Vagus nerve stimulation for primary headache disorders: An anatomical review to explain a clinical phenomenon

Abstract

Background Non-invasive stimulation of the vagus nerve has been proposed as a new neuromodulation therapy to treat primary headache disorders, as the vagus nerve is hypothesized to modulate the headache pain pathways in the brain. Vagus nerve stimulation can be performed by placing an electrode on the ear to stimulate the tragus nerve, which contains about 1% of the vagus fibers. Non-invasive vagus nerve stimulation (nVNS) conventionally refers to stimulation of the cervical branch of the vagus nerve, which is made up entirely of vagal nerve fibers. While used interchangeably, most of the research to date has been performed with nVNS or an implanted vagus nerve stimulation device. However, the exact mechanism of action of nVNS remains hypothetical and no clear overview of the effectiveness of nVNS in primary headache disorders is available. Methods In the present study, the clinical trials that investigated the effectiveness, tolerability and safety of nVNS in primary headache disorders were systematically reviewed. The second part of this study reviewed the central connections of the vagus nerve. Papers on the clinical use of nVNS and the anatomical investigations were included based on predefined criteria, evaluated, and results were reported in a narrative way. Results The first part of this review shows that nVNS in primary headache disorders is moderately effective, safe and well-tolerated. Regarding the anatomical review, it was reported that fibers from the vagus nerve intertwine with fibers from the trigeminal, facial, glossopharyngeal and hypoglossal nerves, mostly in the trigeminal spinal tract. Second, the four nuclei of the vagus nerve (nuclei of the solitary tract, nucleus ambiguus, spinal nucleus of the trigeminal nerve and dorsal motor nucleus (DMX)) show extensive interconnections. Third, the efferents from the vagal nuclei that receive sensory and visceral input (i.e. nuclei of the solitary tract and spinal nucleus of the trigeminal nerve) mainly course towards the main parts of the neural pain matrix directly or indirectly via other vagal nuclei. Conclusion The moderate effectiveness of nVNS in treating primary headache disorders can possibly be linked to the connections between the trigeminal and vagal systems as described in animals.

Brainstem Encephalitis Caused by Listeria monocytogenes

“…The spinal trigeminal nucleus incorporates sensory information from all three branches of the trigeminal nerve in addition to the facial, glossopharyngeal, and vagus nerves [39]. Extensive interconnections are found among the spinal nucleus of the trigeminal nerve and the solitary nucleus, ambiguous nucleus, and dorsal motor nucleus [40]. A functional MRI study demonstrated that the stimulation of the sensory auricular branch of the vagus nerve evokes extensive activities in brainstem regions, including the solitary nucleus, spinal trigeminal nucleus, and other areas [41].…”

Inhibition of Trigeminal Nociception by Non-invasive Vagus Nerve Stimulation: Investigating the Role of GABAergic and Serotonergic Pathways in a Model of Episodic Migraine

“…The mechanism by which triptans function to block trigeminal pain is thought to involve inhibiting the release of calcitonin-gene related peptide (CGRP) and other pro-inflammatory molecules from peripheral and central terminals of the trigeminal nerve as well from the cell body within the ganglion (12). In contrast, the inhibitory effect of nVNS as an acute migraine treatment is proposed to promote multiple distinct cellular changes and pathways within the brain and spinal cord to facilitate descending pain modulation (13). The descending inhibitory pathway is known to involve activation of 5-HT3 and 5-HT7 receptors on inhibitory interneurons that stimulates release of glycine and GABA, which act as inhibitory neurotransmitters of primary or secondary trigeminal nociceptors (14).…”

Daith Piercing: Wonder Treatment or Untested Fad?

“…Even though no clear mechanism of action is known, a multifactorial effect has been proposed [7]. Vagal neuromodulation has been hypothesized to modulate pain pathways of headache [8].…”