Sources of Off-Target Effects of Vagus Nerve Stimulation Using the Helical Clinical Lead in Domestic Pigs

Abstract

Clinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig—an animal model with vagus anatomy similar to human—using the bipolar helical lead deployed clinically. Intrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses. Contraction of the cricoarytenoid muscle occurred at low amplitudes (∼0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (∼1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting Aδ-, B-, and C-fibers. Our data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 µA). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with Aδ- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.

Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat

“…In rats, we collected ∼6 to 8 mm samples where the VN courses straight with the common carotid artery, from the clavicle at the caudal end up to where the VN and carotid intermingle with other nerves. The sampling locations of the cervical VNs are consistent with the placement of VNS electrodes in clinical applications ( Santos, 2004 ; Milby et al, 2008 ), preclinical studies in pigs ( Tosato et al, 2007 ; Wolthuis et al, 2016 ; Nicolai et al, 2020 ), and preclinical studies in rats ( Borovikova et al, 2000 ; Ward et al, 2015 ; Patel et al, 2017 ; McAllen et al, 2018 ; Morrison et al, 2018 ; Pelot and Grill, 2020 ). We excised rat cervical VNs attached to the common carotid artery (i.e., the entire carotid sheath) to provide additional mechanical stability during sample handling and embedding.…”

“…We quantified the morphology of the cervical and subdiaphragmatic VN in humans, pigs, and rats. Healthy and disease model pigs are commonly used in preclinical studies, including for VNS ( Tosato et al, 2007 ; Val-Laillet et al, 2010 ; Wolthuis et al, 2016 ; Nicolai et al, 2020 ), because their size and (patho)physiology approximate certain clinical settings, such as obesity and cardiac conditions, better than other animals ( Johansen et al, 2001 ; Sauleau et al, 2009 ; Clouard et al, 2012 ; Swindle et al, 2012 ; Koopmans and Schuurman, 2015 ; Crisóstomo et al, 2016 ; Roura et al, 2016 ; Wolthuis et al, 2016 ; Bikou et al, 2018 ). Rats are commonly used as small animal models in neural stimulation studies ( Borovikova et al, 2000 ; Waataja et al, 2011 ; Ward et al, 2015 ; Patel et al, 2017 ; McAllen et al, 2018 ; Morrison et al, 2018 ; Pelot and Grill, 2020 ).…”

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

“…The human and swine vagus contain fibers of several types, including myelinated and unmyelinated afferents and efferents [2, 11, 12]. Large myelinated efferents (Aα-type) provide somatic innervation to laryngeal muscles [19, 20]; smaller myelinated efferents (B-type) are typically cholinergic and provide parasympathetic innervation to visceral organs, like the heart and the GI tract [20].…”

“…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].…”

“…The anatomical organization of the vagus could be leveraged by appropriately designed electrodes that target specific sub-populations of fibers in the nerve. More selective devices could lead to reduced side-effects [11, 14], expand the indications of bioelectronic therapies to organs that are currently not targeted [15, 16], and allow the mechanistic study of specific components of autonomic reflexes in health and disease.…”