Saliva molecular inflammatory profiling in female migraine patients responsive to adjunctive cervical non-invasive vagus nerve stimulation: the MOXY Study

Abstract

Background: Rising evidence indicate that oxytocin and IL-1β impact trigemino-nociceptive signaling. Current perspectives on migraine physiopathology emphasize a cytokine bias towards a pro-inflammatory status. The anti-nociceptive impact of oxytocin has been reported in preclinical and human trials. Cervical non-invasive vagus nerve stimulation (nVNS) emerges as an add-on treatment for the preventive and abortive use in migraine. Less is known about its potential to modulate saliva inflammatory signaling in migraine patients. The rationale was to perform inter-ictal saliva measures of oxytocin and IL-1ß along with headache assessment in migraine patients with 10 weeks adjunctive nVNS compared to healthy controls.

Methods: 12 migraineurs and 12 suitably matched healthy control were studied with inter-ictal saliva assay of pro- and anti-neuroinflammatory cytokines using enzyme-linked immuno assay techniques along with assessment of headache severity/frequency and associated functional capacity at baseline and after 10 weeks adjunctive cervical nVNS.

Results: nVNS significantly reduced headache severity (VAS), frequency (headache days and total number of attacks) and significantly improved sleep quality compared to baseline (p < 0.01). Inter-ictal saliva oxytocin and IL-1β were significantly elevated pre- as well as post-nVNS compared to healthy controls (p < 0.01) and similarly showed changes that may reflect the observed clinical effects.

Conclusions: Our results add to accumulating evidence for a therapeutic efficacy of adjunct cervical non-invasive vagus nerve stimulation in migraine patients. This study failed to provide an evidence-derived conclusion addressed to the predictive value and usefulness of saliva assays due to its uncontrolled study design. However, saliva screening of mediators associated with trigemino-nociceptive traffic represents a novel approach, thus deserve future targeted headache research. Trial registration This study was indexed at the German Register for Clinical Trials (DRKS No. 00011089) registered on 21.09.2016.

Keywords: Cervical non-invasive vagus nerve stimulation; MOXY pilot study; Migraine; Saliva oxytocin/IL-1β; Trigemino-nociceptive signaling.

Fig. 1

a–d Pain intensity (VAS) score, migraine frequency (headache days, total number of attacks) and Pittsburgh Sleep Quality Index (PSQI) score at baseline (preVNS) and follow-up (postVNS) in all patients. Mean values with Standard deviations are presented. “*” Indicate the statistical significance

Fig. 2

Total numbers of attacks and distribution of mild/moderate/severe rated attack severity at baseline and post nVNS. Mean values with Standard deviations are presented. “*” Indicate the statistical significance

Fig. 3

a, b Oxytocin and Interleukin-1ß analysis (mean values with standard deviation and p-values). Saliva measurements for Oxytocin and IL-1ß at baseline (preVNS) and follow-up (postVNS) are compared to healthy controls. Mean values with Standard deviations are presented. “*” indicate the statistical significance. Abbreviations: OXY Oxytocin, IL-1ß Interleukin-1ß, HC healthy controls, ns not significant

Fig. 4

Cumulative correlation analysis between pre-/postnVNS OXY levels and nVNS outcome in headache frequency (headache days/month). Assessment of cumulative pre- and post-nVNS OXY levels showed a trend towards association with the headache days per month (r = 0.379, p = 0.08). OXY Oxytocin, IL-1ß Interleukin-1ß, HC healthy controls, ns not significant

Fig. 5

Cumulative correlation analysis between pre-/postnVNS OXY levels and nVNS outcome in headache frequency (attacks/month). Assessment of cumulative pre- and post-nVNS OXY levels showed no association with number of attacks per month (r = 0.343, p = 0.12). OXY Oxytocin, IL-1ß Interleukin-1ß, HC healthy controls, ns not significant