Vagus nerve stimulation modulates the cranial trigeminal autonomic reflex

Abstract

Objective: The trigeminal autonomic reflex plays an important role in primary headache syndromes. Noninvasive vagal nerve stimulation (nVNS) may be an effective modulator of this reflex. Methods: Twenty-two healthy volunteers underwent kinetic oscillation stimulation (KOS) of the left nostril as a reliable trigger of the trigeminal autonomic reflex. Previous to KOS, left cervical nVNS, sham simulation, or no stimulation was applied. Lacrimation was quantified using the standardized Schirmer ll test. Results: Treatment with cervical nVNS significantly reduced lacrimation between no stimulation and nVNS on the ipsilateral side (minute 5: p = 0.026, ηp 2 = 0.85, 95% confidence interval [CI] = 1.39-18.04; no stimulation: minute 5, 14.4 AE 9.3 mm; nVNS: minute 5, 4.7 AE 8.6 mm, mean AE standard deviation) as well as between sham stimulation and nVNS (minute 5: p = 0.030, ηp 2 = 0.85, 95% CI = 1.04-17.24; sham: minute 5, 13.9 AE 6.4 mm). On the contralateral side, no significant increase between baseline and KOS was observed for nVNS (minute 5: p = 0.614, d = 0.12, 95% CI = −7.09 to 4.31; minute 5, 1.4 AE 11.5 mm) compared to both sham stimulation (minute 5: p = 0.023, d = 0.57, 95% CI = −11.46 to −0.96; minute 5, 6.2 AE 10.9 mm) and no stimulation (minute 5: p < 0.030, d = 0.62, 95% CI = −13.45 to −0.81; minute 5, 7.1 AE 11.4 mm). Interpretation: Cervical nVNS resulted in a robust bilateral reduction of provoked lacrimation. This effect could be mediated either by direct bilateral activation of structures such as the nucleus of the solitary tract or by a top-down modulation via the hypothalamus.

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

“…Hence, sumatriptan's mechanism of action would inhibit neurogenic inflammation in the dura, inhibit neuron-glia communication in the ganglion, and also inhibit activation of second order neurons and glia cells within the spinal cord to decrease peripheral and central sensitization of the trigeminal system. In contrast, the primary effects of nVNS are likely to be multimodal and would involve modulation of central cellular activities that regulate descending pain inhibition pathways (37). The findings from our study provide evidence for the involvement of GABA A receptors and 5-HT3 and 5-HT7 receptors in mediating the inhibitory effect of nVNS in an episodic migraine model.…”

Visualizing the trigeminovagal complex in the human medulla by combining ex-vivo ultra-high resolution structural MRI and polarized light imaging microscopy

“…Other observations concerned the indirect activation of a subpopulation of second- and higher-order neurons, suggesting that afferent mechanisms and central neuron activation may be responsible for VNS efficacy 61 . Other functional evidence of a trigeminovagal complex in humans is derived from observations that VNS can modulate the cranial trigeminal autonomic reflex 62–64 . The existence of trigeminovagal connections have also been hypothesized based on findings from trigeminal nerve stimulation.…”

Targeted Vagus Nerve Stimulation for Rehabilitation After Stroke

“…This method of non-invasive stimulation has shown efficacy for the treatment of acute episodes of cluster headaches and migraine (Silberstein et al, 2016; Goadsby et al, 2018; Grazzi et al, 2018; Tassorelli et al, 2018). The mechanism of action is thought to arise from VNS-driven activation of NTS, which in turn modulates the activity of the trigeminal cervical complex (TCC) (Moeller et al, 2018) and suppresses the transmission of nociceptive signals to higher pain processing centers (Bohotin et al, 2003). However, NTS also receives direct inputs from the trigeminal and cervical nerves.…”