Functional Vagotopy in the Cervical Vagus Nerve of the Domestic Pig: Implications for the Study of Vagus Nerve Stimulation

Abstract

Given current clinical interest in vagus nerve stimulation, there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the domestic pig, whose vagus nerve organization and size approximates the human cervical vagus nerve. We provide data on key features across the cervical vagus nerve including diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for vagus nerve stimulation with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the cervical vagus nerve. This often leads to a distinct bimodal organization, or ‘vagotopy’ that may be advantageous to exploit in design of electrodes/stimulation paradigms. Finally, we placed our data in context of historic and recent histology spanning mouse, rat, canine, pig, non-human primate and human models, thus providing a comprehensive resource to understand similarities and differences across species.

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

“…In addition, the relatively "simple" anatomy of the vagus in rodents, with one or two fascicles, is different than the multi-fascicular anatomy found in large animals and in humans [70]. This fascicular organization of the human cervical vagus will likely affect the coefficients of the models, as different fascicles seem to contain populations of different fiber sub-types [70]. Finally, given the lack of a clinical, fully implantable recording vagus electrode, collecting detailed eCAP and physiological measurements in humans outside of the operating room is currently not feasible; intra-operative experimental sessions are a possibility but those would be limited in time and will likely not generate enough data to train models that generalize well.…”

“…It is likely that the resolution of eCAP components at a more "expanded" temporal scale in the large animal model will result in different, and more accurate, model coefficients. In addition, the relatively "simple" anatomy of the vagus in rodents, with one or two fascicles, is different than the multi-fascicular anatomy found in large animals and in humans [70]. This fascicular organization of the human cervical vagus will likely affect the coefficients of the models, as different fascicles seem to contain populations of different fiber sub-types [70].…”

“…Our analysis is based on the assumption that fiber engagement and eCAP amplitude are linearly related. However, studies have shown that the distribution of nerve fibers is non-uniform within the cervical vagus nerve, even in the relatively simple rodent nerves [70,71]. Fibers that lie closer to the stimulating or recording electrode are easier to be excited or contribute more heavily to the eCAP measurements; both effects are more prominent with larger fibers.…”

“…Finally, given the lack of a clinical, fully implantable recording vagus electrode, collecting detailed eCAP and physiological measurements in humans outside of the operating room is currently not feasible; intra-operative experimental sessions are a possibility but those would be limited in time and will likely not generate enough data to train models that generalize well. For all those reasons, documenting eCAPs and physiological effects of VNS in a representative large animal model, like the swine [70], will be essential to understanding the clinical application potential of our approach.…”

Anodal block permits directional vagus nerve stimulation

“…Targeted engagement of fibers in VNS could be realized using different approaches: fascicle-directed [58][59][60][61][62] , fiber diameter-based 20,63 or direction-specific 21,[64][65][66][67] . Histological studies show that the spatial organization of fibers in the vagus nerve is complex, as different fiber types, both afferent and efferent, are found together in single fascicles 58,[68][69][70][71] . On the other hand, fibers in different fascicles might project to distinct anatomical targets, central or peripheral 58,59 .…”