Vagus Nerve Stimulation in Rodent Models: An Overview of Technical Considerations

Abstract

Over the last several decades, vagus nerve stimulation (VNS) has evolved from a treatment for select neuropsychiatric disorders to one that holds promise in treating numerous inflammatory conditions. Growing interest has focused on the use of VNS for other indications, such as heart failure, rheumatoid arthritis, inflammatory bowel disease, ischemic stroke, and traumatic brain injury. As pre-clinical research often guides expansion into new clinical avenues, animal models of VNS have also increased in recent years. To advance this promising treatment, however, there are a number of experimental parameters that must be considered when planning a study, such as physiology of the vagus nerve, electrical stimulation parameters, electrode design, stimulation equipment, and microsurgical technique. In this review, we discuss these important considerations and how a combination of clinically relevant stimulation parameters can be used to achieve beneficial therapeutic results in pre-clinical studies of sub-acute to chronic VNS, and provide a practical guide for performing this work in rodent models. Finally, by integrating clinical and pre-clinical research, we present indeterminate issues as opportunities for future research.

Keywords: electrical stimulation; nerve cuff electrode; neuromodulation; vagus nerve; vagus nerve stimulation.

FIGURE 1

Different sized (0.3 and 0.5 mm) cuff electrodes with connectors. Embedded sutures on the electrode can facilitate the surgical implant (inset). Other important electrode elements described in the text are identified. Cuff image reproduced with permission from MicroProbes for Life Science (Gaithersburg, MD).

FIGURE 2

Left panel (top to bottom): Biphasic current-controlled stimulus isolator and biphasic pulse generator (BSI-1A, BPG-1P, respectively; Bak Electronics Incorporated, Umatilla, FL, United States). Right panel (top to bottom): Omnetics mating plug for the externalized connector and awake animal receiving stimulation. All procedures described and animal photography was performed with approval by the Institutional Animal Care and Use Committee (IACUC) at the University of Miami.

FIGURE 3

A depiction of the waveform of one charge-balanced, biphasic, cathodic-leading square pulse cycle, showing pulse width (PW), inter-phase interval (IPI), and pulse amplitude (PA). These components have been explained in detail elsewhere (Merrill et al., 2005). Image adapted with permission (Levine et al., 2014b; Olofsson et al., 2015) under the Creative Commons Attribution License.

FIGURE 4

Surgical preparation of the electrode implant. Close up (inset), where the white dotted line lies parallel to the nerve lying inside the cuff. All procedures described and animal photography was performed with approval by the Institutional Animal Care and Use Committee (IACUC) at the University of Miami.