<i>In vivo</i>visualization of pig vagus nerve ‘vagotopy’ using ultrasound

Settell, Megan L.; Kasole, Maïsha; Skubal, Aaron; Knudsen, Bruce E.; Nicolai, Evan N.; Huang, Chengwu; Zhou, Chenyun; Trevathan, James K.; Pelot, Nicole A.; Grill, Warren M.; Upadhye, Aniruddha R.; Kolluru, Chaitanya; Shoffstall, Andrew J.; Williams, Justin; Suminski, Aaron J.; Chen, Shigao; Ludwig, Kip A.

doi:10.1101/2020.12.24.424256

Cited by 7 publications

(16 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, the swine vagus has 5-10 times more fascicles than the human vagus and accordingly smaller fascicle diameters (Suppl. Figure 1), thereby representing a appropriate and challenging anatomical substrate for testing methods and technologies for selective vagus neuromodulation [2, 11, 15, 45, 46].…”

Section: Discussionmentioning

confidence: 99%

“…Resolving the selectivity profile on a single subject basis requires real-time or semi-real time methods. Recently, it was reported that the large-scale fascicular structure of the swine vagus can be visualized with noninvasive, high resolution ultrasound imaging [46].…”

Section: Discussionmentioning

confidence: 99%

“…Since activation of vagus fibers is largely determined by their distance from the stimulating electrode and the morphology of the surrounding tissue, the swine is an appropriate animal model for testing selective vagus neuromodulation methods and technologies, e.g. [2, 11, 15, 45, 46].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Organ- and function-specific anatomical organization of the vagus nerve supports fascicular vagus nerve stimulation

Jayaprakash

Tóth

Song

et al. 2022

Preprint

View full text Add to dashboard Cite

Afferent and efferent fibers in the vagus travel inside nerve fascicles and form branches to innervate organs and regulate organ functions. The organization of fibers and fascicles in the vagus trunk, with respect to the functions they mediate and the organs they innervate, remains largely unknown. Accordingly, it is unknown whether that anatomical organization can be leveraged by bioelectronic devices for function- and organ-specific neuromodulation. To characterize the microscopic functional anatomy of the vagus we developed a pipeline consisting of micro-computed tomography-based morphometry of fascicles and quantitative immunohistochemistry of single fibers. We found that, in the swine vagus, fascicles form clusters specific to afferent and efferent functions, increasingly separated in the rostral direction, and other clusters specific to the innervated organs, including larynx, lungs and heart, increasingly separated in the caudal direction. Large myelinated and small unmyelinated efferents have small counts, cover large area of the nerve, and are limited to specific fascicles; small unmyelinated afferents have large counts, cover small area, and are uniformly distributed across fascicles. To test whether fiber populations can be selectively modulated, we developed a multi-contact cuff electrode that observes the fascicular vagus anatomy. Targeting of different nerve sub-sections evokes compound action potentials from different fiber types and elicits differential organ responses, including laryngeal muscle contraction, cough reflex, and changes in breathing and heart rate. Our results indicate that vagus fibers are spatially clustered according to functions they mediate and organs they innervate and can be differentially modulated by spatially selective nerve stimulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Organ- and function-specific anatomical organization of the vagus nerve supports fascicular vagus nerve stimulation

Jayaprakash

Tóth

Song

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…3-D plane-by-plane volumetric B-mode images were collected ( Figures 1D–F ). Data associated with this study ( Settell et al, 2021 ), were collected as part of the Stimulating Peripheral Activity to Relieve Conditions (SPARC) program and are available through the SPARC Portal (RRID: SCR_017041) under a CC-BY 4.0 license.…”

Section: Methodsmentioning

confidence: 99%

In vivo Visualization of Pig Vagus Nerve “Vagotopy” Using Ultrasound

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background: Placement of the clinical vagus nerve stimulating cuff is a standard surgical procedure based on anatomical landmarks, with limited patient specificity in terms of fascicular organization or vagal anatomy. As such, the therapeutic effects are generally limited by unwanted side effects of neck muscle contractions, demonstrated by previous studies to result from stimulation of (1) motor fibers near the cuff in the superior laryngeal and (2) motor fibers within the cuff projecting to the recurrent laryngeal.Objective: Conventional non-invasive ultrasound, where the transducer is placed on the surface of the skin, has been previously used to visualize the vagus with respect to other landmarks such as the carotid and internal jugular vein. However, it lacks sufficient resolution to provide details about the vagus fascicular organization, or detail about smaller neural structures such as the recurrent and superior laryngeal branch responsible for therapy limiting side effects. Here, we characterize the use of ultrasound with the transducer placed in the surgical pocket to improve resolution without adding significant additional risk to the surgical procedure in the pig model.Methods: Ultrasound images were obtained from a point of known functional organization at the nodose ganglia to the point of placement of stimulating electrodes within the surgical window. Naïve volunteers with minimal training were then asked to use these ultrasound videos to trace afferent groupings of fascicles from the nodose to their location within the surgical window where a stimulating cuff would normally be placed. Volunteers were asked to select a location for epineural electrode placement away from the fascicles containing efferent motor nerves responsible for therapy limiting side effects. 2-D and 3-D reconstructions of the ultrasound were directly compared to post-mortem histology in the same animals.Results: High-resolution ultrasound from the surgical pocket enabled 2-D and 3-D reconstruction of the cervical vagus and surrounding structures that accurately depicted the functional vagotopy of the pig vagus nerve as confirmed via histology. Although resolution was not sufficient to match specific fascicles between ultrasound and histology 1 to 1, it was sufficient to trace fascicle groupings from a point of known functional organization at the nodose ganglia to their locations within the surgical window at stimulating electrode placement. Naïve volunteers were able place an electrode proximal to the sensory afferent grouping of fascicles and away from the motor nerve efferent grouping of fascicles in each subject (n = 3).Conclusion: The surgical pocket itself provides a unique opportunity to obtain higher resolution ultrasound images of neural targets responsible for intended therapeutic effect and limiting off-target effects. We demonstrate the increase in resolution is sufficient to aid patient-specific electrode placement to optimize outcomes. This simple technique could be easily adopted for multiple neuromodulation targets to better understand how patient specific anatomy impacts functional outcomes.

show abstract

“…For example, there is evidence for somatotopic organization of the pseudounipolar cell bodies of sensory afferents in nodose ganglia. However, more recent research has suggested that this organization may only be present in pigs but not in humans ( Settell et al, 2021 ). Large differences also exist in the diameter of the VN between species; this should be considered when evaluating the translational potential of VNS techniques demonstrated in small animals (such as rodents).…”

Section: Introductionmentioning

confidence: 99%

Selective Neuromodulation of the Vagus Nerve

2021

View full text Add to dashboard Cite

Vagus nerve stimulation (VNS) is an effective technique for the treatment of refractory epilepsy and shows potential for the treatment of a range of other serious conditions. However, until now stimulation has generally been supramaximal and non-selective, resulting in a range of side effects. Selective VNS (sVNS) aims to mitigate this by targeting specific fiber types within the nerve to produce functionally specific effects. In recent years, several key paradigms of sVNS have been developed—spatially selective, fiber-selective, anodal block, neural titration, and kilohertz electrical stimulation block—as well as various stimulation pulse parameters and electrode array geometries. sVNS can significantly reduce the severity of side effects, and in some cases increase efficacy of the treatment. While most studies have focused on fiber-selective sVNS, spatially selective sVNS has demonstrated comparable mitigation of side-effects. It has the potential to achieve greater specificity and provide crucial information about vagal nerve physiology. Anodal block achieves strong side-effect mitigation too, but is much less specific than fiber- and spatially selective paradigms. The major hurdle to achieving better selectivity of VNS is a limited knowledge of functional anatomical organization of vagus nerve. It is also crucial to optimize electrode array geometry and pulse shape, as well as expand the applications of sVNS beyond the current focus on cardiovascular disease.

show abstract

In vivovisualization of pig vagus nerve ‘vagotopy’ using ultrasound

Cited by 7 publications

References 33 publications

Organ- and function-specific anatomical organization of the vagus nerve supports fascicular vagus nerve stimulation

Organ- and function-specific anatomical organization of the vagus nerve supports fascicular vagus nerve stimulation

In vivo Visualization of Pig Vagus Nerve “Vagotopy” Using Ultrasound

Selective Neuromodulation of the Vagus Nerve

Contact Info

Product

Resources

About