Objective: To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs. Methods: This double-blinded, sham-controlled study enrolled 48 subjects and measured headache severity, frequency [headache days/month, number of total and mild/moderate/severe classified attacks/ month], functional state [sleep, mood, body weight, migraine-associated disability] and serum levels of inflammatory markers [inter-ictal] using enzyme-linked immunoassays at baseline and after 2 months of adjunctive nVNS compared to sham stimulation and suitably matched controls. Results: No significant differences were observed at baseline and after 2 months for headache severity, total attacks/month, headache days/month and functional outcome [sleep, mood, disability] between verum and sham nVNS. However, the number of severe attacks/month significantly decreased in the verum nVNS group and circulating pro-inflammatory IL-1b was elevated significantly in the sham group compared to nVNS. Levels of anti-inflammatory IL-10 were significantly higher at baseline in both groups compared to healthy controls, but not at 2 months follow-up [p < 0.05]. Concentrations of high-mobility group box-1 (HMGB-1), IL-6, tumor-necrosis factor-a (TNF-a), leptin, adiponectin, ghrelin remained unchanged [p > 0.05]. No severe device-/stimulation-related adverse events occurred. Conclusion: 2 months of adjunctive cervical nVNS significantly declined the number of severe attacks/ month. Pro-inflammatory IL-1b plasma levels [inter-ictal] were higher in sham-treated migraine patients compared to verum nVNS. However, pro-[IL-6, HMGB-1, TNF-a, leptin] and anti-inflammatory [IL-10, adiponectin, ghrelin] mediators did not differ statistically. Profiling of neuroinflammatory circuits in migraine to predict nVNS responsiveness remains an experimental approach, which may be biased by pre-analytic variables warranting large-scale biobank-based systematic investigations [omics].

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 antinociceptive 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 proand 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.

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ObjectivesCervical noninvasive vagus nerve stimulation (nVNS) emerged as an adjunctive neuromodulation approach for primary headache disorders with limited responsiveness to pharmacologic and behavioral treatment. This narrative review evaluates the safety and efficacy of invasive and noninvasive peripheral nerve stimulation of the cervical branch of the vagal nerve (afferent properties) for primary headache disorders (episodic/chronic migraine [EM/CM] and cluster headache [ECH/CCH]) and provides a brief summary of the preclinical data on the possible mechanism of action of cervical vagus nerve stimulation (VNS) and trigemino-nociceptive head pain transmission.Materials and methodsA systematic search of published data was performed in PubMed for randomized controlled trials (RCTs) and prospective cohort clinical studies assessing the efficacy/safety and cost-effectiveness of cervical VNS in primary headache disorders and related preclinical studies.ResultsThree RCTs were identified for ECH/CCH (ACT-1, ACT-2 and PREVA), one RCT for migraine (EVENT) and several prospective cohort studies and retrospective analyses for both headache disorders. In ACT-1, a significantly higher response rate, a higher pain-free rate and a decrease in mean attack duration were found in nVNS-treated ECH/CCH patients compared to sham stimulation. ACT-2 confirmed these findings (e.g., significantly higher pain-free attacks, pain severity decline and increased responder-rate [defined as ≥50% reduction]). The PREVA study demonstrated the superiority of adjunctive nVNS to standard care alone and observed a significantly higher attack reduction (p=0.02) and responder rate (defined as ≥50% reduction). For CM, the EVENT study assessed a significantly higher frequency of decline in the open-label phase. Mostly transient mild/moderate adverse events were recorded, and no severe device-related adverse events occurred.ConclusionCervical nVNS represents a novel, safe and efficient adjunctive treatment option for primary headache disorders. In particular, preliminary observations suggest enhanced nVNS responsiveness in favor of episodic subtypes (EM and ECH). However, preclinical studies are urgently warranted to dissect the mechanism of action.

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