Glymphatic System Dysfunction: A Novel Mediator of Sleep Disorders and Headaches

Abstract

Sleep contributes to the maintenance of overall health and well-being. There are a growing number of patients who have headache disorders that are significantly affected by poor sleep. This is a paradoxical relationship, whereby sleep deprivation or excess sleep leads to a worsening of headaches, yet sleep onset also alleviates ongoing headache pain. Currently, the mechanism of action remains controversial and poorly understood. The glymphatic system is a newly discovered perivascular network that encompasses the whole brain and is responsible for removing toxic proteins and waste metabolites from the brain as well as replenishing nutrition and energy. Recent studies have suggested that glymphatic dysfunction is a common underlying etiology of sleep disorders and headache pain. This study reviews the current literature on the relationship between the glymphatic system, sleep, and headaches, discusses their roles, and proposes acupuncture as a non-invasive way to focus on the glymphatic function to improve sleep quality and alleviate headache pain.

Brain Waste Removal System and Sleep: Photobiomodulation as an Innovative Strategy for Night Therapy of Brain Diseases

“…Aristotle came up with the brilliant idea that sleep triggers brain cleansing [ 22 ]. After 2000 years, his idea was confirmed by several studies suggesting that sleep activates unique brain processes for the removal of metabolites and wastes [ 15 , 23 , 24 , 25 , 26 , 27 , 28 ] ( Figure 1 ). However, not all sleep is crucial to CNS health.…”

Enlarged perivascular spaces in patients with migraine: a case–control study based on 3T MRI

“…When the glymphatic system is damaged, it disrupts the brain's microenvironment, leading to an imbalance in the homeostasis of its internal environment, which inversely causes an increase in pro‐inflammatory substances in the brain, 23,24 resulting in headaches. Calcitonin gene‐related peptide (CGRP) is a neuropeptide that is widely distributed in the central and peripheral nervous system and can be present in three different locations upon release: the venous blood plasma, cerebrospinal fluid (CSF), and possibly the glymphatic system 7,25 . As an essential element of headaches, especially migraine, CGRP is a vasodilator and regulator of neuronal excitability 26 .…”

“…Most patients with headaches would gradually experience sleep problems 33 . Moreover, sleep disturbance can also lead to a decrease in substance exchange through the glymphatic system 7 . It is thought that awakening elicits the discharge of norepinephrine, resulting in the contraction of the interstitial space, which then inhibits substance exchange 23 .…”

“…The brain's glymphatic system is currently considered to be a perivascular pathway in the central nervous system that promotes the exchange of cerebrospinal and intercellular fluids to ultimately carry solutes and waste products out of the brain 4 . Studies have suggested that the impairment of the glymphatic system may be an underlying cause of sleep disorders, headaches, and cortical spreading depression (CSD) 5–8 . A diffusion tensor imaging (DTI) analysis of the perivascular space (DTI‐ALPS) in patients with cluster headache found that the DTI‐ALPS index was lower in patients than in healthy controls (HCs), suggesting a dysfunction of the glymphatic system in patients with cluster headache 9 .…”

Practice recommendations for the role of physiotherapy in the management of sleep disorders: the 2022 Brazilian Sleep Association Guidelines

“…Sleep health is related to individual, social and contextual factors 18 . Increasing evidence demonstrates the association of sleep disorders with other comorbidities and indicates the crucial role of sleep deprivation and/or dysfunction in the development of these diseases 18 , 19 .…”