Review Article

Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive

Review: Part II

Hsiangkuo Yuan, MD, PhD; Stephen D. Silberstein, MD

The development of vagus nerve stimulation (VNS) began in the 19th century. Although it did not work well initially, it

introduced the idea that led to many VNS-related animal studies for seizure control. In the 1990s, with the success of sev-

eral early clinical trials, VNS was approved for the treatment of refractory epilepsy, and later for the refractory depression.

To date, several novel electrical stimulating devices are being developed. New invasive devices are designed to automate

the seizure control and for use in heart failure. Non-invasive transcutaneous devices, which stimulate auricular VN or

carotid VN, are also undergoing clinical trials for treatment of epilepsy, pain, headache, and others. Noninvasive VNS

(nVNS) exhibits greater safety profiles and seems similarly effective to their invasive counterpart. In this review, we discuss

the history and development of VNS, as well as recent progress in invasive and nVNS.

Key words: vagus nerve, vagus nerve stimulation

(Headache 2016;56:259-266)

HISTORY OF VAGUS NERVE

STIMULATION

In the late 19th century, American neurologist

James Corning was the first to use vagus nerve

stimulation (VNS) to treat epilepsy, then thought

to be due to excessive cerebral blood flow (CBF).

He applied a “carotid fork” for partial bilateral

carotid artery compression and attached it to direct

current electrodes for crude transcutaneous stimula-

tion of the vagus nerve (VN) and sympathetic

nerves in an attempt to reduce the CBF and slow

the heart rate (Fig. 1).1 Though it did not work

well, Corning introduced the idea of VNS into the

world.

Half a century later, several animal studies

started to shed some light on the mechanism of

VNS. Bailey and Bremer developed the “enc�ephale

isol�e” procedure on vagotimized cats. They

observed an increased electrical potential on the

contralateral orbitofrontal cortex during Faradic

stimulation (24-50 Hz) of the afferent VN.3 In

1952, using “enc�ephale isol�e” cats with strychnine-

induced seizures, Zanchetti et al found global corti-

cal desynchronization and sleep spindle blockage

during VNS (2 volts, 50 Hz, 0.5 ms pulse).4 Magnes

et al stimulated the nucleus of the solitary tract at

low (1-16 Hz) or high (>30 Hz) frequencies, pro-

ducing EEG synchronization or desynchronization,

From the Jefferson Headache Center, Thomas Jefferson

University, Philadelphia, PA, USA.

Address all correspondence to Stephen D. Silberstein, MD,

FACP, Jefferson Headache Center, Thomas Jefferson Uni-

versity, 900 Walnut Street, Suite 200, Philadelphia, PA

19107, USA, email: Stephen.silberstein@jefferson.edu

Accepted for publication July 27, 2015.

Conflict of Interest: Dr. Yuan serves as a consultant for Super-

nus Pharmaceuticals, Inc., as a consultant and/or advisory panel

member. Dr. Silberstein receives honoraria from Alder Bio-

pharmaceuticals, Allergan, Inc., Amgen, Avanir Pharmaceuti-

cals, Inc., Depomed, Dr. Reddy’s Laboratories, eNeura Inc.,

electroCore Medical, LLC, Ipsen Biopharmaceuticals, Med-

scape, LLC, Medtronic, Inc., Mitsubishi Tanabe Pharma Amer-

ica, Inc., NINDS, St. Jude Medical, Supernus Pharmaceuticals,

Inc., Teva Pharmaceuticals, and Trigemina, Inc.

259

ISSN 0017-8748Headache doi: 10.1111/head.12650VC 2015 American Headache Society Published by Wiley Periodicals, Inc.

respectively.5 Chase et al stimulated the afferent

VN and discovered that EEG synchronization and

desynchronization were likely due to the stimula-

tion of fast and slow conducting fibers (<15 m/s),

respectively.6 In the strychnine dog model of status

epilepsy, Zabara et al reported that VNS (20-30

Hz, 0.2 ms pulse) interrupted the seizure and

induced an extended seizure inhibitory period.7

Other animal models also demonstrated potential

antiepileptic properties of VNS.8 While C-fibers

were thought to be the primary nerve type involved

in seizure control in animal models, A- and B-fibers

were later found to play the major role in antisei-

zure efficacy in humans.

DEVELOPMENT OF CLINICAL VNS

With the success in animal studies, human stud-

ies ensued in the early 1990s. Uthman et al and

Penry et al reported 2 pilot studies showing signifi-

cant seizure reduction following VNS in patients

with intractable epilepsy.9,10 In 1994, a randomized,

multicenter, double-blind study on 67 patients with

refractory partial seizures showed significant reduc-

tion in seizure frequency after 14 weeks of VNS.11

The US Food and Drug administration (FDA) later

approved an implanted left cervical VNS device for

managing treatment-refractory epilepsy (TRE) in

1997,12,13 and for chronic treatment-resistant depres-

sion (TRD) in 2005 (NeuroCybernetic Prosthesis

System, Cyberonics, Inc, Houston, TX, USA).14

Novel implantable devices are currently being

engineered. An investigational closed-loop technol-

ogy, which senses the increased heart rate at the onset

or during a seizure, automates the delivery of addi-

tional stimulation for improved seizure control

(AspireSR, Cyberonics).15 A recent phase II study

suggests the potential role of right cervical unidirec-

tional VNS for managing chronic heart failure (Cardi-

oFit System, BioControl Medical Ltd, Yehud,

Israel).16,17 Further, a miniaturized implant is under-

going trials for rheumatoid arthritis and inflammatory

bowel disease (SetPoint Medical, CA, USA).18

Noninvasive VNS (nVNS) devices have also been

developed. A noninvasive transauricular VNS (taVNS)

device, which stimulates the auricular branch of the

VN, was approved in Europe for the treatment of epi-

lepsy and depression in 2010, and pain in 2012

(NEMOS; Cerbomed GmbH, Erlangen, Germany).19,20

A similar auricular VNS, neuro-electric therapy

(NET; Auri-Stim Medical Inc., Denver, CO, USA), is

Fig. 1.—(A) Corning’s “carotid fork” with electrical wires. (a) Sponge electrodes, (b) electric wirings, (c) adjusting wheel,

(d) screw, (e) fork armature. (B) A drawing of the application of carotid fork (f), which was connected to a galvanic battery

(g). Another electrode (h) was placed behind the neck. A galvanometer (i) was connected to a thermoelectric pile (j) on the

left hand and head to measure the small temperature difference. (Adapted with permission from Lanska DJ. JL Corning and

vagal nerve stimulation for seizures in the 1880s. Neurology 2002;58:452-459 and Corning JL. Electrization of the sympathetic

and pneumogastric nerves, with simultaneous bilateral compression of the carotids. New York Med J 1884;39:212-215.)1,2

260 February 2016

not widely available and currently marketed as a micro-

current/music therapy device. A customized taVNS

also demonstrated its potential in seizure frequency

reduction.21 In addition, a non-invasive transcervical

VNS (tcVNS) device, which stimulates the cervical

branch of the VN (gammaCore; electroCore LLC,

Basking Ridge, NJ, USA), has received European

clearance for the acute and prophylactic treatment

of primary headaches (cluster headache, migraine,

hemicrania continua), medication overuse headache,

and reactive airway disease (asthma, exercise-

induced bronchospasm, COPD), as well as adjunc-

tive therapy for epilepsy prevention and reducing

the symptoms of certain anxiety/depression condi-

tions (eg, panic disorder, posttraumatic stress

disorder, major depressive disorder, obsessive-

compulsive disorder), gastric mobility disorders, and

irritable bowel syndrome.22,23

To date, VNS is also being investigated for bipolar

disorder, Alzheimer’s disease, obesity, impaired glu-

cose tolerance, gastroparesis, asthma, fibromyalgia,

traumatic brain injury, stroke (neuroprotection, neuro-

genesis), hemostasis, cerebellar tremor, and involun-

tary movement disorders.14,24-33

RECENT PROGRESS IN INVASIVE VNS

Left cervical VNS received FDA approval for

TRE and TRD.34-36 By August 2013, more than

100,000 VNS devices had been implanted in more

than 70,000 patients worldwide. The NCP system

received FDA approval for use in conjunction with

drugs or surgery as an adjunctive treatment for

adults and adolescents over 12 years of age with

medically refractory partial onset seizures, and for

the adjunctive long-term treatment of chronic or

recurrent depression for patients 18 years of age or

older who are experiencing a major depressive epi-

sode and have not had an adequate response to 4

or more adequate antidepressant treatments.37 The

American Academy of Neurology guideline states

that VNS is possibly associated with an increase in

the number of patients achieving a �50% reduction

in seizures (Level C). While VNS may be consid-

ered for seizures in children, for LGS-associated

seizures, and for improving mood in adults with

epilepsy, more information is needed on the treat-

ment of primary generalized epilepsy in adults.12

Right cervical VNS, which has received Euro-

pean clearance, is undergoing a phase III clinical

trial for the treatment of heart failure.17 The ration-

ale was to increase the parasympathetic outflow

(B-fiber) to lower heart rate, reduce arrhythmia,

and exert positive effects on LV function.38 Anti-

apoptotic, anti-inflammatory, and antiadrenergic

effects of VNS may induce remodeling and improve

left ventricle ejection fraction. The CardioFit Sys-

tem is designed to sense the heart rate via an intra-

cardiac implanted electrode, and deliver stimulation

at preset delays from the R wave, as well as inter-

rupt stimulation when the heart rate reaches the

bradycardia limit (eg, 55/min). The stimulation lead

is an asymmetric, bipolar, multicontact cuff elec-

trode specifically designed for cathodic induction of

action potentials in the VN while simultaneously

applying asymmetrical anodal blocks. These anodal

blocks minimize activation of A-fibers (60% reduc-

tion in A-fiber compound action potential to reduce

side effects) but preferentially activate parasympa-

thetic efferent B-fibers.17,39 Compared with other

stimulation electrodes that activate nerves bi-

directionally, this new design allows for unidirec-

tional activation directed to the heart. Schwartz

et al first reported this experience using right VNS

for treating heart failure.40 In an open-labeled,

phase II study using the CardioFit System in CHF

patients with severe systolic dysfunction, the investi-

gators showed an improved quality of life and left

ventricle ejection fraction after 1 year of use.16 A

similar unidirectional VNS system (FitNeS System)

was designed for epilepsy to preferentially activate

the afferent VN with minimal efferent stimulation-

associated side effects.41

VNS DEVICE IMPLANTATION AND

COMPLICATIONS

NCP implantation is performed under general

anesthesia in an outpatient setting. The electrodes

(3 spiral coils: anode, cathode, and anchor tether)

are attached to the left VN below where the supe-

rior and inferior cervical cardiac branches come off

(Fig. 2). Stimulation of these 2 cardiac branches

Headache 261

may cause bradycardia and/or rarely asystole.42

Lead misplacement can usually be identified intra-

operatively by the lead test. Stimulation parameters

are adjusted by a programming wand placed over

the device. Stimulation is turned on or off by a

magnet. The NCP device operates on a wide vari-

ety of stimulation parameters (output current, sig-

nal frequency, pulse width, signal ON time, signal

OFF time). Approved stimulation parameters are

0.25-3.5 mA (0.25 mA steps), 20-30 Hz (<10 Hz

ineffective, >50 Hz might induce nerve damage),

0.25-0.5 ms pulse, signal ON for 30-60 seconds, and

signal OFF for 5 minutes.43,44 A rapid stimulation

of signal ON for 7 seconds and OFF for 14-21 sec-

onds is also available.12 The optimal VNS stimula-

tion settings, however, remain unknown. Based on

clinical effect and tolerability, it is recommended to

start low (0.25-0.75 mA) and gradually increase the

amplitude to compensate the tissue resistance.37

The device can be activated by a magnet to provide

on-demand stimulation to prevent or shorten a sei-

zure.45 The magnet can also be used to temporarily

inhibit stimulation.

NCP implantation is associated with certain com-

plications. Intraoperatively, bradycardia and asystole

can occur, albeit rarely, during lead impedance test-

ing. This could be due to either collateral current

spread or inadvertent placement of electrodes on VN

cardiac branches.42 In animal studies, right VNS

resulted in more bradycardia than left VNS. In human

series, right VNS was as effective as left VNS without

observable cardiac side effects.46 Although rare,

delayed arrhythmias and syncope have been reported

after long-term use.47 Surgical trauma may result in

peritracheal hematoma or VN trauma, with unilateral

vocal cord dysfunction and dyspnea.48 Voice altera-

tion can occur in up to 62% of subjects during the pre-

ceding months after surgery. Cough, dyspnea,

paresthesia, and pain occurred in about 20-25%.34

After 5 years, voice alteration occurred in fewer than

20% and other AEs were fewer than 5%.49 VNS-

associated airway obstruction causing sleep apnea was

not uncommon, but can depend on the stimulation

settings.50 The overall mortality rate was similar to

non-VNS patients with refractory epilepsy. Longer

VNS use was associated with lower epilepsy mortal-

ity.51 Exposure of the NCP System to any radiofre-

quency (RF) transmitter coil must be avoided. RF

energy (eg, ECT, MRI, electrocautery, shock wave

lithography, defibrillation) induces heat on the

Fig. 2.—(A) The VN anatomy and placement of the electrical lead. (B) The schematic of the 3 electrodes. (Adapted with per-

mission from Cyberonics. VNS Therapy System Physician’s Manual. Houston, TX: Cyberonics, Inc.; 2015.)37

262 February 2016

implant and may cause thermal injury to the VN and

adjacent structures.48 For MRI imaging, only a local

receiver coil under 1.5-3 Tesla is allowed.37

RECENT PROGRESS IN NONINVASIVE

VNS

To avoid surgical implant-related complica-

tions, researchers developed 2 types of nVNS:

transauricular and transcervical.52 The transauricu-

lar VNS (taVNS) stimulates the auricular branch of

the VN (ABVN), which innervates the cavity of

conchae and cymba conchae. ABVN has been asso-

ciated with ear-cough reflex, ear-vomiting reflex,

and auriculo-cardiac reflex.19 The transcervical

VNS (tcVNS) most likely stimulates both efferent

and afferent VN fibers in the carotid sheath. So far,

there are no Phase III studies on nVNS showing

efficacy in reducing seizures in epilepsy patients.

taVNS Device.—NEMOS (Fig. 3), which delivers

biphasic pulses (25 Volts, 10 Hz, 0.3 ms pulse),

received European clearance in 2010 for the indica-

tion of epilepsy. It is applied through a patient-

controlled stimulation session that usually last for 1

hour, 3-4 times per day. Stefan et al observed

reduced seizure frequency in TRE patients using

taVNS for 9 months.53 Busch et al found that 1 hour

taVNS influences the central pain processing in

healthy human and increases mechanical and pres-

sure pain thresholds.54 The NEMOS device is gener-

ally well tolerated. In subjects with no known pre-

existing cardiac pathology, preliminary data do not

indicate arrhythmic effects of taVNS.55 To activate

the myelinated afferent VN fibers, the stimulus

intensity is adjusted to a level between patients’

detection threshold (first perceptible or tingling sen-

sation) and pain threshold (first pricking or unpleas-

ant sensation). Typically, the detection threshold is

around 0.8 mA on the cymba conchae.19 Because the

tingling sensation is similar to tactile sensation, Ell-

rich et al suggested that such nonpainful peripheral

nerve stimulation preferentially activates Ab-fibers

but not Ad-nociceptive fibers.56 The actual fibers

being stimulated remains to be confirmed but can

depend on stimulation settings.

In a functional brain imaging study (fMRI) of

16 patients, Kraus et al studied BOLD signal follow-

ing transcutaneous stimulation on the left auditory

canal (anterior, posterior) and center of the ear lobe

(sham control). Comparing anterior with posterior

stimulation, they found an increased signal in many

regions but decreased signals in the left para-

hippocampal gyrus, left posterior cingulate cortex,

Fig. 3.—Two nVNS devices. NEMOS is a transauricular VNS device that stimulates the cymba chonca (Cy). The auricular

branch of the VN innervates Cy, cavum chonca (Ca), and Tragus (T). GammaCore is a transcervical, self-administered VNS

device stimulating through the neck to the cervical VN.

Headache 263

and right thalamus pulvinar. Comparing anterior

with sham stimulation, in addition to above regions,

they found signal decreases in the LC and the area

of the solitary tract. Comparing posterior with sham

stimulation, decreased signals were found in left

uncus, medial frontal gyrus, insula, anterior cingulate

cortex, subgenual cingulate cortex, right superior

frontal gyrus, and medial frontal gyrus.57 Brain acti-

vation patterns from tVNS were similar to those

observed in invasive VNS (eg, diminished activity in

thalamus, hippocampus, amygdala, cingulate).58

tcVNS Device.—The gammaCore device (Fig. 3) is

a handheld tcVNS device that stimulates the cervical

VN with a 1 ms pulse (of 5 kHz sine waves) repeated

at 25 Hz. The pulse waveform was designed to pene-

trate the biological barrier (eg, skin, tissue, nerve

sheath) to stimulate the cervical VN. The stimulation

intensity is self-controlled (up to 24 V and 60 mA)

and lasts 2 minutes. It can be repeated multiple times

safely; multiple stimulations (doses) have been admin-

istered up to 6-12 times per day in clinical studies. By

adjusting the intensity of stimulation, one gets mild

facial twitching through the stimulation of A- but not

C-fibers. The optimal stimulation settings (number of

stimulations per day, total stimulation duration) to

reach a satisfactory response for each disorder remain

to be determined. At the moment, the gammaCore

device has been studied for the treatment of cluster

headache,23,59,60 migraine,22,61-63 and hemicrania con-

tinua,64,65 and may also improve gastroparesis and

asthma.31,66 In all of these studies, tcVNS was well tol-

erated without any major cardiac AEs.52,55

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