Vagally mediated heart rate variability in headache patients—a systematic review and meta-analysis

OBJECTIVE: Vagal nerve activity-indexed by heart rate variability (HRV)-has been linked to altered pain processing and inflammation, both of which may underpin headache disorders and lead to cardiovascular disease (CVD). Here we examined the evidence for differences in parasympathetic (vagal) activity indexed by time- and frequency-domain measures of HRV in patients with headache disorders compared to healthy controls (HCs). METHODS: A systematic review and meta-analysis was conducted on studies investigating group differences in vagally mediated HRV (vmHRV) including time- (root-mean-square of successive R-R-interval differences (RMSSD)) and frequency- (high-frequency HRV) domain measures. Studies eligible for inclusion were identified by a systematic search of the literature, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Seven studies reporting a total of 10 comparisons of patients with headache disorders (HF-HRV n = 67, RMSSD n = 122) and HCs (HF-HRV n = 64, RMSSD n = 125) were eligible for inclusion. Random-effects meta-analysis revealed a significant main effect on RMSSD (Z = 2.03, p = 0.04; Hedges' g = -0.63; 95% CI (-1.24, -0.02); k = 6) and similar pooled effect size estimates for HF-HRV when breathing was controlled (g = -0.30; 95% CI (-0.69; 0.10)) but not when breathing was not controlled (g = 0.02; 95% CI (-0.69; 0.74)). Controlling for breathing had no effect on RMSSD. CONCLUSION: vmHRV is reduced in patients with headache disorders, findings associated with a medium effect size. Suggestions for future research in this area are provided, emphasizing a need to investigate the impact of headache disorders and commonly comorbid conditions-including mental disorders-as well as the investigation of the risk for CVD in migraine in particular. We further emphasize the need for large-scale studies to investigate HRV as a mechanism mediating the association of migraine and CVD.