavior and energy balance and discuss engineering considerations for understanding and improving the therapy. Clinical cervical VNS (≤30 Hz) to treat epilepsy or depression has produced mixed effects on weight loss as a side effect, albeit in uncontrolled, retrospective studies. Conversely, preclinical studies (cervical and subdiaphragmatic VNS) mostly report decreased food intake and either decreased weight gain or weight loss. More recent clinical studies report weight loss in response to kilohertz frequency VNS applied to the subdiaphragmatic vagi, albeit with a large placebo effect. Rather than eliciting neural activity, this therapy putatively blocks conduction in the vagus nerves. Overall, stimulation parameters lack systematic exploration, optimization, and justification based on target nerve fibers and therapeutic outcomes. The vagus nerve transduces, transmits, and integrates important neural (efferent and afferent), humoral, energetic, and inflammatory information between the gut and brain. Thus, improved understanding of the biophysics, electrophysiology, and (patho)physiology has the potential to advance VNS as an effective therapy for a wide range of diseases.

Keywords: Energy balance; Feeding behavior; Neural engineering; Obesity; Vagus nerve stimulation; Weight loss.

Figure 1. Distributions of fibers in the cervical (A) and subdiaphragmatic (B) vagus nerve (VN) in cat [9]

These data, as well as fiber distributions in other species, are shown in Table 1. All data were obtained from electron micrographs.

Figure 2. Percent excess weight loss (EWL) in EnteroMedics’ clinical trials (mean ± SEM)

Twelve-month data are shown for the first clinical trial, EMPOWER, for all patients (n_ctl=88, n_treat=165) and for patients who used vBloc® at least 12 hours per day (n_ctl=14, n_treat=16) [51]. Data are also shown for the second clinical trial, ReCharge, at 12 months (primary efficacy end point) (n_ctl=77, n_treat=162) [52,53], at 18 months (n_ctl=77, n_treat=162) [53], and at 24 months (n_treat=103) [54]. For both trials, the primary efficacy end point was defined as significantly greater percent EWL in the treatment group by at least 10 percentage points at 12 months. Missing data are assumed to be missing at random, except the 24-month data which exclude patients with missing data.