The glymphatic system as a mechanistic bridge between migraine and sleep: Evidence from clinical studies and animal...

Migraine is a highly prevalent, disabling neurological disorder often accompanied by sleep disturbances; however, the mechanisms linking sleep disturbance to migraine susceptibility remain unclear. The glymphatic system, a sleep-modulated perivascular clearance network facilitated by astrocytic aquaporin-4 (AQP4) and functionally connected to meningeal lymphatic drainage, is a potential mechanistic link between migraine and sleep disturbances. This review synthesizes evidence from clinical neuroimaging, cerebrospinal fluid and blood biomarker studies, and preclinical animal models to evaluate glymphatic involvement in migraine. Astrocytic AQP4 polarization, perivascular patency, and meningeal lymphatic drainage directly intersect with core migraine mechanisms, including cortical spreading depression-induced perivascular closure and calcitonin gene-related peptide (CGRP)-mediated meningeal lymphatic dysfunction. Although clinical findings are heterogeneous, glymphatic-related imaging and biomarker abnormalities appear to be more evident in association with higher attack frequency, longer disease duration, and poorer sleep quality. Animal models have linked sleep disruption, cortical spreading depression, and CGRP signaling to altered glymphatic and meningeal lymphatic functions. Four complementary hypotheses-waste accumulation, bidirectional disruption loop, the meningeal lymphatic-CGRP axis, and chronification-provide an integrative framework for this relationship across multiple timescales. These findings support the integration of sleep assessment with a glymphatic-informed framework in migraine evaluation and generate testable hypotheses that sleep-directed interventions may influence glymphatic function and that anti-CGRP therapies may partly act through meningeal lymphatic mechanisms, although these clearance-related therapeutic mechanisms remain unconfirmed in patients.