Closed-loop neuroelectric control of emesis and gastric motility

Gastroparesis has a prevalence of nearly 80,000 people in the USA and is associated with significant morbidity, including chronic nausea and vomiting. Current strategies to control nausea and vomiting in this patient group are largely unsuccessful. Closed-loop neuromodulation technology could potentially provide a precision therapy for these patients because nausea signaling is associated with bioelectric disruption of gastric motility and electrical stimulation of the vagus nerve can increase motility. The goal of the proposed research is to apply closed-loop technology using neuroelectric recording and stimulation devices to improve gastric motility and inhibit emetic signaling. We will initially conduct preclinical testing in ferrets to customize the technology to record gastric myoelectric signals and electrically stimulate the abdominal vagus. The ferret will be used because it is the “gold- standard” model for emesis testing by industry and is one of the few commonly used models that possesses an emetic reflex, which is lacking in laboratory rats and mice. After proof-of-concept testing in the ferret, we will perform a good laboratory practice (GLP) study in the minipig, a model species for safety testing prior to clinical trials. We will complete the following three Aims: (1) Establish flexible electrode attachment, recording, and stimulation parameters in the ferret. Studies will include testing abdominal vagus nerve stimulation and electrogastrography recording using ultra- precision laser-patterned, and nano-fiber reinforced micro-cuff and conformal planar electrode arrays; (2) Test the efficacy of closed-loop control of emesis in the ferret. Animals will be implanted with vagus and gastric electrodes for awake testing. Emetic-related gastric responses will be produced by gastric emetic stimuli to trigger gastric dysrhythmia and electrical stimulation of the vagus; and (3) Conduct GLP safety testing of electrode implants and abdominal vagus electrical stimulation in the minipig. Animals will be implanted with vagus and gastric electrodes followed by a long-term safety test, with daily stimulation of the vagus. Completion of our Aims will produce the essential efficacy and safety data to enable an Investigational Device Exemption (IDE) submission to the FDA for a subsequent clinical pilot study. This project is significant because it targets an unmet therapeutic need of patients with refractory gastroparesis who experience highly aversive chronic nausea and vomiting.