Autonomic Neuroscience: Basic and Clinical 243 (2022) 103038

Contents lists available at ScienceDirect

Autonomic Neuroscience: Basic and Clinical

journal homepage: www.elsevier.com/locate/autneu

Review

Transcutaneous vagus nerve stimulation - A brief introduction

and overview
Max J. Hilz a, b, *
a
Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany
b
Icahn School of Medicine at Mount Sinai, New York, NY, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Invasive cervical vagus nerve stimulation (VNS) is approved for the treatment of epilepsies, depression, obesity,
Transcutaneous vagus nerve stimulation and for stroke-rehabilitation. The procedure requires surgery, has side-effects, is expensive and not readily
Nucleus tractus solitarii available. Consequently, transcutaneous VNS (tVNS) has been developed 20 years ago as non-invasive, less
Locus coeruleus
expensive, and easily applicable alternative. Since the vagus nerve reaches the skin at the outer acoustic canal
Auricular branch of the vagus nerve
and ear, and reflex-responses such as the ear-cough-reflex or the auriculo-cardiac reflex have been observed upon
Concha cymba
Tragus auricular stimulation, the ear seems well suited for tVNS. However, several sensory nerves with variable fiber-
density and significant overlap innervate the outer ear: the auricular branch of the vagus nerve (ABVN), the
auriculotemporal nerve, greater auricular nerve, and to some extent the lesser occipital nerve. VNS requires
activation of Aβ-fibers which are far less present in the ABVN than the cervical vagus nerve. Thus, optimal
stimulation sites and parameters, and tVNS-algorithms need to be further explored. Unravelling central pathways
and structures that mediate tVNS-effects is another challenge. tVNS impulses reach the nucleus of the solitary
tract and activate the locus-coeruleus-norepinephrine system. However, many more brain areas are activated or
deactivated upon VNS, including structures of the central autonomic network and the limbic system. Still, the
realm of therapeutic tVNS applications grows rapidly and includes medication-refractory epilepsies, depressive
mood disorders, headaches including migraine, pain, heart failure, gastrointestinal inflammatory diseases and
many more. tVNS might become a standard tool to enhance autonomic balance and function in various auto­
nomic, neurological, psychiatric, rheumatologic, as well as other diseases.

1. Invasive vagus nerve stimulation in epilepsy, depression,
obesity, and heart failure
Effects of Vagus Nerve stimulation (VNS) on brain activity have been
studied already in 1938 by Bailey and Bremer (1938) and in 1951 by
Dell and Olson (1951). Based on the observation of antiepileptic VNS
effects, an implantable VNS was developed in 1987, first implanted in
1988, and approved by the United States Food and Drug Administration
(FDA) in 1997 as adjunctive treatment tool for adult and adolescent
patients with partial onset seizures that are refractory to antiepileptic
drugs (Gonzalez et al., 2019). Nowadays, the implantable VNS is also
approved for patients aged four years and older suffering from partial
onset seizures refractory to antiepileptic medication drugs (Gonzalez
et al., 2019). In epilepsy patients, a pulse generator implanted in a
subcutaneous pocket below the clavicle delivers stimuli via electrodes,
usually to the left cervical vagus nerve, in order to activate afferent
vagus nerve fibers (Garamendi-Ruiz and Gomez-Esteban, 2019). The
electrodes must be surgically positioned around the left cervical vagus
nerve using an approach similar to that for anterior cervical discectomy
(Reid, 1990; Giordano et al., 2017). Left-sided stimulation is preferred to
reduce the risk of bradycardia or asystole that may be induced by
stimulating the sinoatrial node via right-sided cervical VNS (Giordano
et al., 2017).
The observation of mood improvement in epilepsy patients receiving
VNS treatment prompted studies that showed not only improved quality
of life, emotional adjustment, concentration, and cognitive functioning
upon VNS (Austelle et al., 2022); in furtherance of potential antide­
pressant VNS effects, Ben-Menachem et al. also found that VNS treat­
ment of 16 patients with complex partial seizures had effects on amino
acid levels in the patients’ cerebrospinal fluid: levels of inhibitory
gamma-aminobutyric acid were higher while levels of excitatory
glutamate were somewhat lower after three months of VNS than before

* Corresponding author at: University of Erlangen-Nuremberg, Schlossplatz 4, D-91054 Erlangen, Germany.

E-mail address: max.hilz@outlook.com.

https://doi.org/10.1016/j.autneu.2022.103038
Received 23 July 2022; Received in revised form 25 September 2022; Accepted 25 September 2022
Available online 27 September 2022
1566-0702/© 2022 Elsevier B.V. All rights reserved.
M.J. Hilz
VNS, supporting the antiseizure effects of VNS. However, the study also
showed a trend towards increased levels of 5-hydroxyindoleacetic acid,
the main serotonin metabolite, upon VNS (Ben-Menachem et al., 1995)
The increase of 5-hydroxyindoleacetic acid suggests that VNS might
have effects on serotoninergic modulation and thus antidepressant ef­
fects (Austelle et al., 2022).
Further studies confirmed that VNS yields improvements in the pa­
tient’s sense of well-being and quality of life, concentration, cognitive
and social functioning, and emotional adjustment (Dodrill and Morris,
2001), improved mood scores (Harden et al., 2000), as well as signifi­
cant improvement of mild depressive mood disorders (Elger et al.,
2000). Promising results of many successive studies (e.g., Sackeim et al.,
2001; Marangell et al., 2002; Nahas et al., 2005; Rush et al., 2005a; Rush
et al., 2005b) in 2005 finally led to the FDA approval of VNS for the
treatment of major depressive disorders (Austelle et al., 2022).
In 2015, VNS also obtained FDA approval for the treatment of pa­
tients with moderate to severe obesity (Garamendi-Ruiz and Gomez-
Esteban, 2019). For obesity treatment, a pulse generator again had to
be positioned subcutaneously to induce intermittent vagal blockade via
two leads that must be positioned around the anterior and posterior
vagal trunks close to the gastroesophageal junction (Ikramuddin et al.,
2014). In the so-called ReCharge trial, patients with a body mass index
of at least 35 underwent intermittent vagus nerve blockade with the
stimulator delivering charges between 6 and 8 mA for at least 12 h per
day (Ikramuddin et al., 2014). Compared to a control group that
received sham stimulation, the patients who had received intermittent
vagus nerve blockade had lost 8.5 % more of their excess weight
(Ikramuddin et al., 2014). Side-effects were rare and mainly consisted of
mild or moderate heartburn, dyspepsia, and abdominal pain (Ikra­
muddin et al., 2014). In 2016, a two-year follow-up study confirmed that
the technique induces a medically beneficial weight loss with a mean
decrease in excess weight of 21 % and significant improvements in lipid
levels, HbA1c, systolic and diastolic blood pressure, and quality of life,
but also corroborated a favorable safety profile (Apovian et al., 2017).
Even in heart failure patients, implanted Vagus nerve stimulators
have been used – but are not yet officially approved - to ameliorate the
imbalance between augmented sympathetic and diminished para­
sympathetic activity in heart failure and thus amend ventricular
remodeling of the failing heart (Klein and Ferrari, 2010; Garamendi-
Ruiz and Gomez-Esteban, 2019). Different from the stimulation in epi­
lepsy patients, the stimulating electrodes are surgically positioned
around the right cervical vagus nerve with the cathode distal to the
anode in order to activate the sinoatrial node in the right cardiac atrium
(Garamendi-Ruiz and Gomez-Esteban, 2019).
While the technique yielded quality-of-life improvement in symp­
tomatic heart failure patients, it so far has not reached study end-points
such as improvement in left ventricular end-systolic diameter or other
echocardiographic indices (Zannad et al., 2015).
2. Possible side-effects of invasive VNS
In general, the application of implanted vagus nerve stimulators is
associated with a variety of drawbacks and side-effects (Giordano et al.,
2017). The implantation requires general anesthesia with endotracheal
intubation which might cause vocal cord damage (Giordano et al.,
2017). During intraoperative impedance testing there is a risk of
bradycardia or asystole. According to Giordano et al. further surgery
related risks include peritracheal hematoma, infections, vagus nerve
injury causing left vocal cord paralysis with hoarseness, dyspnea, and
dysphagia; related to the stimulating system, there may be postsurgical
or later infections and wound healing difficulties as well as later injuries
of the vagus nerve; the cervical vagus nerve stimulation itself may cause
arrhythmias, hoarseness, dyspnea, or coughing; even obstructive sleep
apnea may occur; there might be stimulation of the adjacent phrenic
nerve, and tonsillar pain (Giordano et al., 2017). 66 % of patients
experience - usually transient - laryngopharyngeal dysfunction with
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Autonomic Neuroscience: Basic and Clinical 243 (2022) 103038
stimulation of the recurrent laryngeal nerve while surgical removal,
revision or replacement of the device is considered in 4–16.8 % of cases
due to device malfunction, failure of VNS therapy, severe side effects, or
based on the patient’s request (Giordano et al., 2017).
3. The approach towards noninvasive VNS
While invasive VNS is widely used in epilepsy centers (Gonzalez
et al., 2019; Toffa et al., 2020; Ryvlin et al., 2021), the above mentioned
side-effects and risk factors as well as the cost of the device and its im­
plantation have limited the use of invasive VNS in psychiatry (Austelle
et al., 2022).
More than 20 years ago, an alternative concept was developed based
on the positive results of invasive VNS, on experience with the already
accepted use of transcutaneous electrical nerve stimulation, TENS, e.g.
for pain control or muscle healing, and on the fact that the vagus nerve
reaches the skin in the so called Ramsay Hunt zone of the external
auditory canal (Ventureyra, 2000). In many persons, tactile stimulation
of the posterior and inferior quadrants of the external auditory canal
triggers coughing, i.e. the so called Arnold’s ear-cough reflex, but might
also induce tear-flow, via an auriculo-lacrimal reflex (Engel, 1979;
Gupta et al., 1986; Ellrich, 2019). There were also reports on physio­
logical interactions between stimuli applied to the external auditory
canal and internal organs, such as the stomach, esophagus, lungs, heart,
uterus, and male or female sexual organs with the vagus nerve as
mediator between auricular impulses and the internal organ responses;
some of the interactions with organs occurring upon stimulation of the
external auditory canal are known as ear-vomiting reflex, auriculo-
cardiac reflex with cardiac inhibition and subsequent syncope, or gas­
troauricular phenomenon; in cats stimulation of the external auditory
canal may induce the auriculo-uterine reflex or auriculo-genital reflex
consisting of muscle contractions around the cat’s vaginal orifice
respectively cutaneous muscle contractions in the penile and perineal
area of male cats (Engel, 1979; Ellrich, 2019).
Moreover, there were conference reports suggesting that acupunc­
ture in the region of the auricular branch of the vagus nerve had bene­
ficial effects on seizure control (Ventureyra, 2000). Based on these
reports and the known interactions between various organs and sensory
sites of the external acoustic canal and outer ear, transcutaneous elec­
trical stimulation was suggested as a readily and widely available non-
invasive treatment option in epilepsy patients (Ventureyra, 2000).
4. Innervation of the external ear
In fact, the sensory innervation of the external ear is intricate and not
only provided by the auricular branch of the vagus nerve (ABVN) but also
by the auriculotemporal nerve, a branch of the mandibular and thus
trigeminal nerve, and by the greater auricular nerve (Fig. 1) (Butt et al.,
2020).
The auriculotemporal nerve has connections to the facial nerve and to
the ganglion oticum where it receives parasympathetic fibers from the
glossopharyngeal nerve which then supply the parotid gland (Butt et al.,
2020).
The greater auricular nerve branches off the cervical plexus and arises
from the spinal nerves C2 and C3 (Ginsberg and Eicher, 2000). More­
over, there may be contributions from the lesser occipital nerve that also
arises from the cervical plexus and contains C2 and C3 fibers (Butt et al.,
2020).
5. A beta fibers, not C-fibers mediate afferent VNS impulses to
the nucleus tractus solitarii
In human patients and in animals, invasive cervical VNS studies
provided evidence that therapeutic effects are mediated via A beta nerve
fiber activation (Vonck et al., 2007; Ellrich, 2019). For example, in rats
capsaicin-induced destruction of C-fibers did not compromise VNS-
M.J. Hilz
Fig. 1. The outer ear and its cutaneous innervation: mainly three nerves
contribute to the innervation of the outer ear: the auricular branch of the vagus
nerve (ABVN), the greater auricular nerve (GAN), and the auriculotemporal
nerve (ATN) (Murray et al., 2016).
[Reprinted from Autonomic Neurosciences: Basic & Clinical, 2016, Vol 199,
Murray, A. R., L. Atkinson, M. K. Mahadi, S. A. Deuchars and J. Deuchars. The
strange case of the ear and the heart: The auricular vagus nerve and its influ­
ence on cardiac control. Pages 48–53, Copyright 2016, with permission
from Elsevier].
mediated suppression of pentylenetetrazol triggered seizures (Krahl
et al., 2001). Yet, afferent A beta fibers are five or six times less common
in the ABVN than in the cervical vagus nerve, and the fiber count may
even vary more between individuals which may hamper transcutaneous
VNS in some persons (Butt et al., 2020).
The facts that there are relatively less A beta fibers in the ABVN than
in the cervical vagus nerve, that there are interconnections and overlap
of the ABVN with the various aforementioned nerves (Fig. 2), and that
cadaveric studies of the ABVN distribution and fiber density show het­
erogeneous results explain why the determination of the optimal
auricular stimulation site is still ongoing (Badran et al., 2018a; Badran
et al., 2019). Still, it seems that the concha, particularly the cymba
conchae are sites of adequate ABVN presentation and thus particularly
suitable for noninvasive auricular VNS (Yakunina et al., 2017; Butt et al.,
2020). In contrast, there is an overlap of nerves at various other areas, e.
g. the ear lobe (He et al., 2012).
6. Auricular stimulation parameters
Mostly, auricular stimulation is delivered at the left ear as this side
has been thought to be safer although Badran et al. report that data from
a large trial do not show an increased risk of adverse events with right
ear stimulation (Badran et al., 2019).
Stimulation parameters also vary between studies (Badran et al.,
2019; Butt et al., 2020). Activation of the thickly myelinated A beta fi­
bers that mediate proprioceptive sensation such as touch or vibration
perception, is assured by electrical stimulus intensities slightly above the
lowest stimulus intensity evoking a perceivable, somewhat tingling
sensation (Ellrich, 2019). Stimulus intensities are kept below levels that
reach or exceed the pain threshold, i.e. the threshold at which stimuli
induce unpleasant or pricking sensations via C fiber activation (Ellrich,
2019). Since nerve fiber depolarization not only depends on stimulus
intensity but also on stimulus duration and its frequency, parameters
vary between studies but are mostly delivered at a stimulus frequency of
10–15 Hz with a stimulus pulse-width between 250 μs and 500 μs, and
constant current intensities below 5 mA (Badran et al., 2019). However,
3
Autonomic Neuroscience: Basic and Clinical 243 (2022) 103038
Fig. 2. Distribution and overlap of the ABVN (green) with the auriculotemporal
nerve (red), greater auricular nerve (yellow), and minor occipital nerve (blue)
according to He et al. (2012). (For interpretation of the references to color in
this figure legend, the reader is referred to the web version of this article.)
[Reprinted from Evidence-Based Complementary and Alternative Medicine,
Volume 2012, Article ID 786839, Hindawi Publishing Corporation; He, W., X.
Wang, H. Shi, H. Shang, L. Li, X. Jing and B. Zhu (2012). Auricular acupuncture
and vagal regulation. Pages 1–6; Copyright © 2012 Wei He et al. This is an open
access article distributed under the Creative Commons Attribution License; no
formal permissions required].
studies evaluating functional magnetic resonance imaging (fMRI) re­
sponses or somatosensory evoked potentials induced by auricular VNS
also used different frequencies, intensities, and stimulus duration as
summarized by Butt et al. (2020). Side-effects are minor with these
auricular tVNS parameters and mainly include skin reddening and irri­
tation (Badran et al., 2019).
7. The complex pathways mediating autonomic and other
responses to auricular tVNS
While VNS is not considered to induce its physiological effects by C-
fiber depolarization but via A beta fiber activation (Butt et al., 2020),
autonomic effects still occur with transcutaneous auricular VNS. [For
reviews see Butt et al., 2020]. However, cardiovascular autonomic ef­
fects vary and seem to depend on the auricular stimulation site and
varying stimulation parameters (Butt et al., 2020). For example, Badran
et al. tested effects of inner tragus stimulation on heart rate using nine
varying stimulation blocks with frequencies set at 1 Hz, 10 Hz, and 25
Hz and pulse widths at 100 μs, 200 μs, and 500 μs and found that only
stimuli of 500 μs width delivered at 10 Hz and at 20 Hz significantly
reduced heart rate (Badran et al., 2018b). Clancy and coworkers induced
a shift in spectral powers of sympathetically and parasympathetically
mediated heart rate modulation towards relatively less sympathetic and
more parasympathetic activity, and moreover recorded a decrease in
muscle sympathetic nerve activity (MSNA) upon 15 min of tragus
stimulation with 30 Hz pulses of 200 μs width and intensities of 10-50
mA adjusted to the level of sensory thresholds (Clancy et al., 2014).
With adequate stimulation parameters, tVNS not only enhances
parasympathetic activity but also attenuates sympathetic activity as
shown not only by the MSNA decrease recorded by Clancy et al. (2014)
but also in a tVNS study conducted in dogs with surgically induced
myocardial infarction. After 90 days, the dogs who had received 4 h per
M.J. Hilz
diem of ABVN stimulation had a significantly better infarct-size reduc­
tion and significantly lower noradrenaline levels than the dogs without
ABVN stimulation (Wang et al., 2014).
Murray et al. assume that the parasympathetic upregulation and
sympathetic withdrawal upon ABNV stimulation is mediated via
afferent impulses travelling along the ABNV towards the nucleus of the
solitary tract (NTS) which receives around 95 % of afferent vagus nerve
impulses (Murray et al., 2016; Butt et al., 2020). Upon receipt of these
stimuli, the NTS sends impulses to the dorsal vagal nucleus (DVN) and
the nucleus ambiguus which both generate efferent impulses that reach
the heart via cardiovagal fibers and thus slow heart rate. Simulta­
neously, the NTS might send activating impulses to the caudal ventro­
lateral medulla (CVLM) which in turn inhibits the rostroventrolateral
medulla (RVLM), i.e. the main source of activating preganglionic sym­
pathetic neurons in the intermediolateral column (Fig. 3). The subse­
quently reduced sympathetic outflow could explain the decrease in
MSNA or noradrenaline levels upon ABVN stimulation (Murray et al.,
2016).
7.1. Widespread central nervous system involvement upon auricular tVNS
However, auricular tVNS activates not only the NTS. In rats, the use
of C-Fos immunochemistry as marker of neuronal activity upon left
cavum conchae stimulation demonstrated bilateral C-Fos staining in the
NTS and loci coerulei, i.e. the major noradrenergic cerebral areas (Ay
et al., 2015). In animals, retrograde tracing studies of the ABVN by
means of transganglionic horseradish peroxidase (HRP) moreover
showed HRP staining of the NTS, nucleus cuneatus, and the caudal tri­
geminal nucleus [for review see (Butt et al., 2020)].
Various fMRI studies confirmed that vagus nerve stimulation acti­
vates the NTS which projects not only to the nucleus coeruleus, the area
assumed to be significantly involved in therapeutic VNS effects, partic­
ularly in seizure control (Fig. 4) (Fornai et al., 2011; Butt et al., 2020).
Depending on the auricular stimulation site and stimulation parameters,
the NTS projects to various other brain regions (Yakunina et al., 2017;
Ellrich, 2019; Butt et al., 2020). Among these are brainstem areas such
4
Autonomic Neuroscience: Basic and Clinical 243 (2022) 103038
as the dorsal raphe nuclei that provide the serotonergic innervation of
central autonomic regions and further transfer stimuli to the spinal cord,
hypothalamus, and brainstem areas, including the rostroventrolateral
medulla where the serotonergic impulses inhibit sympathetic RVLM
outflow (Benarroch, 1997).
Furthermore, the NTS directly or indirectly projects to many central
structures [for review see (Butt et al., 2020) and (Yakunina et al.,
2017)]. Among the direct projections are for example the spinal tri­
geminal nucleus, the parabrachial region, periaqueductal gray, the
thalamus, amygdala, insula, bed nucleus of the stria terminalis, or the
hypothalamus (Komisaruk and Frangos, 2022). Indirectly, the NTS
projects onto further structures: the parabrachial nuclei reach the par­
aventricular nucleus of the hypothalamus, the lateral hypothalamus,
and the central amygdala (Komisaruk and Frangos, 2022). Indirect
projections may reach of the cingulate gyrus, nucleus accumbens, the
limbic system - which is also rich in serotoninergic receptors (Benarroch,
1997), and thus might hold therapeutic promise, e.g. in tVNS treatment
of depressive disorders - and forebrain regions [for review see (Butt
et al., 2020) and (Yakunina et al., 2017)]. Additional details regarding
tVNS related central projections are beyond the scope of this review and
subject to further research.
8. Clinical tVNS proof-of-concept studies encouraged further
therapeutic approaches
Early proof of concept studies, e.g., in patients with pharmaco-
resistant epilepsies showed that transcutaneous VNS is suitable to
reduce seizure frequency and is moreover safe and well-tolerated (Stefan
et al., 2012).
Similarly, tVNS benefits were demonstrated in chronic migraine
patients, particularly with 1 Hz stimulation but also - albeit to a lesser
degree - with 25 Hz stimuli (Straube et al., 2015).
In healthy persons, an early tVNS study showed that left outer
auditory canal stimulation improved the sense of well-being and
decreased fMRI BOLD-signals in limbic brain areas, including the
amygdala, hippocampus, parahippocampal gyrus, and the middle and
Fig. 3. Possible pathways of ABVN stimulation
inducing cardiovascular effects via nucleus tractus
solitarii (NTS) stimulation. Upon ABVN stimulation,
the NTS activates the dorsal vagal nucleus (DVN) and
the nucleus ambiguus (NA) in the medulla which
both generate cardiovagal outflow. With ABVN
stimulation, the NTS may also activate the caudal
ventrolateral medulla (CVLM) which will in turn
inhibit the rostroventrolateral medulla (RVLM) and
thus sympathetic outflow to the neurons of the
intermediolateral cell column (IML) in the spinal cord
(Murray et al., 2016).
[Reprinted from Autonomic Neurosciences: Basic &
Clinical, 2016, Vol 199, Murray, A. R., L. Atkinson,
M. K. Mahadi, S. A. Deuchars and J. Deuchars. The
strange case of the ear and the heart: The auricular
vagus nerve and its influence on cardiac control.
Pages 48–53, Copyright 2016, with permission from
Elsevier.]
M.J. Hilz
Fig. 4. Main pathways that may result from cervical VNS activation of the
nucleus tractus solitarii (NTS) according to Fornai et al. (2011).
NTS impulses, elicited by cervical VNS, reach the locus coeruleus (LC) via the
nucleus paragiganto-cellularis (PGi) and the nucleus prepositus hypoglossi
(Prep). The locus coeruleus conveys noradrenergic (NE) impulses to the cere­
bral cortex, thalamus, and dorsal raphe nuclei (DRN). The thalamus projects
glutamatergic signals (GLU) to the cortex; the dorsal raphe nuclei convey
serotoninergic (5HT) impulses to the cortex but also to central autonomic re­
gions, the spinal cord, hypothalamus, and brainstem areas, including the ros­
troventrolateral medulla (Benarroch, 1997; Fornai et al., 2011).
[Reprinted from European Journal of Neuroscience 2011: 33(12); Fornai, F., R.
Ruffoli, F. S. Giorgi and A. Paparelli. The role of locus coeruleus in the anti­
epileptic activity induced by vagus nerve stimulation. Pages 2169–2178;
Copyright 2011, with permission from John Wiley & Sons].
superior temporal gyrus, while the stimulation increased BOLD signals
in the insula, precentral gyrus, and thalamus, i.e. tVNS generated brain
activation patterns similar to those induced by invasive vagus nerve
stimulation (Kraus et al., 2007).
Several studies in patients with major depression support the hy­
pothesis that tVNS ameliorates depression in patients with major
depressive disorder and modulates the resting state functional connec­
tivity between the right amygdala and left dorsolateral prefrontal cortex
(Liu et al., 2016), and also suggest that tVNS might be a feasible treat­
ment option for patients with treatment-resistant depression (e.g. (Rong
et al., 2016, Trevizol et al., 2016, Evensen et al., 2022)).
By now, transcutaneous vagus nerve stimulation has become a
promising alternative to invasive VNS. The transcutaneous approach is
used not only in patients with epilepsy, depression or anxiety disorders
but tVNS has also been tested for the treatment of migraine, chronic
pain, tinnitus, Alzheimer’s disease, heart failure, obesity, inflammatory
diseases, or to improve cardiovascular autonomic modulation and bar­
oreflex sensitivity, to mention only a few indications (Clancy et al.,
2014; Hyvarinen et al., 2015; Mertens et al., 2018; Badran et al., 2019;
Butt et al., 2020).
Several studies use tVNS for rehabilitation in post-stroke patients (for
5
Autonomic Neuroscience: Basic and Clinical 243 (2022) 103038
review see Li et al., 2022). For example, Redgrave et al. evaluated tVNS
effects in patients with post-stroke upper limb dysfunction and showed a
significant improvement of the upper limb Fugl-Meyer score after the
patients had completed 18 one-hour sessions of repetitive arm move­
ments combined with auricular tVNS (Redgrave et al., 2018).
Finally, non-invasive VNS might be used to evaluate or predict the
responsiveness e.g. of epilepsy patients to invasive VNS (Mertens et al.,
2018).
So far, various stimulators have been developed for auricular trans­
cutaneous stimulation (Mertens et al., 2018). There is also a hand-held,
transcutaneous stimulator used to stimulate the cervical branch of the
vagus nerve; this GammaCore device (Electrocore LLC, Basking Ridge,
USA) has received FDA approval for the treatment of episodic cluster
headache (Holle-Lee and Gaul, 2016; Mwamburi et al., 2017).
As of July 2022, a Pubmed search for “transcutaneous vagus nerve
stimulation” shows 547 publications most of which have been published
within the last three years. While the field of noninvasive VNS is rapidly
expanding questions regarding optimal stimulus frequencies, pulse
widths, intensities, and best suited treatment duration and intervals,
central pathways, as well as successful areas of application still require
further studies. Yet, tVNS may become a useful and readily available
therapeutic tool for many different neurological and other indications.
Dedication
This paper is dedicated to Professor Dr. Bernhard Neundörfer,
Chairman Emeritus of the Department of Neurology at the University of
Erlangen-Nuremberg, Germany, on the occasion of his 85th birthday
and in gratitude to an enthusiastic physician, academic teacher, and
mentor who promoted clinical autonomic research and served as
founding President of the German Autonomic Society and co-founder of
the European Federation of Autonomic Societies.
Declaration of competing interest
The author has no conflict of interest.
Data availability
No data was used for the research described in the article.
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