Vagal nerve stimulation beyond epilepsy.

Abstract

Video Podcast: https://www.youtube.com/watch?v=YvSVHZ3tqh8&feature=youtu.be 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 reduction in seizure severity, duration, and frequency in a clinically 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 outcomes remain to be clarified. The vagus nerve is the principal component of the parasympathetic nervous system.1 Its afferent fibres connect 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 GABAA receptor expression. 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 widespread interest for VNS.2 This pathway appears to involve cholinergic transmission mediated by nicotinic acetylcholine receptors (composed of only alpha 7 subunits) expressed by neurons and immune cells that activate inflammation-dampening signalling. Together with continuing empirical animal and human research in the context of electrical neuromodulation (from transcranial electrical or magnetic stimulation to deep brain stimulation),3 these various physiological perspectives have led to exploration of potential therapeutic indications for VNS. In addition to epilepsy, clear benefits have been recognized 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, unresponsive wakefulness syndrome, tinnitus, sleep disorders, eating disorders, and substance use disorders. VNS has also been suggested as an adjuvant therapy for children with autism spectrum disorder, Down syndrome, fragile X syndrome, Rett syndrome, and other neurodevelopmental disorders.4 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 combined with rehabilitation.4 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 population, with some positive results in working memory performance 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 transcutaneous 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 paediatric neurology and neurodevelopmental disorders) lacks a firm evidence base and still relies on empiricism and familiarity with current physiological knowledge.5 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 conditions. 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.