Glymphatic System Dysfunction in Migraine: From Cortical Spreading Depression to Migraine Chronification

Migraine has traditionally been understood as a neurovascular and neuroinflammatory disorder, but the glymphatic system, a brain-wide waste-clearance network mediated by cerebrospinal fluid and interstitial fluid exchange, has been proposed as a contributor to migraine pathophysiology. This review synthesizes current evidence on the role of glymphatic system dysfunction in migraine onset and chronification, integrating findings from preclinical animal models and multimodal clinical neuroimaging studies. Converging data suggest that cortical spreading depression during migraine attacks induces astrocyte swelling and aquaporin-4 (AQP4) depolarization, leading to physical collapse of the perivascular space, disruption of convective bulk flow, and impaired glymphatic clearance. This clearance failure may prolong the accumulation of nociceptive molecules, including calcitonin gene-related peptide, potassium ions, and glutamate, within the brain parenchyma, thereby exacerbating trigeminovascular sensitization and potentially contributing to migraine chronification. Clinically, alterations in neuroimaging markers such as the diffusion tensor imaging analysis along the perivascular space index and enlarged perivascular spaces have been associated with progressive fluid stagnation and an increased brain age gap in patients with chronic migraine. Glymphatic clearance failure may therefore contribute to the cycle of neuroinflammation and pain that sustains migraine. Future therapeutic strategies may benefit from moving beyond single-receptor blockade toward approaches that normalize the brain microenvironment, potentially by supporting glymphatic clearance through targeted pharmacological interventions and AQP4 channel modulation.