Glymphatic-Hippocampal Axis Alterations Across the Migraine-Medication Exposure Continuum: A Multi-modal Neuroimaging Study.

INTRODUCTION: Medication-overuse headache (MOH) is a debilitating consequence of analgesic use, yet its pathophysiology remains incompletely characterised. Impaired glymphatic clearance may contribute to headache chronification. We investigated whether glymphatic-structural alterations progress across the migraine-medication exposure continuum and their biomarker potential. METHODS: This cross-sectional study enrolled 149 right-handed participants: 29 MOH patients, 34 patients with migraine and moderate medication use (MM), 46 medication-naive migraine patients (MN), and 40 healthy controls (HCs). The diffusion tensor imaging along the perivascular space (DTI-ALPS), perivascular space volume fraction (PVSVF), free water, and regional brain volumes were quantified. Group differences, imaging-clinical correlations, and diagnostic utility were assessed. RESULTS: Right-hemispheric centrum semiovale (CSO) PVSVF increased progressively across the continuum (HC < MN < MM < MOH; linear trend p = 0.003), with elevation in MOH versus controls (Cohen's d = 0.59, p = 0.014). Hippocampal volume was reduced in all migraine groups, most in MOH (d =  - 0.61, p = 0.001). DTI-ALPS and free water showed no group differences. Lower DTI-ALPS was associated with higher hippocampal free water in MOH (r =  - 0.539, pFDR = 0.043). Hippocampal decline accelerated beyond approximately 11 years disease duration (exploratory). A combined right PVSVF-CSO and hippocampal volume model distinguished MOH from controls, with an area under the curve (AUC) of 0.75. CONCLUSION: A graded, cross-sectional increase in perivascular space burden and reduced hippocampal volume, with right-hemispheric predominance, were observed across the migraine-medication exposure continuum. These markers may serve as adjunctive tools for MOH evaluation, meriting independent cohorts.