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.
ABSTRACT
Background: The auricular branch of the vagus nerve runs superficially, which makes it a favorable target for non-invasive stimulation techniques to modulate vagal activity. For this reason, there have been many early-stage clinical trials on a diverse range of conditions. These trials often report conflicting results for the same indication. Methods: Using the Cochrane Risk of Bias tool we conducted a systematic review of auricular vagus nerve stimulation (aVNS) randomized controlled trials (RCTs) to identify the factors that led to these conflicting results. The majority of aVNS studies were assessed as having "some" or "high" risk of bias, which makes it difficult to interpret their results in a broader context. Results: There is evidence of a modest decrease in heart rate during higher stimulation dosages, sometimes at above the level of sensory discomfort. Findings on heart rate variability conflict between studies and are hindered by trial design, including inappropriate washout periods, and multiple methods used to quantify heart rate variability. There is early-stage evidence to suggest aVNS may reduce circulating levels and endotoxin-induced levels of inflammatory markers. Studies on epilepsy reached primary endpoints similar to previous RCTs testing implantable vagus nerve stimulation therapy. Preliminary evidence shows that aVNS ameliorated pathological pain but not evoked pain. Discussion: Based on results of the Cochrane analysis we list common improvements for the reporting of results, which can be implemented immediately to improve the quality of evidence. In the long term, existing data from aVNS studies and salient lessons from drug development highlight the need for direct measures of local neural target engagement. Direct measures of neural activity around the electrode will provide data for the optimization of electrode design, placement, and stimulation waveform parameters to improve on-target engagement and minimize off-target activation. Furthermore, direct measures of target engagement, along with consistent evaluation of blinding success, must be used to improve the design of controls-a major source of concern identified in the Cochrane analysis. The need for direct measures of neural target engagement and consistent evaluation of blinding success is applicable to the development of other paresthesia-inducing neuromodulation therapies and their control designs.
