Therapeutic potential of vagal neurostimulation to reduce food intake

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Obesity affects almost 40% percent of US adults and is associated with high levels of comorbidities, including cancer, cardiovascular disease, and diabetes. Although effective treatments with minimal side effects are lacking, vagus nerve stimulation (VNS) can reduce body weight and suppress feeding behavior. There is little insight, however, into its mechanism and it is unclear whether VNS effects on feeding and body weight result from non-specific side effects, such as nausea. The current application directly addresses these issues by assessing gastrointestinal (GI) myoelectric changes as a potential mechanism for effects of VNS on feeding behavior, while comparing these responses to emetic activation. We plan to accomplish this by using a ferret model, which is a gold-standard for studying emesis, vagus nerve, and GI physiology. We will test the hypothesis that electrical stimulation of the vagus nerve can reduce food intake without triggering indicators of nausea, such as disrupted GI myoelectric responses, retching, and vomiting. We will complete three Aims. Aim 1: Define the individualized GI myoelectric patterns during feeding behavior using machine learning classification. Animals will be implanted with planar electrodes attached to the GI serosal surface from proximal gastric fundus to distal duodenum. We will use machine learning to classify GI myoelectric patterns of meal consumption compared to emetic-related states, including those elicited by intragastric emetine and high amplitude and frequency VNS known to trigger emesis. Aim 2: Test the efficacy of abdominal VNS on reducing meal size without triggering disruptions of GI myoelectric responses, retching, and emesis. Animals will be assessed for effects of abdominal VNS using a variety of stimulus parameters on feeding behavior and multi-site GI myoelectric recordings. Aim 3: Determine the efficacy of cervical VNS in controlling meal size without producing off-target effects (disruptions of GI myoelectric responses, retching, emesis, changes in heart rate, or blood pressure). We will test the impact of cervical VNS parameters on feeding behavior, GI myoelectric responses, retching, emesis, hear rate variability, and blood pressure. Our approach is innovative because we will use machine learning classification to detect individualized GI myoelectric response patterns in an awake free-moving animal for comparing therapeutic and off-target effects of VNS on feeding, GI activity, emesis, and cardiovascular function. This planned research is significant because VNS therapy can potentially provide a frontline treatment option for patients with high levels of obesity refractory to behavioral or pharmacological therapy, which unlike other surgical interventions for weight loss, such as gastric bypass, is potentially tunable and reversible by changing stimulation parameters, switching the device off, or complete removal.