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

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. 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. 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. 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. Medication overuse headache is a condition in which headaches become more frequent because a person takes acute headache medication too often. It is common in people with migraine, and how migraine shifts into this more constant form of head ache is still unclear. The brain has a system that clears waste, partly through small fluid-filled spaces that surround its blood vessels. Researchers have suggested that poor waste clearance may make headaches more frequent, and we used MRI to look for such changes. We studied 149 adults in four groups: patients with medication-overuse headache, patients with migraine who used a moderate amount of medication, patients with migraine who used none, and people without migraine. In each person we examined several brain regions, measuring the fluid filled spaces around blood vessels, the sizes of brain structures, and two further fluid measures. Most of these measures were similar across the four groups, but two changes stood out. The fluid-filled spaces in the centrum semiovale became enlarged on the right side of the brain; more so as medication use increased. The hippocampus was smaller in all migraine groups and smallest in medication-overuse headache. The two fluid measures showed no difference between the groups. Using these two measurements could help tell patients with medication-overuse headache apart from people without migraine. They may serve as supporting markers in future, but larger studies that follow people over time are needed before they could be used in practice.