Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat

Abstract

It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness. The human and pig VNs were comparable sizes (∼2 mm cervically; ∼1.6 mm subdiaphragmatically), while the rat nerves were ten times smaller. The pig nerves had ten times more fascicles—and the fascicles were smaller—than in human nerves (47 vs. 7 fascicles cervically; 38 vs. 5 fascicles subdiaphragmatically). Comparing the cervical to the subdiaphragmatic VNs, the nerves and fascicles were larger at the cervical level for all species and there were more fascicles for pigs. Human morphology generally exhibited greater variability across samples than pigs and rats. A prior study of human somatic nerves indicated that the ratio of perineurium thickness to fascicle diameter was approximately constant across fascicle diameters. However, our data found thicker human and pig VN perineurium than those prior data: the VNs had thicker perineurium for larger fascicles and thicker perineurium normalized by fascicle diameter for smaller fascicles. Understanding these differences in VN morphology between preclinical models and the clinical target, as well as the variability across individuals of a species, is essential for designing suitable cuff electrodes and stimulation parameters and for informing translation of preclinical results to clinical application to advance the therapeutic efficacy of VNS.

Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases

“…VN morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode ( Pelot et al, 2020 ). Miniaturization of the VNS device is also warranted.…”

Rapid and Low Cost Manufacturing of Cuff Electrodes

“…Although contacts as small as 0.2 mm can be embedded in the cuff, based on our experience with this process, we expect that its principles will be most viable for cuffs with inner diameters of at least 0.5 mm. Thus, future investigators can use this report as a basis for constructing cuff electrodes for smaller nerves, such as the rat vagus nerve whose diameter Pelot et al (2020) report is 0.260 ± 0.025 mm at the cervical level ( Noller et al, 2019 ).…”

Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents

“…This means that these manipulations may be translatable to the vagus of large animals which, at a microscopic scale, comprises the same fiber types 86 . In addition, the cervical vagus of the mouse and rat is small, 180 um and 260 um in diameter respectively 86,87 , and is organized in one or two fascicles 58,86,87 . As a consequence, all fiber types are represented within a small surface area, lying relatively close to the stimulating electrode, which facilitates a relatively uniform exposure to the generated electric fields in both animal species.…”

“…As a consequence, all fiber types are represented within a small surface area, lying relatively close to the stimulating electrode, which facilitates a relatively uniform exposure to the generated electric fields in both animal species. However, for these reasons, there will be challenges with translating these manipulations to the human and swine vagus nerve: those nerves have large diameters and complex, multi-fascicular structures 86,87 , which result in longer distances between the electrodes and the fibers of interest and in intra-neural connective tissue “barriers” to the generated fields. Special electrode designs with multiple contacts 84 , placed epineurally or intraneurally 85 , may have to be combined with the proposed stimulus manipulations to provide additional spatial selectivity with regard to the targeted fascicles.…”