title: Cortical Spreading Depression Closes Paravascular Space and Impairs Glymphatic Flow: Implications for Migraine Headache.
abstract: Functioning of the glymphatic system, a network of paravascular tunnels through which cortical interstitial solutes are cleared from the brain, has recently been linked to sleep and traumatic brain injury, both of which can affect the progression of migraine. This led us to investigate the connection between migraine and the glymphatic system. Taking advantage of a novelin vivomethod we developed using two-photon microscopy to visualize the paravascular space (PVS) in naive uninjected mice, we show that a single wave of cortical spreading depression (CSD), an animal model of migraine aura, induces a rapid and nearly complete closure of the PVS around surface as well as penetrating cortical arteries and veins lasting several minutes, and gradually recovering over 30 min. A temporal mismatch between the constriction or dilation of the blood vessel lumen and the closure of the PVS suggests that this closure is not likely to result from changes in vessel diameter. We also show that CSD impairs glymphatic flow, as indicated by the reduced rate at which intraparenchymally injected dye was cleared from the cortex to the PVS. This is the first observation of a PVS closure in connection with an abnormal cortical event that underlies a neurological disorder. More specifically, the findings demonstrate a link between the glymphatic system and migraine, and suggest a novel mechanism for regulation of glymphatic flow.SIGNIFICANCE STATEMENTImpairment of brain solute clearance through the recently described glymphatic system has been linked with traumatic brain injury, prolonged wakefulness, and aging. This paper shows that cortical spreading depression, the neural correlate of migraine aura, closes the paravascular space and impairs glymphatic flow. This closure holds the potential to define a novel mechanism for regulation of glymphatic flow. It also implicates the glymphatic system in the altered cortical and endothelial functioning of the migraine brain.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and.|Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Aaron J
authors.identifier: 0000-0001-7707-3556
authors.initials: AJ
authors.lastname: Schain
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and.|Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Agustin
authors.initials: A
authors.lastname: Melo-Carrillo
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and.|Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Strassman
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, and rburstei@bidmc.harvard.edu.|Harvard Medical School, Boston, Massachusetts 02215.
authors.forename: Rami
authors.identifier: 0000-0003-3763-8916
authors.initials: R
authors.lastname: Burstein
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology / Q000502:physiology*; D002536:Cerebral Arteries / Q000473:pathology / Q000502:physiology*; D002550:Cerebral Veins / Q000473:pathology / Q000502:physiology*; D002555:Cerebrospinal Fluid / Q000166:cytology / Q000502:physiology; D013181:Cortical Spreading Depression / Q000502:physiology*; D045604:Extracellular Fluid / Q000166:cytology / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008881:Migraine Disorders / Q000134:cerebrospinal fluid / Q000473:pathology / Q000503:physiopathology*
keywords: aura; glymph; interstitial fluid; lymph; neurodegeneration; trigeminovascular