Brain Glymphatic and Lymphatic Systems in Migraine: Mechanistic Insights and Neuromodulation Perspectives with an Emphasis on Ultrasound-Based Approaches

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.