Vagus Nerve Stimulation: Mechanism of Action

Anatomy of the Vagus Nerve

The vagus nerve is the 10th cranial nerve, which is a mixed nerve consisting of approximately 80% afferent and 20% efferent fibers ( ). A schematic overview of the anatomic pathways is provided in Fig. 18.2 . The nerve exits the brainstem bilaterally at the level of the medulla oblongata and leaves the skull through the foramen magnum to run in parallel with the carotid arteries ( ). The cervical part of the vagus nerve gives off several branches, which provide sensory and parasympathetic innervation to the heart, lungs, and esophagus ( ). Two other vagus nerve branches are relevant to the clinical application of vagus nerve stimulation (VNS). The recurrent laryngeal nerve branches off caudally to the aortic arch to innervate the laryngeal muscles. Coactivation of this branch during VNS may cause typical side effects such as hoarseness and a tingling throat sensation in patients ( ). It also provides the anatomical basis of laryngeal muscle evoked potentials (LMEPs), which have been recorded with VNS ( ) and can potentially serve as noninvasive biomarkers for fiber activation. The auricular branch of the vagus nerve (ABVN) carries sensory afferents of the auricular concha and most of the area around the auditory meatus; the ABVN travels alongside vagus nerve fibers. This ABVN is used in transcutaneous auricular VNS (tVNS) ( ), a recently developed, noninvasive, neurostimulation technique. The vagus nerve passes through the diaphragm alongside the esophagus and gives off several subdiaphragmatic vagal branches, which provide sensory and parasympathetic innervation to the remaining parts of the gastrointestinal (GI) tract, the pancreas, the liver, and the adrenal glands ( ).

The cell bodies of primary vagal afferents reside in the nodose and jugular ganglia located just outside of the skull and project predominantly to the nucleus of the solitary tract (NTS) bilaterally in the brainstem ( ). These afferents transmit sensory information of several modalities, including blood pH and blood pressure, that are sensed by chemoreceptors and baroreceptors in major arteries, as well as sensations like hunger, satiety, and nausea, based on sensory information arising from the GI tract ( ). An estimated 80%–90% of vagal afferents are unmyelinated, multimodal C-fibers, conveying mainly chemical information ( ). The remaining 10%–20% are B- and A-fibers that convey mainly mechanical information ( ). The vast majority of efferent, parasympathetic fibers are thinly myelinated or unmyelinated B- or C-fibers that arise from the dorsal vagal motor nucleus and the nucleus ambiguous, with the exception of the thick, myelinated motor fibers, innervating the laryngeal muscles ( ).

The History of Vagus Nerve Stimulation

The oldest record of VNS in the PubMed database dates back to 1886 ( ), describing mechanical stimulation of the vagus nerve via carotid massage to halt seizures. Though early animal experiments showed desynchronization of brain rhythms along with attenuation or elimination of strychnine-induced spike activity during electrical VNS ( ), it was only in the late 1980s that VNS was systemically investigated in experimental seizure models ( ). Convincing outcomes of these studies led to the first clinical implantation of a VNS device in 1988 ( ) and full clinical development and regulatory clearance of VNS for the treatment of drug-resistant epilepsy by the European Medicines Agency in 1994 and by the US Food and Drug Administration (FDA) in 1997. The finding of mood improvement in patients with epilepsy treated with VNS ( ) led to clinical trials for depression and the approval of VNS for drug-resistant depression in 2005. Today, more than 100,000 patients are being treated with VNS.

Electrical Activation of Vagus Nerve Fibers

Clinical VNS is applied to the fibers in the cervical trunk of the left vagus nerve ( Fig. 18.1A ). Electrical activation of axons will, under most circumstances, result in a bidirectional conduction of action potentials (APs), although in most cases only the orthodromically conducted potentials are effective. The pair of helical electrodes that are surgically implanted around the cervical vagus nerve for clinical applications in VNS has the anode placed caudally to induce an anodal block of efferent APs and thus prevent side effects due to activation of parasympathetic vagal efferent fibers. An anodal block refers to the fact that an electrical stimulus of positive polarity will hyperpolarize the axons and attenuate or even block the generation of APs for a short period of time. Preclinical evidence, however, suggests that this concept is mostly theoretical ( ). When electrically stimulating nerves, nerve fibers are recruited in an orderly fashion, with large-diameter, thickly myelinated A-fibers being recruited at the lowest intensities, thinly myelinated B-fibers being recruited at intermediate intensities and thin, unmyelinated fibers being recruited at the highest intensities ( ). The pulse intensity is a function of the pulse width and the output current. A study in dogs ( ), where the size and geometry of the vagus nerve are comparable to those of humans, found that afferent A-fibers were recruited at a mean threshold of 0.37 ± 0.18 mA, fast B-fibers at a threshold of 1.6 ± 0.36 mA, slow B-fibers at a threshold of 3.8 ± 0.84 mA, and C-fibers at a threshold of 17 ± 7.6 mA, using a pulse width of 300 μs. Additionally, thick, myelinated, laryngeal motor fibers were recruited at a threshold of 0.36 ± 18 mA, similar to the threshold for recruitment of type A afferents. Interestingly, LMEPs in rats were found to be recruited at a threshold of around 0.3 mA ( ), suggesting that these intensities, despite differences in stimulation geometry, may be comparable across smaller and larger species.

Though initial evidence suggested the necessity of recruiting C-fibers, in order to produce anticonvulsant effects of VNS, due to the high stimulation intensities used (5–15 mA, 500-μs pulse width) ( ), more recent studies have found anticonvulsant effects using much lower intensities (<1 mA, 250–500 μs pulse width) ( ). The observation that neonatal capsaicin treatment, which eliminates C-fiber afferents, had no influence on the anticonvulsant effects of VNS ( ) further supported the predominant involvement of type A- and B-fibers. In rats, VNS has been found to affect brain physiology and excitability at intensities as low as 250 μA ( ), which theoretically rules out a role for B-fibers.

Recent lines of evidence, discussed later, have focused on using VNS to regulate both the heart and the immune system by stimulating B-fiber efferents. This requires higher stimulation intensities than those used to modulate brain physiology, which indeed is suggested by a previously published study ( ).

Important parameters for the effectiveness of activation of vagal fibers include both output current amplitude and pulse width. Commercially available VNS systems, however, also allow adjustment of both pulse frequency and duty cycle. Using a higher pulse frequency may result in a higher rate of generation of APs. When the frequency is sufficiently high, this may summate postsynaptically and potentially augment associated effects. Early preclinical studies showed that pulse frequencies of 20–30 Hz were superior to lower frequencies ( ), while high pulse frequencies (>50 Hz) have been associated with irreversible nerve damage and therefore are not recommended for clinical applications ( ). For this reason, most clinicians use a pulse frequency in the 20–30 Hz range. Studies on duty cycle efficiency remain relatively sparse. The use of duty cycles for VNS is based on the observation that anticonvulsant effects in preclinical experiments were found to outlast the active stimulation period. Although there is no clear evidence to support its use, the most commonly used duty cycle in the clinic is 30 s ON/300 or 600 s OFF. Some retrospective studies have argued that duty cycles with a higher percentage ON-time provide little additional effect ( ), but it must be noted that these studies generally have been confounded by the tendency to treat the most resistant patients with more intense VNS duty cycles. Recent preclinical observations on the other hand suggest that a more intense rapid VNS duty cycle (7 s ON/18 s OFF) had a greater impact on brain physiology than a lighter, more clinically used standard VNS duty cycle (30 s ON/300 s OFF) ( ). The current guidelines for selection of VNS parameters are thus based mainly on empirical clinical evidence, warranting larger systemically conducted trials.