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Abstract
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.
Glossary
- KOS=
- kinetic oscillation stimulation;
- PREMIUM=
- A Randomized, Sham-Controlled Study of gammaCore® (nVNS) for Prevention of Episodic Migraine;
- PRESTO=
- RCT of Non-Invasive Vagus Nerve Stimulation (nVNS) With gammaCore® for the Acute Treatment of Migraine Attacks;
- nVNS=
- noninvasive vagal nerve stimulation
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
- Received November 7, 2018.
- Accepted in final form March 18, 2019.
- © 2019 American Academy of Neurology
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