DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY EDITORIAL
Vagal nerve stimulation beyond epilepsy
Vagal nerve stimulation (VNS) has been used to treat
drug-resistant epilepsy for the last 30 years. Rhythmic
electrical stimulation is typically delivered to the left vagus
nerve at the neck level from a generator implanted under
the skin. VNS has been associated with long-lasting reduc-
tion in seizure severity, duration, and frequency in a clini-
cally meaningful proportion of patients with cumulative
beneﬁt over time and improvements in quality of life.
Therefore, it is an important treatment option for patients
with drug-resistant epilepsy in whom neurosurgery is not
indicated. However, the mechanisms underlying these out-
comes remain to be clariﬁed.
The vagus nerve is the principal component of the
parasympathetic nervous system.
Its afferent ﬁbres con-
nect to the nucleus of the solitary tract, which projects to
many parts of the central nervous system. One early
assumption, now partially documented, has been that
induced volleys of action potentials desynchronize neural
activity in the cortex, thereby interfering with oscillatory
processing and precluding epileptic discharges. In search
for more precise physiological explanations, effects of VNS
on neurotransmitter systems have also been reported,
including potentiation of norepinephrine release in various
brain structures and enhanced GABA
Furthermore, regional changes in cerebral blood ﬂow have
been associated with VNS. In addition, insights into anti-
inﬂammatory properties of vagal nerve activation through
both its afferent and efferent ﬁbres have generated wide-
spread interest for VNS.
This pathway appears to involve
cholinergic transmission mediated by nicotinic acetyl-
choline receptors (composed of only alpha 7 subunits)
expressed by neurons and immune cells that activate
Together with continuing empirical animal and human
research in the context of electrical neuromodulation (from
transcranial electrical or magnetic stimulation to deep brain
these various physiological perspectives have
led to exploration of potential therapeutic indications for
VNS. In addition to epilepsy, clear beneﬁts have been recog-
nized in major depressive disorders. Effects have been
reported in other neurological and psychiatric conditions,
such as traumatic brain injury, ischaemic stroke, chronic
migraine, chronic cluster headache, Alzheimer disease, unre-
sponsive wakefulness syndrome, tinnitus, sleep disorders,
eating disorders, and substance use disorders. VNS has also
been suggested as an adjuvant therapy for children with aut-
ism spectrum disorder, Down syndrome, fragile X syn-
drome, Rett syndrome, and other neurodevelopmental
It has been postulated that ‘VNS pairing therapy
can reorganize the brain in a manner that is both highly
speciﬁc to the paired experience and long lasting’ when com-
bined with rehabilitation.
Inspired by considerations relating more speciﬁcally to
vagus nerve function, VNS targeting efferent ﬁbres has
been tested in chronic heart failure, and ﬁndings on the
cholinergic anti-inﬂammatory pathway have prompted trials
in inﬂammatory diseases such as Crohn disease. A cognitive
enhancement effect has been studied in the general popula-
tion, with some positive results in working memory perfor-
mance and VNS has even been proposed for relaxation,
further extending the pool of potential users. In parallel,
portable devices are now being developed to provide tran-
scutaneous VNS stimulation without requiring surgery.
All this appears to confer a central role for the vagus nerve
in our physiology and present it as the best mediator for
health. Admittedly, much of our practice (including paedi-
atric neurology and neurodevelopmental disorders) lacks a
ﬁrm evidence base and still relies on empiricism and famil-
iarity with current physiological knowledge.
Yet, at a time
when precision medicine is championed towards exclusive
custom-ﬁtted treatment tailored to each patient’s individual
needs and characteristics, it is unfortunate that hopes are so
actively being placed in a single remedy for such diverse con-
ditions. If one considers that the brother of Panacea (the
Greek goddess of universal remedy) excelled in diagnosis,
accurate diagnoses are likely to remain essential for adequate
management. The physiological and pathophysiological
knowledge gained through VNS research will contribute to
better identiﬁcation and treatment of a host of disorders.
Editor in Chief
1. Dan B. Understanding the autonomic nervous system in
cerebral palsy. Dev Med Child Neurol 2017; 59: 668.
2. Bonaz B, Sinniger V, Pellissier S. The vagus nerve in the
neuro-immune axis: implications in the pathology of the
gastrointestinal tract. Front Immunol 2017; 8: 1452.
3. Dan B. Transcranial direct current stimulation for
rehabilitating the brain. Dev Med Child Neurol 2017; 59:
4. Engineer CT, Hays SA, Kilgard MP. Vagus nerve stimu-
lation as a potential adjuvant to behavioral therapy for
autism and other neurodevelopmental disorders. J Neu-
rodev Disord 2017; 9: 20.
5. Chambers HG. Selective percutaneous muscle lengthen-
ing in cerebral palsy: when there is little or no evidence.
Dev Med Child Neurol 2018; 60: 328.
634 © 2018 Mac Keith Press