chronic electrophysiology testing and abdominal vagus nerve stimulation using an implanted electrode array in awake rats

Abdominal VNS for Treating Inflammatory Conditions in Rat Models

Vagus nerve stimulation (VNS) delivered at the cervical site in the neck is The United States Food and Drug Administration (FDA)-approved treatment for refractory epilepsy, refractory depression, and post-ischemic stroke rehabilitation1, and European Commission-approved for heart failure in Europe2. Non-invasive cervical VNS is FDA-approved for migraine and headache1. Its application is expected to expand, with recent clinical trials showing efficacy of VNS in other indications such as Crohn&#39;s disease3, rheumatoid arthritis4,5 and impaired glucose tolerance and type 2 diabetes6,7. Although promising, cervical VNS can cause bradycardia and apnea due to off-target activation of the nerve fibers that innervate the lungs and the heart8,9,10. Side effects such as cough, pain, voice alteration, headache and increase in apnea-hypopnea index are commonly reported in patients receiving cervical VNS11,12. Reduction in stimulation strength is a common strategy for reducing these side effects, however reduced charge may limit efficacy of VNS therapy by failing to activate therapeutic fibers11. In support of this hypothesis, the responder rate of patients receiving high intensity stimulation for the treatment of epilepsy was higher than that of patients receiving low intensity stimulation13.
Abdominal VNS is applied on the subdiaphragmatic vagus nerve, above the hepatic and celiac branches14 (Figure 1). Our previous study demonstrated that in rats abdominal VNS does not cause cardiac or respiratory side effects associated with cervical VNS10. Earlier studies also demonstrate anti-inflammatory effects of abdominal VNS in a rat model of inflammatory bowel disease and rheumatoid arthritis10,15 as well as reduction in glycemia in a rat model of type 2 diabetes16. Recently, the abdominal VNS technology has been translated for a first-in-human clinical trial for the treatment of inflammatory bowel disease (NCT05469607).
The peripheral nerve electrode array used to deliver stimulation to the abdominal vagus nerve (WO201909502017) has been custom developed for use in rats, and comprises of two to three platinum electrode pairs placed 4.7 mm apart, supported by a medical-grade silicone elastomer cuff, a suturing tab to anchor the array to the esophagus, a lead wire and a percutaneous connector to be mounted on the lumbar region (Figure 2). The lead wire is tunneled under the skin on the left side of the animal. Multiple electrode pair design allows for electrical stimulation of the nerve as well as recording electrically evoked compound action potentials (ECAPs), which confirms correct placement of the implant onto the nerve and suprathreshold stimulation intensities. Abdominal VNS is well tolerated in freely moving rats for months10,15,16. This allows for assessment of its efficacy on disease models.
This manuscript describes the methods for the electrode array sterilization, abdominal vagus nerve implantation surgery, and chronic stimulation and recording of ECAPs in awake rats for studying the efficacy of abdominal VNS in a variety of disease models. These methods were originally developed for studying the efficacy of abdominal VNS in the rat model of inflammatory bowel disease10 and have also been successfully used for a rat model of rheumatoid arthritis15 and diabetes16.

Author Spotlight: Exploring Abdominal VNS for Inflammatory Conditions

Implantation Surgery for Abdominal Vagus Nerve Stimulation and Recording Studies in Awake Rats

Abdominal VNS has the advantage of not causing cardiac and respiratory side effects associated with cervical VNS. The aim of the study was to investigate the anti-inflammatory effect of abdominal VNS in a rat model of rheumatoid arthritis. Previously, we have shown that abdominal VNS reduces symptoms of a rat model of inflammatory bowel disease.A first-in-human clinical trial is currently underway to investigate the safety and efficacy of abdominal VNS as a treatment of inflammatory bowel disease. We are expanding our neuromodulation research to investigate whether we can record spontaneous inflammation-induced vagus nerve activity as the next step for developing an adaptive abdominal VNS system for the treatment of inflammatory conditions. We have demonstrated that abdominal VNS causes no cardiac or respiratory off-target effects that are associated with cervical VNS, and it has anti-inflammatory effects in rat models of inflammatory bowel disease and rheumatoid arthritis.The effects of abdominal VNS on the body are not well understood compared to cervical VNS. This protocol may help to establish experimental protocols for testing the effect of abdominal VNS on different physiological parameters in healthy animals or inflammatory conditions such as systemic lupus and chronic kidney disease.

Chronic Electrophysiology Testing and Abdominal Vagus Nerve Stimulation Using an Implanted Electrode Array in Awake Rats

chronic-electrophysiology-testing-abdominal-vagus-nerve-stimulation

Research

JoVE Journal

Neuroscience

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