Headache and Pain Research

Review Articles

Brain Glymphatic and Lymphatic Systems in Migraine: Mechanistic Insights and Neuromodulation Perspectives with an Emphasis on Ultrasound-Based Approaches: Jaeho Kim; Received January 12, 2026 Accepted January 30, 2026 Published online February 19, 2026; DOI: https://doi.org/10.62087/hpr.2026.0003 [Epub ahead of print]

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Abstract PDF: 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.

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
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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