Reduced interictal BOLD cerebrovascular reactivity patterns in migraine patients: toward a functional biomarker of cerebrovascular dysfunction

Abstract Background Migraine is a potentially disabling neurovascular disorder characterized by recurrent headache attacks, associated sensory and transient neurological symptoms such as aura. Structural and functional neuroimaging studies have revealed widespread brain alterations in migraine, yet the underlying vascular mechanisms remain incompletely understood. Blood oxygenation level-dependent cerebrovascular reactivity (BOLD-CVR) imaging offers a non-invasive approach to assess interictal hemodynamic changes in vivo. Methods This observational study with prospectively collected data includes 47 adult participants with migraine (with and without aura, diagnosed according to the International Classification of Headache Disorders 3rd edition (ICHD-3) criteria) and 21 age-matched healthy controls. CVR was quantified via BOLD signals during standardized and controlled carbon dioxide (CO₂) challenge. BOLD-CVR values were assessed globally and in the grey and white matter and expressed as the percentage of BOLD signal change per mmHg CO 2 . Group differences were assessed using a linear mixed-effects model, with group, region of interest and their interaction as fixed effects and a random intercept for participants. Results Migraine participants showed significantly reduced BOLD-CVR compared to healthy controls. Whole brain CVR was 0.15 ± 0.04 %BOLD/mmHg CO 2 in migraine participants versus 0.21 ± 0.05 in controls ( t (79.09) = − 4.73, P FDR < 0.0001). A directionally consistent pattern was observed in grey matter (0.19 ± 0.05 vs. 0.25 ± 0.06) and white matter (0.09 ± 0.03 vs. 0.14 ± 0.04). Effect sizes were large across all regions (Cohen’s d whole brain d = -1.23, grey matter d = -1.07, white matter d = -1.28); the reduction in BOLD-CVR in migraine was consistent across all three regions and statistically significant (all P < 0.001). Individual values below – 2 SD occurred for whole brain in 1/ 32 participants with migraine with aura and in 2/13 participants with migraine without aura, for grey matter in 2/ 32 and 3/13, and for white matter in 1/ 32 and 1/13. Conclusion These preliminary findings demonstrate significantly reduced interictal cerebrovascular reactivity in migraine, involving the whole brain as well as grey and white matter, suggesting altered cerebrovascular function and highlighting the potential of BOLD-CVR as a non-invasive marker of cerebrovascular dysregulation in migraine. Larger, adequately powered studies are warranted to confirm these findings and clarify the diagnostic and prognostic relevance of BOLD-CVR.