Vagus nerve stimulation modulates the cranial trigeminal autonomic reflex

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, eta p(2) = 0.85, 95% confidence interval [CI] = 1.39-18.04; no stimulation: minute 5, 14.4 +/- 9.3 mm; nVNS: minute 5, 4.7 +/- 8.6 mm, mean +/- standard deviation) as well as between sham stimulation and nVNS (minute 5: p = 0.030, eta p(2) = 0.85, 95% CI = 1.04-17.24; sham: minute 5, 13.9 +/- 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 +/- 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 +/- 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 +/- 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.