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

腹部 VNS 治疗大鼠模型中的炎症

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.

作者聚焦：探索腹部 VNS 治疗炎症性疾病

腹部迷走神经刺激植入手术和清醒大鼠的记录研究

在清醒大鼠中使用植入电极阵列进行慢性电生理学测试和腹部迷走神经刺激

首先将电极阵列插入大鼠的腹迷走神经。要进行电生理学测试，请将电缆的一端连接到经皮连接器，另一端连接到刺激器。测量电压波形第一相结束时的峰值电压，并使用OMS定律计算总阻抗。然后将一对电极连接到刺激器，将另一对电极连接到记录设备。使用 VNS 植入物的参比电极应用双极刺激以产生 ECAP，用于 ECAP 的差异记录。使用数据采集和分析软件制作两组记录，每组平均重复 50 次。使用数据分析软件在分析窗口内测量波形的峰峰值电压，以分析ECAP响应。

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

Research

JoVE Journal

Neuroscience

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

98 次观看. 首先将电极阵列插入大鼠的腹迷走神经。要进行电生理学测试，请将电缆的一端连接到经皮连接器，另一端连接到刺激器。测量电压波形第一相结束时的峰值电压，并使用OMS定律计算总阻抗。然后将一对电极连接到刺激器，将另一对电极连接到记录设备。使用 VNS 植入物的参比电极应用双极刺激以产生 ECAP，用于 ECAP 的差异记录。使用数据采集和分析软件制作两组记录，...

视频: 在清醒大鼠中使用植入电极阵列进行慢性电生理学测试和腹部迷走神经刺激

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

Abdominal vagus nerve stimulation (VNS) can be applied to the subdiaphragmatic branch of the vagus nerve of rats. Due to its anatomical location, it does not have any respiratory and cardiac off-target effects commonly associated with cervical VNS. The lack of respiratory and cardiac off-target effects means that the intensity of stimulation does not need to be lowered to reduce side effects commonly experienced during cervical VNS. Few recent studies demonstrate the anti-inflammatory effects of abdominal VNS in rat models of inflammatory bowel disease, rheumatoid arthritis, and glycemia reduction in a rat model of type 2 diabetes. Rat is a great model to explore the potential of this technology because of the well-established anatomy of the vagus nerve, the large size of the nerve that allows easy handling, and the availability of many disease models. Here, we describe the methods for cleaning and sterilizing the abdominal VNS electrode array and surgical protocol in rats. We also describe the technology required for confirmation of suprathreshold stimulation by recording evoked compound action potentials. Abdominal VNS has the potential to offer selective, effective treatment for a variety of conditions, including inflammatory diseases, and the application is expected to expand similarly to cervical VNS.

The present protocol describes the surgical technique for implanting an electrode array onto the abdominal vagus nerve in rats, along with methods for chronic electrophysiology testing and stimulation using the implanted device.

Abdominal vagus nerve stimulation (VNS) can be applied to the subdiaphragmatic branch of the vagus nerve of rats. Due to its anatomical location, it does ...