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

Abstract

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.

A method to establish functional vagus nerve topography from electro-neurographic spontaneous activity

“…In a similar manner, recent stimulation protocols to test organ- and function-specific organization of the pig VN 11 could also be applied to test the efficiency of our localization method by comparing spontaneous localization maps and electrically induced functional maps for a given physiological function. Finally, structural information could also be employed by following a procedure developed previously 22 to visualize the fascicular organization of the pig VN in vivo and build animal-specific structural-functional maps.…”

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

“…A major difference between the human and the swine vagus nerve is the number of fascicles in the cervical vagus nerve: the swine vagus nerve has 5-10 times more fascicles than the human vagus nerve and accordingly smaller fascicle diameters (Suppl. Figure 1), offering a more “granular” anatomical substrate for testing methods and technologies for selective vagus neuromodulation [1, 30, 39, 67, 68].…”

Closed-Loop Vagus Nerve Stimulation for the Treatment of Cardiovascular Diseases: State of the Art and Future Directions

“…The FDA-approved VNS device comprises a spiral anchor and two bipolar helical electrodes with a platinum ribbon functioning as an anode and a cathode. They wrap approximately 270° around the left cervical VN, below the origin of the superior and inferior cervical cardiac branches, and are connected via a cable tunneled subcutaneously to a pulse generator that is most commonly positioned in a infra-clavicular pocket ( 24 , 85 – 90 ). Despite the fact that VNS is a minimally invasive treatment, surgery remains inherently risky and comes with a number of possible side effects ( 91 , 92 ).…”

“…Electrodes commonly used for VNS are not selective enough to achieve targeted neuromodulation in a complex fasciculate nerve like the VN ( 133 ). The direct consequences are the failure to achieve therapeutical effects and the onset of side effects that include hoarseness, throat pain, voice alteration, difficulty swallowing, coughing, abdominal and chest pain, nausea, dyspnea, and bradycardia ( 36 , 85 – 88 , 90 ). The inadvertent stimulation of somatic nerve branches such as the superior and recurrent laryngeal nerve has been addressed as one of the main causes of VNS side effects ( 36 ).…”

“…To achieve such selectiveness, several authors tried the combination of different stimulation parameters or to modify the pulse shape using different techniques such as the anodal block, slowly rising pulses or depolarizing pre-pulses ( 89 ). Other strategies are the modification of electrode design to allow preferential activation of efferent fibers (such as in the case of the CardioFit system) or the development of multicontact electrodes that exploit the topographical architecture of human nerves to target organ-specific fascicles ( 36 , 88 – 90 ). This last approach would provide better spatial resolution and consequently improve the selectivity both for recordings and stimulation ( 36 , 89 ).…”