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.
Highlights
The vagus nerve (VN) innervates most truncal organs and serves important roles in homeostatic regulation
For the rat subdiaphragmatic VN samples, we identified and segmented the largest fascicle on the anterior surface of the esophagus; we segmented smaller fascicles nearby if they were within a distance of approximately twice the diameter of the largest fascicle from the edge of the largest fascicle, as well as an associated nerve boundary where denser connective tissue transitioned to looser connective tissue, to approximate the tissues that would be within a cuff electrode
Cross sections of all collected VN samples stained with Masson’s trichrome (MT) are shown in Supplement 3, and detailed metadata for each subject and each sample are provided in Supplement 1
Summary
The vagus nerve (VN) innervates most truncal organs and serves important roles in homeostatic regulation. To design and deliver effective and selective vagus nerve stimulation (VNS), it is necessary to understand the morphology of the VN. Different neural and connective tissues (Figure 1) have different electrical conductivities (Geddes and Baker, 1967; Gabriel et al, 1996; Pelot et al, 2019), and the morphology of the nerve can influence patterns of stimulation. Data on nerve morphology are necessary to inform computational models to quantify these species- and nervespecific responses to VNS (Helmers et al, 2012; Gómez-Tames et al, 2014; Arle et al, 2016; Mourdoukoutas et al, 2017; Pelot et al, 2017). Morphological considerations are important in selecting appropriate animal models to evaluate and characterize neural stimulation therapies; such data will inform translation of stimulation parameters across species, including from preclinical studies to clinical applications
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
