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Review
. 2024 Mar 11;25(1):34.
doi: 10.1186/s10194-024-01741-2.

The glymphatic system in migraine and other headaches

Maria Grazia Vittorini  1 , Aysenur Sahin  2 , Antonin Trojan  3 , Sevil Yusifli  4 , Tamta Alashvili  5 , Gonçalo V Bonifácio  6 , Ketevan Paposhvili  7 , Viktoria Tischler  8 , Christian Lampl  9 , Simona Sacco  1 ; School of Advanced Studies of the European Headache Federation (EHF-SAS)
Affiliations
Review

The glymphatic system in migraine and other headaches

Maria Grazia Vittorini et al. J Headache Pain. .

Abstract

Glymphatic system is an emerging pathway of removing metabolic waste products and toxic solutes from the brain tissue. It is made of a network of perivascular spaces, filled in cerebrospinal and interstitial fluid, encompassing penetrating and pial vessels and communicating with the subarachnoid space. It is separated from vessels by the blood brain barrier and from brain tissue by the endfeet of the astrocytes rich in aquaporin 4, a membrane protein which controls the water flow along the perivascular space. Animal models and magnetic resonance (MR) studies allowed to characterize the glymphatic system function and determine how its impairment could lead to numerous neurological disorders (e.g. Alzheimer's disease, stroke, sleep disturbances, migraine, idiopathic normal pressure hydrocephalus). This review aims to summarize the role of the glymphatic system in the pathophysiology of migraine in order to provide new ways of approaching to this disease and to its therapy.

Keywords: CGRP; Cerebrospinal fluid; Cortical spreading depression; DTI-ALPS; Glymphatic system; Headache; Migraine; Neurological disorders; Perivascular space.

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Conflict of interest statement

Christian Lampl is a consultant or scientific advisor for Novartis and Teva. Simona Sacco reports personal fees as speaker or advisor from Abbott, Allergan-Abbvie, AstraZeneca, Boheringer, Eli Lilly, Lundbeck, Novartis, NovoNordisk, Pfizer, Teva and research grants from Novartis and Uriach. Other authors have no competing interests.

Figures

Fig. 1
Fig. 1
Representation of the glymphatic system and the glymphatic flow. The glymphatic system is made of a network of PVS around arteries and veins throwing metabolic waste products away from the central nervous system. PVS is limited by the endfeets of astrocytes and is filled with the CSF. CSF is produced in the choroid plexi in the lateral ventricles and then is vehicled into the subarachoid space. From the subarachoid space the CSF streams into the PVS around pial arteries. Here CSF enters the brain tissue and mixes with the ISF. CSF-ISF flows into the perivenous space and reach the dura mater sinuses, the meningeal lymphatics and the cervical lymphnodes. PVS: perivascular space; CSF: cerebrospinal fluid; ISF: interstitial fluid
Fig. 2
Fig. 2
Possible pathogenetic mechanisms of migraine involving the glymphatic system dysfunction. CSD can be responsible for a transient PVS closure causing a GS impairment. The GS dysfunction can lead to the accumulation of excitatory, pro-inflammatory and vasodilator molecules involved in the development and the exacerbation of migraine. CSD: cortical spreading depression; PVS: perivascular space; ROS: reactive oxygen species; CGRP: calcitonin gene-related peptide; ATP: adenosine triphosphate; TNF-α: tumor necrosis factor alpha; IL-1β: interleukin 1-beta; HIF-1α: hypoxia-inducible factor 1-alpha
Fig. 3
Fig. 3
Relationship between glymphatic system impairment, sleep disturbance and headache. Poor sleep can determine an impairment in the glymphatic flow which, in turn, leads to the accumulation of neuroexcitatory and pro-inflammatory chemicals involved in the development of headache. Headache itself can, directly or indirectly (via a dysfunction of the glymphatic system) exacerbate sleep disturbances
See this image and copyright information in PMC

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