Objective. Given current clinical interest in vagus nerve stimulation (VNS), 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 pig, whose vagus nerve organization and size approximates the human vagus nerve. Approach. Here we combined microdissection, histology, and immunohistochemistry to provide data on key features across the cervical vagus nerve in a swine model, and compare our results to other animal models (mouse, rat, dog, non-human primate) and humans. Main results. In a swine model we quantified the nerve 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 VNS 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 vagus nerve. This often leads to a distinct bimodal organization, or ‘vagotopy’. This vagotopy was supported by immunohistochemistry where approximately half of the fascicles were immunoreactive for choline acetyltransferase, and reactive fascicles were generally grouped in one half of the nerve. Significance. The vagotopy observed via histology may be advantageous to exploit in design of electrodes/stimulation paradigms. We also placed our data in context of historic and recent histology spanning multiple models, thus providing a comprehensive resource to understand similarities and differences across species.

Objective 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. Approach 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. Main results 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. Significance 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.

Rapid advancements in neurostimulation technologies are providing relief to an unprecedented number of patients affected by debilitating neurologic and psychiatric disorders. Neurostimulation therapies include invasive and noninvasive approaches that involve the application of electrical stimulation to drive neural function within a circuit. This review focuses on established invasive electrical stimulation systems used clinically to induce therapeutic neuromodulation of dysfunctional neural circuitry. These implantable neurostimulation systems target specific deep subcortical, cortical, spinal, cranial, and peripheral nerve structures to modulate neuronal activity, providing therapeutic effects for a myriad of neuropsychiatric disorders. Recent advances in neurotechnologies and neuroimaging, along with an increased understanding of neurocircuitry, are factors contributing to the rapid rise in the use of neurostimulation therapies to treat an increasingly wide range of neurologic and psychiatric disorders. Electrical stimulation technologies are evolving after remaining fairly stagnant for the past 30 years, moving toward potential closed-loop therapeutic control systems with the ability to deliver stimulation with higher spatial resolution to provide continuous customized neuromodulation for optimal clinical outcomes. Even so, there is still much to be learned about disease pathogenesis of these neurodegenerative and psychiatric disorders and the latent mechanisms of neurostimulation that provide therapeutic relief. This review provides an overview of the increasingly common stimulation systems, their clinical indications, and enabling technologies.