The Role of Vagus Nerve Stimulation in the Treatment of Central and Peripheral Pain Disorders and Related Comorbid Somatoform Conditions

History and Background of Vagus Nerve Stimulation (VNS)

Stimulation of the carotid sinus and the vagus nerve (VN) by manual manipulation (deep carotid massage) has a long history of use for the treatment of medical conditions ranging from supraventricular tachycardia (SVT) to status epilepticus. The first use of electrical stimulation of the VN was proposed in by Dr. Corning, who used an electrified, external device to stimulate and compress the carotid arteries. Several decades later, vagus nerve stimulation (VNS), decoupled from the vascular compression element (directly applying current to the exposed cervical vagal trunk), was successfully shown to have an effect on chemically induced seizure activity ( ). The mechanism of action (MOA) by which this early attempt at neuromodulation was effective and the development of devices better suited to deliver this bioelectric medical therapy remains an active area of study.

In , Zanchetti et al. pioneered the use of EEG to study the effects of VNS on the cortex in strychnine-poisoned animals. A VNS device for use in humans by Houston-based Cyberonics (now LivaNova) followed in the late 1980s with a US Food and Drug Administration (FDA) approval for refractory epilepsy, being granted in 1997. Subsequent approvals for depression (LivaNova, 2006) and obesity ( ; VBLOC, Enteromedics, 2014) have been granted by the FDA for implanted devices that stimulate the VN. With respect to the latter approval, the stimulation parameters are intended to block activity in the VN, however, for reasons described more fully herein, it is possible that the MOA for the VBLOC’s clinical effects are through activation, not suppression, of vagal activity.

From the late 1990s through today, the availability of approved devices for use in humans has permitted a rapid expansion of case series and formal clinical studies centered on VNS, in indications ranging from depression ( ) to intractable hiccups ( ). Attempts have even been made to apply VNS to the treatment of some of the greatest threats to the modern health systems, metabolic disease ( ) and Alzheimer’s disease ( ).

While the evidence for many applications of VNS is preliminary, a growing understanding of the MOA and a recognition of the association of many medical conditions previously considered distinct, offers a new vision of functional disorders and an innovative way to treat them. These treatments have been facilitated by the introduction of new methods of stimulating the VN noninvasively through activation of the tragus nerve, so-called auricular stimulation (transcutaneous vagal nerve stimulation [tVNS]; Nemos, Cerbomed) or the cervical branches of the VN (noninvasive vagal nerve stimulation [nVNS]; gammaCore, electroCore, LLC).

Neuroanatomy of the Vagus Nerve and Selective Activation by Vagus Nerve Stimulation

The VN contains A-, B-, and C-fibers which differ in diameter and degree of myelination and function. Large, myelinated A-fibers have fast conduction velocities, low electrical thresholds, and carry mostly somatic information. Small, myelinated A-fibers have lower conduction velocities, higher electrical thresholds, and primarily transmit visceral afferent information. Sparsely myelinated B-fibers provide efferent sympathetic and parasympathetic, preganglionic innervation, while small, unmyelinated C-fibers carry afferent visceral information. While there is significant overlap of diameter and conduction velocities for the three fiber types, the electrical thresholds for unmyelinated C-fibers tend to be significantly greater than for myelinated A and B-fibers. The majority of cervical, vagal fibers (60%–80%) are afferent nerve fibers and therefore, carry information from visceral organs to the brain ( ). Clinically relevant, biological effects of VNS, as previously described, have been shown to be due to stimulation of efferent fibers, afferent fibers, or a combination of both.

Early studies on the use of invasive VNS (iVNS) for treatment of epilepsy have implicated afferent A- or B-fibers, but not C-fibers ( ). In a rat seizure study by , destruction of peripheral C-fibers by administration of capsaicin did not affect VNS-induced, seizure suppression. To determine which fibers were activated clinically, compound action potentials (CAPs) were recorded in patients undergoing surgical implantation of the Cyberonics, VNS device ( ). Action potentials (APs) in 21 patients were recorded, and based on conduction velocities, the authors reported that, even with stimulation currents of up to 5 mA (the normal range is 0.25–3.5 mA), only A and B fibers were activated, but not C-fibers. This conclusion is supported by canine studies ( ), in which VNS evoked CAPs elicited firing of A and B fibers at relatively low currents, while C-fiber activation (even at chronaxie [the minimum amount of time needed to stimulate a muscle or nerve fiber, using an electric current twice the strength required to elicit a threshold response]) required 40 to 90 times the activation currents necessary for A fiber activation.

As mentioned earlier, two noninvasive VNS devices have recently been developed and tested in multiple clinical studies. These devices represent significant advancements in VNS therapy as they could potentially provide simple noninvasive treatments that eliminate the expense and morbidity of a surgical procedure. Nemos, from Cerbomed (Germany), stimulates the auricular branch of the VN near the cymba conchae, while gammaCore from electroCore LLC (Basking Ridge, NJ) stimulates the cervical branch of the VN. Several animal and human studies, referenced later in this chapter, have demonstrated that both devices appear to excite the same VN fibers as the Cyberonics (iVNS) device.

In similar functional magnetic resonance imaging (fMRI) studies from the same laboratory, both auricular and cervical VNS produces significant activation of the nucleus tractus solitarius (the first central relay of vagal afferents) and many of its projections (e.g., the spinal trigeminal nucleus, dorsal Raphe nucleus (DRN), locus coeruleus (LC), etc.). Deactivations were observed in the hippocampus and hypothalamus. These responses were not seen in active, sham stimulation of the earlobe in the case of auricular stimulation or in muscle stimulation of the sternocleidomastoid muscle with cervical stimulation ( ) and were similar to changes observed with the iVNS device ( ).

VNS has also been shown, in human studies, to produce a specific pattern of early, EEG, evoked potentials, occurring 3–6 μs after stimulation, regardless of whether the stimulation is auricular, cervical, or iVNS. This suggests activation of the same nerve fibers in all three cases ( ). The fact that these methods of VNS stimulation produce similar evoked potentials doesn’t prove that these are the fibers necessary for producing beneficial clinical effects, but clearly demonstrate noninvasive VNS devices can activate the VN. A computational model of VN activation with cervical stimulation supports the conclusion that iVNS can stimulate A and B, but not C-fibers ( ). In addition, two studies demonstrating equivalence of iVNS and cervical nVNS in the same animal model have been reported ( ).

Evidence of Neurotransmitter Modulation

The development efforts, which ultimately led to the European Union and the United States, FDA approvals of the first implanted VNS device for the treatment of epilepsy, shepherded in the first, broad study period of VNS ( ). The early work by Zanchetti et al. within the space, whose research revealed that VNS modulates cortical activity and alters brain wave activity, has given way to more specific research to identify which nuclei in the brainstem are being activated, what changes in firing rates are seen among various classes of neurons, and what changes in various neurotransmitters occur before and after stimulation is applied.

Shortly after the first FDA approval for VNS, in July of 1997, Schacter and Saper published that the MOA, by which VNS is effective for the treatment of epilepsy, is unknown, but is “clearly different from that of AEDs” (antiepileptic drugs) ( ). As discussed later in this chapter, more recent work looking at the effects of VNS on hyperexcitability phenomena like cortical spreading depression, brings that assertion into question. Nevertheless, the authors have laid out the basic understanding of three significant neural relays from the nucleus tractus solitarius (NTS) (where the afferent VN enters the brainstem) to: (1) the autonomic and somatic centers in the medulla and spinal cord, (2) the reticular activation formation of the medulla, and (3) the ascending projections of the forebrain. It is in this third region that the LC, a small cluster of neurons (typically ∼12,000 neurons in a human ( )) that serves as the primary source of the neurotransmitter (NE), for the CNS, is located. The identification that VNS triggers activation and involvement of the LC, and the fact that the noradrenergic network of fibers emanating from there is one of the most extensive in the CNS, providing noradrenergic transmission throughout the brain, has led to a significant body of work that suggests that the antiepileptic effects of VNS are due to NE. This assertion is supported by observations that VNS’s antiepileptic effects are abolished when the LC is lesioned ( ).

Subsequent observations among implanted epilepsy patients, that VNS can have an effect on patients’ moods (an FDA approval for the treatment of refractory depression with implanted VNS was granted in 2005) led to further study of changes in serotonergic activity. In support of this line of thinking, in the following year, it was reported that the firing rates of serotonin releasing neurons of the DRN were enhanced by VNS, beginning at day 14 of stimulation, and increasing steadily over a 90-day period, while LC firing rates rose nearly immediately, with statistically significant increases observed within the first hour after initiation of stimulation ( ).

An additional mechanism involving the modulation of GABA-ergic transmission has also been proposed. Genetic mutation of the GABA receptor and/or antagonism of GABAergic transmission, are associated with seizure activity. These observations, coupled with clinical successes of drugs that enhance GABAergic activity ( ), have sparked a line of research among the VNS research community. In 2003, Marrosu et al. reported on long-term changes in GABA receptor density among a small group of human subjects after at least 1 year of VNS therapy, when compared with matched, VNS-eligible, nonimplanted controls. Their findings demonstrated that efficacious response to VNS significantly correlates with a normalization of GABA receptor expression, while the controls showed no change in GABA receptor density ( ).