Noninvasive vagus nerve stimulation and the trigeminal autonomic reflex: An fMRI study.

OBJECTIVE: The 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. METHODS: Twenty-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. RESULTS: nVNS 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). CONCLUSIONS: These findings indicate a complex network involved in the modulatory effect of nVNS including the hypothalamus, the sTN, the pontine nucleus, and the parahippocampal gyrus.

nVNS sham significantly affects the trigeminal-autonomic reflex: A randomized controlled study.

OBJECTIVE: To determine whether high placebo effects observed in recently published clinical noninvasive vagal nerve stimulation (nVNS) trials can be attributed to an active modulation of the trigeminal-autonomic reflex by the sham device. METHODS: Twenty-eight healthy participants were investigated in a randomized, controlled, single-blind, within-participant design. The 4 different conditions of no stimulation, regular nVNS of the left cervical vagal nerve, stimulation of the posterior neck with the same device (sham I), and stimulation of the left cervical vagal nerve with a sham device (sham II) were applied in randomized order. Parasympathetic output (lacrimation) was provoked with kinetic oscillation stimulation (KOS) of the nasal mucosa. Lacrimation was quantified with the Schirmer II test, an objective measure of lacrimal secretion after local anesthesia, and the difference between baseline and KOS-induced lacrimation served as a measure of autonomic output. RESULTS: nVNS treatment resulted in a significant reduction of ipsilateral KOS-induced lacrimation compared to no stimulation (p = 0.003) and sham I (p = 0.02). A similar effect was observed for sham II (p = 0.003, p = 0.001). There was no significant difference between nVNS and sham II. CONCLUSION: These results suggest that both the regular nVNS and the sham device used in some of the clinical nVNS trials modulate the trigeminal-autonomic reflex. This could explain the high sham effect in these trials and suggests that stimulation of the posterior neck may be considered as a real sham condition.

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, ηp2 = 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, ηp2 = 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. Ann Neurol 2018;84:886-892.