Reviews
Vagus-nerve stimulation for the treatment of
epilepsy
Elinor Ben-Menachem
Vagus-nerve stimulation (VNS) is now an accepted treatment
for patients with refractory epilepsy. There have been many
studies suggesting that VNS affects the brain in such areas
as the thalamus and other limbic structures. In addition,
there is some evidence that norepinephrine is important in
the prophylactic antiseizure effects of VNS. The efficacy of
VNS has been established for partial seizure types, even in
refractory patients who did not respond to surgical treatment
for epilepsy. There are also data, from open-label studies,
that suggest efficacy in other seizure types. Therefore, VNS
seems to be a broad-spectrum treatment for epilepsy.
Improvement is not immediate but increases over 18–24
months of treatment. Most studies report subjective
improvements in various quality-of-life measurements during
treatment with VNS—objective trials have confirmed this
observation. Side-effects are mainly stimulation related and
reversible and they tend to decrease over time. They are
generally mild to moderate and seldom necessitate the
removal of the device. No idiosyncratic side-effects have
been reported in 12 years of experience, and VNS does not
interact with antiepileptic drugs. Most adverse events are
predictable and related to the specific stimulation regimen.
VNS does not have cognitive and systemic side-effects and
can, therefore, be a valuable treatment approach even for
patients who have poor tolerance of antiepileptic drugs.
Lancet Neurology 2002; 1: 477–82
Corning created the first, although crude and external, vagus-
nerve stimulator (VNS) in the 1880s. He lowered the number of
seizures in patients treated with cardioinhibitory vagal
stimulation to reduce cerebral blood flow.1 VNS was, however,
forgotten as a useful antiseizure therapy until Zabara2–4 began to
analyse the effect of stimulation in chemically induced seizures
in dogs. The results were striking, and the technique has become
an accepted and registered form of treatment for epilepsy;
worldwide, more than 15 000 patients receive this therapy.
That peripheral stimulation of the vagus nerve can affect
the brain and cause striking changes in electroen-
cephalographic patterns has been described several times since
the 1930s.5–10 Most animal experiments were done in cats that
had been given strychnine; VNS lowered the frequency of
spiking activity in this model. VNS was later shown to inhibit
seizures in the maximum electroshock and pentylenetetrazol
models in rats11 and monkeys.12 A recent study suggests that
VNS also inhibits spiking activity in human encephalograms.13
Results of the first trial of VNS in human beings were
published in 199014,15 and 1993.16 In this trial, 16 patients with
refractory partial-onset seizures received vagus-nerve
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stimulators and were given intermittent stimulation of a 30 s
train of impulses (on) every 5 min (off). The positive results of
these pilot studies led to double-blind, low-dose, placebo-
controlled trials to elucidate further the efficacy of VNS in
partial seizures.17,18
Anatomy
Studies in cats have shown that the vagus nerve consists of
80% afferent fibres projecting from the viscera to the nucleus
tractus solitarius.19 Efferent fibres provide parasympathetic
innervation primarily to the lungs, heart, and gastrointestinal
tract, and they also innervate the voluntary muscles in the
larynx and pharynx. These fibres originate from the
paraganglionic neurons in the dorsal motor nucleus of the
vagus nerve. There is an asymmetrical innervation to the
heart—the right vagus nerve innervates the sinoatrial node
and the left innervates the atrioventricular node. In dogs,
when the right vagus nerve is stimulated, bradycardia is
elicited to a greater degree than when the left nerve is
stimulated.20 For this reason, VNS implants are placed on the
left side of the neck and not the right side. Afferent fibres arise
from receptors in the lungs, heart, aorta, gastrointestinal tract,
and aortic chemoreceptors, and a small group arise from the
concha of the ear. The afferent fibres have their cell bodies in
the nodose and jugular ganglia and project to the nucleus
tractus solitarius as well as to the dorsal motor nucleus, area
postrema, and nucleus cunneatus. From the nucleus tractus
solitarius there are synaptic connections to higher centres in
the brain such as the hypothalamus, dorsal raphe, nucleus
ambigus, dorsal motor nucleus of the vagus nerve, amygdala,
and thalamus, which in turn project to the insular cortex.21
Positron-emission tomography and functional magnetic
resonance imaging of the effects of VNS in human beings have
confirmed the influence the vagus nerve on higher brain
structures. These studies have shown increases and decreases
in blood flow in response to VNS. In one of the first positron-
emission tomography studies, Ko and co-workers22 found that
VNS increased blood flow to the right thalamus, the right
posterior temporal cortex, the left putamen, and the left
inferior cerebellum. In positron-emission tomography studies
by Henry and colleagues23,24 blood flow was increased to the
EBM is at the Department of Clinical Neuroscience, Sahlgrenska
Academy, Göteborg University, Sweden.
Correspondence: Prof Elinor Ben-Menachem, Department of
Clinical Neuroscience, Sahlgrenska Academy, Göteborg University,
413 45 Göteborg, Sweden. Tel +46 31 3421000;
fax +46 31 211552; email ebm@neuro.gu.se
477
 Review
Caudal Cephalad
Anchor
tether
Negative
electrode
Positive
electrode
Figure 1. Top: surgical implantation of VNS device. Bottom: position of
VNS device once implanted.
inferior cerebellum, hypothalamus, and thalamus and
decreased in the areas of the hippocampus, amygdala, and
posterior cingulated gyrus during VNS. Generally, changes in
blood flow were greater in the right hemisphere than in the
left. The main conclusions from these studies are that the
thalamus is consistently involved, and that there are
pronounced changes in blood flow in the brain during VNS
that correspond to anatomical synaptic projections. In recent
experiments with functional magnetic resonance imaging,
Bohning and colleagues25 found that the areas of significant
activation in response to VNS were the bilateral orbitofrontal
and parieto-occipital cortex, the left temporal cortex, and the
left amygdala. Besides these specific areas there was a general
diffuse increase in brain activity.
The vagus nerve in the neck is enclosed in the carotid
sheath, which lies beneath the sternocleidomastoid muscle. In
the midcervical area the superior laryngeal nerve branches off
rostrally to the carotid bifurcation. This nerve is secondarily
stimulated during VNS and can give rise to a feeling of tightness
or even pain in the throat area. The recurrent laryngeal nerve
travels alongside the vagal nerve, and hence is also affected by
VNS causing vibration of the left vocal cord during stimulation
and subsequent hoarseness during on times.
478 THE LANCET Neurology Vol 1 December 2002
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Vagus-nerve stimulation
Mechanism of action
The mechanism of action of VNS is not fully understood.
Stimulation causes increases in cerebral blood flow and can
alter electroencephalographic patterns. CSF studies in
human beings have shown changes in the concentrations of
several amino acids and neurotransmitters that might play
a part—especially ethanolamine, which is a sign of
increased turnover of membrane components.26 Perhaps
this is an indication of an increased amino-acid turnover in
a more general sense as is also implied by the observation of
high neuronal fos expression in the vagal areas of the
medulla (the locus coeruleus, the thalamic and
hypothalamic nuclei, the amygdala, the cingulate cortex,
and the retrosplenial cortex) in rats undergoing VNS.27
There is fierce debate about whether conditions used in
human beings stimulate only A and B myelinated fibres or
whether C fibres, which are thin and unmyelinated, are also
needed for the antiepileptic effect. Evidence against the
influence of C fibres includes the lack of significant effect
on heart rate or blood pressure, and that there is no change
noted in gastrin concentrations or any other autonomic
function that would be expected if C fibres were stimulated
in human beings.18,28–30 In a recent study by Krahl and
colleagues,31 C fibres in rat vagal nerves were destroyed with
capsaicin. Despite the lack of C fibres, VNS had the same
striking efficacy in preventing pentelyntetrazol-induced
seizures.
Besides the increased fos expression in the locus
coeruleus, there is other evidence that this area is involved
in VNS antiseizure activity. When norepinephrine was
depleted by 6-hydroxydopamine infusion into the locus
coeruleus of rats, the seizure-suppressive effect of VNS was
abolished.32
In summary, current information suggests that VNS
activates neuronal networks in the thalamus and other limbic
structures and that norepinephrine may mediate the
antiseizure activity of VNS.
The device and its implantation
The stimulation device is similar to a cardiac pacemaker and is
implanted under the left clavicle in a procedure similar to that
used to implant a pacemaker in the chest wall or more
laterally in the axilla. Two helical bipolar stimulating
electrodes33 are placed around the left vagus nerve after it has
been exposed in the neck distal to the branching of the
recurrent laryngeal nerve (figure 1). The left vagus nerve,
never the right, is used to limit the risk of bradycardia or
arrhythmias.20 The operation can be done under local or
general anaesthesia and takes about 1–2 h. Recovery is rapid,
and some centres do implantation on an outpatient basis.
After the operation, the VNS can be turned on by use of a
computer and program wand. The starting level of
stimulation is 0·25 mA in most cases; stimulation is increased
to 1·25–2·00 mA over several weeks. The most common
settings for the stimulator are frequency of 20–30 Hz (animal
studies showed the best effect in the range of 10–60 Hz),4,12
pulse width of 250–500 ␮s, time on of 30 s, and time off of
3–5 min. The times on and off can be changed, and many
clinicians use rapid cycling of 7 s on and 0·2 s off, thereby
http://neurology.thelancet.com
 Vagus-nerve stimulation
increasing the amount of stimulation time given daily.
However, there is no hard evidence that one time setting is
better than the others. Increases in the amount of stimulation
will decrease battery life; therefore, high stimulation should be
used only if shown to be effective. Even the optimum current
can vary among individuals. Thus, after 12 years of use the
optimum VNS settings are still unknown.
Efficacy in epilepsy
Randomised, placebo-controlled, double-blind
studies
Two pivotal studies have attempted to answer the question
of whether VNS really does have an antiseizure effect. These
two trials also served as the main evidence for approval of
the US and European regulatory boards for the use of VNS
in patients with refractory partial-onset seizures.
The first trial (EO3)17 was an international multicentre
trial that included 114 patients over the age of 12 years who
completed the prospective baseline phase of the study. All
had more than six partial-onset seizures per month despite
treatment with antiepileptic drugs. 113 had devices
implanted and were randomly assigned to two groups. The
high-stimulation group received 30 s of VNS every 5 min
(30 Hz, 500 ␮s, up to 3·5 mA) and the other group received
30 s of VNS every 90 min (1 Hz, 130 ␮s, ⭐3·5 mA). No
changes in the antiepileptic-drug treatments were allowed.
After 3 months of treatment with VNS, there was a 24·5%
decrease in seizures in the high-stimulation group compared
with 6·1% in the low-stimulation group (p=0·01). 31% of
the high-stimulation group had seizure reduction of more
than 50% compared with 13% in the low-stimulation group.
In EO5,18 a multicentre USA based trial, 199 patients
with refractory partial seizures received implants and were
followed up for 3 months. 103 patients were in the low-
stimulation group and 95 were in the high-stimulation
group with similar stimulation regimens to the EO3 study.
After 3 months of stimulation there was a 28% decrease in
seizures in the high-stimulation group and a 15% decrease in
the low-stimulation group (p=0·039). Between-group
comparisons for 50% responders were not significant
(23·4% vs 15·7%). However, the high-stimulation group was
more likely to achieve a 75% seizure reduction than the low-
stimulation group (10·6% vs 2·0%).
Long-term follow-up studies
There have been two prospective, long-term, follow-up
studies that assessed the change in seizure frequency and
tolerability from the end of the clinical trials for up to 1 year
(EO5 study)30 and up to 3 years (EO1–EO5 studies).34
In the EO5 study, 195 patients were followed up for
12 months from the time they completed the double-blind
phase and went into the open-label phase of the trial. These
studies were analysed by three methods: a last-visit carried
forward method, in which the last reported observation was
used at each subsequent time point; a constant-cohort
method, in which the patients who reached a particular
endpoint were analysed at each previous time point; and a
declining N method, in which all available patients were
analysed at each time point. Although there are strengths
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Review
80
70
Patients continuing (%)
60
50
40
30
20
10
0
VNS LVT TPM LTG
Therapy
Figure 2. Comparison of long-term, 3-year continuation rates of patients
continuing treatment with VNS,34 levetiracetam (LVT),35 topiramate (TPM),
and lamotrigine (LTG).36
and weaknesses associated with each analysis, the interesting
finding was that the outcomes for VNS were similar for each
analysis. In the last-visit carried forward analysis, by
3 months after the end of the double-blind trial, patients had
a median seizure reduction of 34%, and by the end of the
year the median seizure reduction was 45% (p<0·0001). 34%
of patients had a seizure reduction of more than 50% and
20% had a reduction of more than 75%. The stimulation
current was around 1·7 mA at the end of the year.
In the EO1–EO5 study, 440 patients were followed up for
as long as 3 years. The same three analyses were used. The
amount by which seizures were reduced increased from
baseline to 3 months into the follow-up phase and then at
2 years, after which it reached a plateau. Seizure reduction of
more than 50% was seen in 23% of patients at 3 months,
37% at 1 year, and 43% at both 2 years and 3 years.
Continuation rates are shown in figure 2, referenced in
comparison with published information on the newer
antiepileptic drugs.35,36 Side-effects decreased progressively
during the 3-year follow-up. A compilation of long-term
median change and response rates from three different
studies30,34,37 is shown in figure 3.
Studies in children with epilepsy
There have been no controlled trials of VNS in children.
However, the EO4 study (a prospective open safety study of
VNS)38 did include 60 children aged 3–18 years. 16 of the
patients were under 12 years of age. In this study, patients with
various types of refractory seizures could be included and
some with primary generalised seizures (27%) were included.
After 3 months of stimulation, the median reduction in the
number of seizures was 23%; it was 42% at 6 months (n=46),
34% at 12 months (n=51), and 42% at 18 months (n=46).
There was no association between improvement and seizure
type.
Another large study with 95 patients was a six-centre
retrospective study of efficacy and tolerability of VNS in
children.39 There was an average seizure reduction of 36·1% at
3 months and 44·7% at 6 months.
479
 Review Vagus-nerve stimulation

Lennox-Gastaut syndrome were assessed at baseline and again

50 3 and 6 months after implantation. The median age at
E05
45 E03 implantation was 13 years. 60% of patients had IQ scores
40 All VNS studies below 70, 36% had tried the ketogenic diet, and five had
previously had callosotomy. The median seizure reduction
Seizure reduction (%)

35
was 58·2% at 3 months (n=43) and 57·9% at 6 months
30 (n=24). By 6 months, there was a decrease of at least 50% in
25 58% of patients. The falling number of patients in this study
20 was due to study cut-off and not to patients’ dissatisfaction.
The number of atonic seizures was reduced by 55% at
15
3 months and by 88% at 6 months. In the five patients who
10 had had callosotomy, the number of seizures was reduced by
5 73% at 3 months and by 69% at 6 months.44 Other smaller
0 studies have shown similar results 45,46
In conclusion, the efficacy of VNS seems to be established
Patients with >50% seizure reduction (%)

50 for focal-onset seizure types, and there is evidence that it has

45 efficacy for other seizure types as well. Therefore, VNS can be
40 considered to be a broad-spectrum treatment. It seems to be
effective in the most refractory focal-onset seizure patients,
35
even in those who have already had surgical treatment.
30 Improvement is not immediate but tends to increase over
25 18–24 months of treatment. Most of the studies cited above
20 report subjective improvements in various quality-of-life
measures while on VNS. Moreover, recent objective studies
15
have shown improvements in mood,47,48 memory,49 and
10 quality of life.50 A problem is that there have been few
5 prospective and randomised studies, but there is much
0 evidence in open label retrospective studies. One prospective
3 months 1 year 2 years study with a follow-up of 5 years also dealt with various
seizure types and again showed sustained efficacy and
tolerability over time.51
Figure 3. Top: median seizure reduction (%) of patients participating in
E03 (n=114) and E05 (n=105) randomised placebo-controlled trials as Safety and tolerability
well as all VNS studies combined (E01-E05, N=440) at 3 months, 1 year, Acute side-effects
and 2 years of follow-up (intent-to-treat analysis). Bottom: proportion of
Most of the acute complications of VNS implantation have
patients with at least 50% seizure reduction in E03 (N=114) and E05
(N=195) randomised placebo-controlled trials as well as all VNS studies been common infections, vocal-cord pareses, lower facial
combined (E01–E05, N=440) at 3 months, 1 year, and 2 years of follow- weakness, and, in a few cases, bradycardia and asystole.
up (intention-to treat analysis).30,34,37 Postoperative infections occur in 3–6% of patients. Most
are treated with oral antibiotics; rarely are the generator or
VNS and other epileptic disorders electrodes removed.18,30,51 In the EO3 study, infections were not
There have been many case-reports of VNS in different types reported; however, many patients received prophylactic
of epilepsy such as tuberous sclerosis,40 status epilepticus,41 antibiotic treatment. In the EO5 study, infection led to device
hamartoma syndrome,42 infantile spasms, and progressive removal in three of 198 patients (1·5%).18
myoclonic epilepsy of Unverricht-Lundborg type.43 All Paralysis of the left vocal cord occurred in one patient in
reported good efficacy and low frequency of side-effects. the EO3 study but resolved when the device was removed. In
In another six-centre retrospective study, 50 patients with the EO5 study reversible paralysis of the left vocal cord was
reported in two patients.
Proportion of patients with side-effects at stages in
Lower facial weakness was reported in the EO5 study in
long-term treatment
two patients and in one in the EO3 study. This side-effect was
Proportion (%) of patients with side-effects probably due to misplaced surgical incisions when the
Side-effect 3 months18 12 months30 5 years51 electrodes were being connected to the vagus nerve. This side-
effect has become very rare with the improvement of surgical
Cough 21 15 1·5
Voice alteration 62 55 18·7 techniques.
Dyspnoea 16 13 2·3 Ventricular asystole during testing of the device on
Pain 17 15 4·7 implantation has been reported in five patients.52,53 No
Paraesthesia 25 15 1·5 asystolic events have occurred outside the operating room,
Headache 20 16
Pharyngitis 9 10
and patients have been able to use the VNS postoperatively.
Depression 3 5 Similar events have not been reported during device
Infection 4 6 implantation in the clinical trials. The occurrence of this

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 Vagus-nerve stimulation
adverse event is estimated to be one in 875 or 0·1%. Possible
reasons could be abnormal electrode placement, indirect
stimulation of the cervical cardiac nerves, technical
malfunction of the device, polarity reversal of the leads by the
surgeon, or an idiosyncratic reaction.
Adverse events related to long-term use
Most of the data on side-effects are based on studies in adult
patients. The most common adverse-side-effects are
stimulus-related coughing, throat pain, and hoarseness, all of
which tend to improve with time.34 In the EO3 study the only
side-effects to occur in more than 10% of patients were voice
alteration (37·2%), hoarseness (37·2%), and throat pain
(11%). In the EO5 study, side-effects were reported to be
more diverse and more common: voice alteration in 66·3% of
patients on high stimulation and 30·0% on low stimulation,
cough in 45·0% and 42·0%, throat pain in 28·1% on high
stimulation, dyspnoea in 25·0%, vomiting and paresthesias in
17·9%, and infection in 11·6%.18 The symptoms were mild or
moderate and rarely required adjustment of the stimulation
variables. No changes in autonomic function were seen in
tests such as blood pressure, heart rate, Holter monitor
measures, lung function, or blood chemistry.
In children, the main side-effects reported are the same as
in adults—that is, transient hoarseness, throat pain, and
coughing, all of which are stimulus dependent and tend to
improve over time.54,55 Difficulties in swallowing have been
reported in two young children with VNS.54 Examination with
videoradiography with and without stimulation showed an
increase in aspiration when the device was on. The two
children, who also had severe motor disabilities, had difficulty
in swallowing and needed assisted feeding before VNS.
Schallert and colleagues56 tested swallowing in eight children
with VNS in both the on and off phases and did not observe
difficulties with aspiration.
Tolerability
There have been three long-term follow-up reports.30,34,51 195
patients were included in the 12 month follow-up for the
EO5.30 No cardiac events or changes (eg, variability in the
intervals between R waves) have been seen. Results of
pulmonary function tests and blood-chemistry tests were
unchanged from baseline. 97·8% of the adverse events were
reported as mild to moderate and were reversible with a
reduction in stimulation. Noteworthy is the lack of CNS or
cognitive side-effects (table).
In the 3 year follow-up of all patients in EO1–EO5,34
paraesthesias, cough, and hoarseness became less common
with time. Dyspnoea was the most common adverse event
reported at 3 years (3·2%). Three serious events of respiratory
difficulties and three of hoarseness were reported, and there
were nine deaths. No changes in Holter monitor or lung-
function tests or blood chemistries that could be attributed to
VNS were noted.
In a 5 year follow-up of 64 patients, Ben-Menachem and
co-workers51 reported mainly mild side-effects almost all
related to stimulation. One patient complained about device
placement and had it moved twice without satisfaction. One
patient experienced a reversible vocal-cord paresis after
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Review
Search strategy and selection criteria
Data for this review were identified by searches of Medline,
references from the relevant articles, the Cochrane Library,
and the files of the author. Search terms included “vagus-
nerve stimulation”, “epilepsy”, “clinical trials”, and “side-
effects”. Only papers published in English were reviewed.
Abstracts were used only when no other information was
available.
replacement of a lead. Hoarseness was reported in 11 patients
(18·7%) and throat pain in three (4·7%), Paraesthesia was
reported in one patient from whom the device and the
electrodes were removed bacause the side-effect was severe.
Four patients died—three because of status epilepticus, which
was caused by infection in two of these patients. The other
patient died of sudden, unexplained death in epilepsy
(SUDEP).
Deaths
In 440 patients with refractory epilepsy in the EO1–EO5
studies, there were nine deaths: four SUDEP one accident,
one thrombocytopenia, one aspiration pneumonia, one renal
failure, and one pneumonia–sepsis. Annegers and
colleagues57 reviewed all deaths in 1819 patients with VNS.
The patients were followed up for 3176·3 person-years from
implantation and 25 deaths were reported. Rates of SUDEP
were 4·1 per 1000 in patients treated with VNS and 4·5 per
1000 for a control population with refractory epilepsy. After
stratification for duration of VNS use, the prevalence of
SUDEP was 5·5 per 1000 for the first 2 years and then
dropped to 1·7 per 1000 for the subsequent years. Thus,
excessive death rates have not been seen in patients with
epilepsy treated with VNS. In fact, there was a tendency for
SUDEP rates to be lower than in similar groups of patients
not treated with VNS.
In conclusion, side-effects are mainly stimulation related
and reversible, and they tend to decrease over time. They are
mild to moderate in most cases and seldom necessitate
removal of the device. No idiosyncratic side-effects have been
reported after 12 years of experience, and VNS does not
interact with antiepileptic drugs. Most adverse events are
predictable and related to stimulation variables. CNS side-
effects such as tiredness, psychomotor slowing, irritation, and
nervousness have not been frequently reported and they do
not stand out as major side-effects of VNS.
Conclusion
There is now strong, level I evidence that VNS is an effective
treatment for patients with partial-onset seizures.58,59 There is
level II evidence that VNS is effective in most seizure types
from large open-label studies with long-term follow-up
indicating a broad range of activity. Currently, VNS devices
are being implanted in patients with refractory seizures who
cannot have resective surgery or who have had surgery with
poor results. Many of these patients have been treated with
several antiepileptic drugs before receiving VNS implants.
There is, however, preliminary evidence that VNS can be
effective in less refractory epilepsy as well,60 and this may be
the future use of VNS. More research needs to be done to
481
 Review
provide evidence of efficacy in patients with less refractory
disease. VNS, therefore, is now a treatment for
pharmacoresistant epilepsy. Although fewer than 10% of
patients were reported as seizure-free from the clinical trials,
this proportion is similar to that seen with antiepileptic drugs
in a population with similarly intractable epilepsy.50
Most paediatric neurologists and neurosurgeons also
agree that VNS should be offered to patients before
callosotomy because VNS is less invasive and seems to be
effective in patients who would be considered for surgery.
VNS is well tolerated—side-effects tend to diminish over
time, and continuation rates for VNS compare favourably
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482
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with those for antiepileptic drugs. VNS does not have the
cognitive and systemic side-effects seen with the use of drugs
and therefore can be a valuable treatment modality for
patients who have poor tolerance of effective antiepileptic
drugs.61
Conflict of interest
The author has previously received research grants from Cyebronics,
the company that manufactures vagus-nerve stimulators.
Role of the funding source
No funding source was involved in the preparation of this review or the
decision to submit it for publications.
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