Headache and Pain Research

Review Articles

Glymphatic System Dysfunction in Migraine: From Cortical Spreading Depression to Migraine Chronification: Jeongwook Park; Headache Pain Res. 2026;27(3):174-185. Published online October 30, 2026; DOI: https://doi.org/10.62087/hpr.2026.0033

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Abstract PDF: 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.

Brain Glymphatic and Lymphatic Systems in Migraine: Mechanistic Insights and Neuromodulation Perspectives with an Emphasis on Ultrasound-Based Approaches: Jaeho Kim; Headache Pain Res. 2026;27(1):13-20. Published online February 19, 2026; DOI: https://doi.org/10.62087/hpr.2026.0003

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Migraine is a prevalent and disabling neurological disorder in which established pathophysiological mechanisms, including trigeminovascular activation and calcitonin gene-related peptide (CGRP) signaling, do not fully account for interindividual susceptibility, chronification, or treatment refractoriness. Advances in neurobiology have drawn attention to brain clearance pathways, specifically the glymphatic system and meningeal lymphatic vessels, as potential modulators of neuroinflammation and cerebrospinal fluid (CSF) dynamics. These systems regulate the exchange and drainage of CSF, interstitial solutes, and immune mediators and are strongly influenced by sleep and state-dependent physiology, both of which are closely linked to migraine pathophysiology. In this narrative review, we describe the anatomical and functional organization of brain lymphatic and glymphatic systems and critically evaluate emerging evidence connecting these pathways to migraine. Indirect human imaging studies and experimental models indicate that alterations in perivascular transport, meningeal lymphatic drainage, sleep disruption, and CGRP-related signaling may converge to modulate brain clearance efficiency in migraine. Although the available evidence remains heterogeneous and largely indirect, these findings offer a coherent framework for integrating clearance-related physiology into existing migraine models. We further discuss neuromodulation as a potential strategy for influencing brain clearance mechanisms. In particular, transcranial low-intensity ultrasound has been shown to enhance CSF movement in vivo, providing direct mechanistic support for clearance modulation. Other neuromodulation modalities may exert indirect effects through autonomic regulation, neural oscillations, or vascular dynamics. While clinical evidence remains preliminary, a clearance-oriented perspective may help guide future biomarker development and translational research in migraine.

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Comments on “Brain Glymphatic and Lymphatic Systems in Migraine: Mechanistic Insights and Neuromodulation Perspectives with an Emphasis on Ultrasound-Based Approaches”
Soo-Jin Cho
Headache and Pain Research.2026; 27(2): 169. CrossRef

Understanding the Connection between the Glymphatic System and Migraine: A Systematic Review: Myoung-Jin Cha, Kyung Wook Kang, Jung-won Shin, Hosung Kim, Jiyoung Kim; Headache Pain Res. 2024;25(2):86-95. Published online July 31, 2024; DOI: https://doi.org/10.62087/hpr.2024.0014

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The glymphatic system is a brain-wide perivascular pathway that functions similarly to the lymphatic system in the periphery of the body, playing a crucial role in removing waste from the brain. Although impaired glymphatic function has a well-known relationship with neurodegenerative diseases through abnormal protein accumulation, it is also associated with migraine. While still in its nascent phase, research on the glymphatic system in migraine patients is gradually increasing. This systematic literature review focuses on studies investigating the glymphatic system in migraineurs. Furthermore, it examines the methods used to evaluate the glymphatic system in these studies and their main findings.

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Chronic Migraine Is Associated With Region-Specific High-Grade Enlarged Perivascular Spaces: Retrospective Matched Case-Control Study
Jae Wook Cho, Gha-Hyun Lee, Jiyoung Kim
Journal of Clinical Neurology.2026; 22(1): 113. CrossRef
No Glymphatic Dysfunction in Trigeminal Neuralgia: A Preliminary Study
Barış Genç, Kerim Aslan
Brain and Behavior.2026;[Epub] CrossRef
Brain Glymphatic and Lymphatic Systems in Migraine: Mechanistic Insights and Neuromodulation Perspectives with an Emphasis on Ultrasound-Based Approaches
Jaeho Kim
Headache and Pain Research.2026; 27(1): 13. CrossRef
New Directions in Migraine Pathophysiology: The Glymphatic System and PACAP
Dan Iulian Cuciureanu, Cătălina Elena Bistriceanu, Georgiana-Anca Vulpoi, Victor Constantinescu, Diana Laura Blajuta, Ana-Maria Nădejde, Florina Antochi, Adina-Maria Roceanu
Life.2026; 16(5): 767. CrossRef
Comments on “Brain Glymphatic and Lymphatic Systems in Migraine: Mechanistic Insights and Neuromodulation Perspectives with an Emphasis on Ultrasound-Based Approaches”
Soo-Jin Cho
Headache and Pain Research.2026; 27(2): 169. CrossRef
Diffusion Tensor Imaging-Based Glymphatic Dysfunction Assessments in Migraine Syndromes: Mechanisms and Diagnostic Implications
Emily Lai, Joshua Estin, Jiahao Zhou, Roger Sheffmaker, Manisha Koneru
Biomedicines.2025; 13(12): 2981. CrossRef

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