Noninvasive vagus nerve stimulation and the trigeminal autonomic reflex

Abstract

ObjectiveThe trigeminal autonomic reflex is a physiologic reflex that plays a crucial role in primary headache and particularly in trigeminal autonomic cephalalgias, such as cluster headache. Previous studies have shown that this reflex can be modulated by the vagus nerve, leading to an inhibition of the parasympathetic output of the reflex in healthy participants. The aim of the present study was to characterize neural correlates of the modulatory effect of noninvasive vagus nerve stimulation (nVNS) on the trigeminal autonomic reflex.MethodsTwenty-one healthy participants were included in a 2-day, randomized, single-blind, within-subject design. The reflex was activated inside the MRI scanner using kinetic oscillation stimulation placed in the left nostril, resulting in an increase in lacrimation. After the first fMRI session, the participants received either sham vagus nerve stimulation or nVNS outside the scanner and underwent a subsequent fMRI session.ResultsnVNS prompted an increase in activation of the left pontine nucleus and a decreased activation of the right parahippocampal gyrus. Psychophysiologic interaction analyses revealed an increased functional connectivity between the left pontine nucleus and the right hypothalamus and a decreased functional connectivity between the right parahippocampal gyrus and the bilateral spinal trigeminal nuclei (sTN).ConclusionsThese findings indicate a complex network involved in the modulatory effect of nVNS including the hypothalamus, the sTN, the pontine nucleus, and the parahippocampal gyrus.

Non-invasive vagus nerve stimulation for primary headache: A clinical update

“…By applying nVNS, the user activates afferent pathways that project to numerous brain regions to trigger modulation of descending pain pathways (16,28); top-down modulation strategies such as this have been hypothesized to progressively reduce allostatic load, which results in symptomatic improvement (64). Headache pathophysiology involves multiple mechanisms that differ depending on the type of headache and the individual patient.…”

“…The existence of a trigeminovagal complex has been reported as a basis for the connections between the trigeminal and vagus systems (15). Recent functional MRI findings in humans suggest that nVNS may modulate the trigeminal autonomic reflex via a complex network that includes the hypothalamus, the spinal trigeminal nuclei, the left pontine nucleus, and the parahippocampal gyrus (16).…”

Indomethacin‐responsive headaches—A narrative review

“…The unilateral stimulation of the cervical tract of the vagal nerve inhibits trigeminal autonomic reflex bilaterally. This effect may be mediated by the hypothalamus, by the SSN, 205 or by connections with other cerebral structures 206 . It may also have a modulation role in the levels of extracellular neurotransmitters, such as a reduction in the increased levels of glutamate in the trigeminal nucleus caudalis when GTN was administered 207 …”

“…This effect may be mediated by the hypothalamus, by the SSN, 205 or by connections with other cerebral structures. 206 It may also have a modulation role in the levels of extracellular neurotransmitters, such as a reduction in the increased levels of glutamate in the trigeminal nucleus caudalis when GTN was administered. 207 nVNS was approved for the prevention of cluster headache following two randomized controlled trials.…”

Peptides, MAbs, Molecules, Mechanisms, and More: Taking a Stab at Cluster Headache

“…Vagal stimulation also modulates the TAR. fMRI studies of CH patients demonstrate a complex modulatory network including the hypothalamus, spinal trigeminal nuclei pontine nucleus, and parahippocampal gyrus 14,15 …”