Panamerican Journal of Trauma, Critical Care & Emergency Surgery

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VOLUME 11 , ISSUE 2 ( May-August, 2022 ) > List of Articles


Pathobiology of the Glymphatic System in the Traumatic Brain Injury: A Narrative Review

Juan Jose Beltran-Ruiz, Juan Sebastian Reyes-Bello, Claudia Marcela Restrepo-Lugo

Keywords : Brain trauma, Craniocerebral trauma, Glymphatic system

Citation Information : Beltran-Ruiz JJ, Reyes-Bello JS, Restrepo-Lugo CM. Pathobiology of the Glymphatic System in the Traumatic Brain Injury: A Narrative Review. Panam J Trauma Crit Care Emerg Surg 2022; 11 (2):82-87.

DOI: 10.5005/jp-journals-10030-1389

License: CC BY-NC 4.0

Published Online: 31-08-2022

Copyright Statement:  Copyright © 2022; The Author(s).


The glymphatic system (GS) is responsible in the brain for transporting substances toward the interstitium and then out of it; it is essential for neuronal functioning and even more so after any brain injury. It is a fragile system, its functioning is altered with age, sleep disorders, and neuronal damage as in head trauma, causing a decrease in the clearance of neurotoxic and inflammatory substances, which triggers neurodegeneration and alterations in neuro repair, despite having different mechanisms that allow the flow of nutrients and clearance of harmful substances for neuronal survival and rehabilitation. This article describes the relationship between head trauma and dysfunction of the GS, as well as the negative effects on the brain parenchyma and secondary neuroinflammation. This system is not only affected by the change in the “polarization” of the aquaporin (AQP) four channels of the astrocytes but also by the characteristics of the substances in the neuronal environment, that opt for a different transport mechanism from the GS.

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  1. Piantino J, Lim MM, Newgard CD, et al. Linking traumatic brain injury, sleep disruption and post-traumatic headache: a potential role for glymphatic pathway dysfunction. Curr Pain Headache Rep 2019;23(9):62. DOI: 10.1007/s11916-019-0799-4
  2. Xiong Y, Mahmood A, Chopp M. Current understanding of neuroinflammation after traumatic brain injury and cell-based therapeutic opportunities. Chin J Traumatol 2018;21(3):137–151. DOI: 10.1016/j.cjtee.2018.02.003
  3. Plog BA, Nedergaard M. The glymphatic system in central nervous system health and disease: past, present, and future. Annu Rev Pathol 2018;13:379–394. DOI: 10.1146/annurev-pathol-051217-111018
  4. Nagelhus EA, Ottersen OP. Physiological roles of aquaporin-4 in brain. Physiol Rev 2013;93(4):1543–1562. DOI: 10.1152/physrev.00011.2013
  5. Meyerhoff J, Chakraborty N, Hammamieh R. Glymphatics: a transformative development in medical neuroscience relevant to injuries in military central nervous system. Mil Med 2021;usab344. DOI: 10.1093/milmed/usab344
  6. May R, Reddy U. Cerebrospinal fluid and its physiology. Anaesth Intensive Care Med 2020;21(1):60–61. DOI: 10.1016/j.mpaic.2019.10.017
  7. Louveau A, Plog BA, Antila S, et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest 2017;127(9):3210–3219. DOI: 10.1172/JCI90603
  8. Martin BA, Heidari Pahlavian S. Chapter 5 - Anatomy and physiology of cerebrospinal fluid dynamics. In: Lonser RR, Sarntinoranont M, Bankiewicz K, editors. Nervous System Drug Delivery: Academic Press; 2019:73–89. DOI: 10.1016/B978-0-12-813997-4.00005-0
  9. Breslin JW, Yang Y, Scallan JP, et al. Lymphatic Vessel network structure and physiology. Compr Physiol 2018;9(1):207–299. DOI: 10.1002/cphy.c180015
  10. Mogensen FL, Delle C, Nedergaard M. The glymphatic system (En)during inflammation. Int J Mol Sci 2021;22(14):7491. DOI: 10.3390/ijms22147491
  11. Iliff JJ, Nedergaard M. Is there a cerebral lymphatic system? Stroke 2013;44(6 Suppl 1):S93–S95. DOI: 10.1161/STROKEAHA.112.678698
  12. Da Mesquita S, Fu Z, Kipnis J. The Meningeal lymphatic system: a new player in neurophysiology. Neuron 2018;100(2):375–388. DOI: 10.1016/j.neuron.2018.09.022
  13. Li L, Chopp M, Ding G, et al. MRI detection of impairment of glymphatic function in rat after mild traumatic brain injury. Brain Res 2020;1747:147062. DOI: 10.1016/j.brainres.2020.147062
  14. Taoka T, Masutani Y, Kawai H, et al. Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases. Jpn J Radiol 2017;35(4):172–178. DOI: 10.1007/s11604-017-0617-z
  15. Nedergaard M. Neuroscience. Garbage truck of the brain. Science 2013;340(6140):1529–1530. DOI: 10.1126/science.1240514
  16. Ringstad G, Valnes LM, Dale AM, et al. Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 2018;3(13):e121537. DOI: 10.1172/jci.insight.121537
  17. Eide PK, Vatnehol SAS, Emblem KE, et al. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci Rep 2018;8(1):7194. DOI: 10.1038/s41598-018-25666-4
  18. Eide PK, Mariussen E, Uggerud H, et al. Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood. JCI Insight 2021;6(9):e147063. DOI: 10.1172/jci.insight.147063
  19. Eide PK, Ringstad G. MRI with intrathecal MRI gadolinium contrast medium administration: a possible method to assess glymphatic function in human brain. Acta Radiol Open 2015;4(11): 2058460115609635. DOI: 10.1177/2058460115609635
  20. Ringstad G, Vatnehol SAS, Eide PK. Glymphatic MRI in idiopathic normal pressure hydrocephalus. Brain 2017;140(10):2691–2705. DOI: 10.1093/brain/awx191
  21. Eide PK, Pripp AH, Ringstad G. Magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in idiopathic normal pressure hydrocephalus. Brain Commun 2020;2(2):fcaa187. DOI: 10.1093/braincomms/fcaa187
  22. Edeklev CS, Halvorsen M, Løvland G, et al. Intrathecal use of gadobutrol for glymphatic MR imaging: prospective safety study of 100 patients. AJNR Am J Neuroradiol 2019;40(8):1257–1264. DOI: 10.3174/ajnr.A6136
  23. Roncali L, Virgintino D, Coltey P, et al. Morphological aspects of the vascularization in intraventricular neural transplants from embryo to embryo. Anat Embryol (Berl) 1996;193(3):191–203. DOI: 10.1007/BF00198323
  24. Bolte AC, Dutta AB, Hurt ME, et al. Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis. Nat Commun 2020;11(1):4524. DOI: 10.1038/s41467-020-18113-4
  25. Hauglund NL, Kusk P, Kornum BR, et al. Meningeal lymphangiogenesis and enhanced glymphatic activity in mice with chronically implanted EEG electrodes. J Neurosci 2020;40(11):2371–2380. DOI: 10.1523/JNEUROSCI.2223-19.2020
  26. Jessen NA, Munk AS, Lundgaard I, et al. The glymphatic system: a beginner's guide. Neurochem Res 2015;40(12):2583–2599. DOI: 10.1007/s11064-015-1581-6
  27. Lucke-Wold BP, Smith KE, Nguyen L, et al. Sleep disruption and the sequelae associated with traumatic brain injury. Neurosci Biobehav Rev 2015;55:68–77. DOI: 10.1016/j.neubiorev.2015.04.010
  28. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science 2013;342(6156):373–377. DOI: 10.1126/science.1241224
  29. Lee H, Xie L, Yu M, et al. The Effect of body posture on brain glymphatic transport. J Neurosci 2015;35(31):11034–11044. DOI: 10.1523/JNEUROSCI.1625-15.2015
  30. Fuxe K, Agnati LF, Marcoli M, et al. Volume transmission in central dopamine and noradrenaline neurons and its astroglial targets. Neurochem Res 2015;40(12):2600–2614. DOI: 10.1007/s11064-015-1574-5
  31. Kiviniemi V, Wang X, Korhonen V, et al. Ultra-fast magnetic resonance encephalography of physiological brain activity - glymphatic pulsation mechanisms? J Cereb Blood Flow Metab 2016;36(6):1033–1045. DOI: 10.1177/0271678X15622047
  32. Rajna Z, Kananen J, Keskinarkaus A, et al. Detection of short-term activity avalanches in human brain default mode network with ultrafast MR encephalography. Front Hum Neurosci 2015;9:448. DOI: 10.3389/fnhum.2015.00448
  33. Sullan MJ, Asken BM, Jaffee MS, et al. Glymphatic system disruption as a mediator of brain trauma and chronic traumatic encephalopathy. Neurosci Biobehav Rev 2018;84:316–324. DOI: 10.1016/j.neubiorev.2017.08.016
  34. Hsieh CL, Niemi EC, Wang SH, et al. CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury. J Neurotrauma 2014;31(20):1677–1688. DOI: 10.1089/neu.2013.3252
  35. Arguello J. TCE - Traumatismo craneoencefálico Foro Iberoamericano de discusiones sobre la Familia de Clasificaciones Internacionales de la OMS (FCI-OMS) 2018 [Available from:
  36. Simon DW, McGeachy MJ, Bayir H, et al. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol 2017;13(3):171–191. DOI: 10.1038/nrneurol.2017.13
  37. Bolte AC, Lukens JR. Neuroimmune cleanup crews in brain injury. Trends Immunol 2021;42(6):480–494. DOI: 10.1016/
  38. Christensen J, Wright DK, Yamakawa GR, et al. Repetitive Mild traumatic brain injury alters glymphatic clearance rates in limbic structures of adolescent female rats. Sci Rep 2020;10(1):6254. DOI: 10.1038/s41598-020-63022-7
  39. Killen MJ, Giorgi-Coll S, Helmy A, et al. Metabolism and inflammation: implications for traumatic brain injury therapeutics. Expert Rev Neurother 2019;19(3):227–242. DOI: 10.1080/14737175.2019.1582332
  40. Lv T, Zhao B, Hu Q, et al. The glymphatic system: a novel therapeutic target for stroke treatment. Front Aging Neurosci 2021;13:689098. DOI: 10.3389/fnagi.2021.689098
  41. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 2012;4(147):147ra111. DOI: 10.1126/scitranslmed.3003748
  42. Christensen J, Yamakawa GR, Shultz SR, et al. Is the glymphatic system the missing link between sleep impairments and neurological disorders? Examining the implications and uncertainties. Prog Neurobiol 2021;198:101917. DOI: 10.1016/j.pneurobio.2020.101917
  43. Smith AJ, Yao X, Dix JA, et al. Test of the ‘glymphatic’ hypothesis demonstrates diffusive and aquaporin-4-independent solute transport in rodent brain parenchyma. Elife 2017;6:e27679. DOI: 10.7554/eLife.27679
  44. Mestre H, Mori Y, Nedergaard M. The brain's glymphatic system: current controversies. Trends Neurosci 2020;43(7):458–466. DOI: 10.1016/j.tins.2020.04.003
  45. Koundal S, Elkin R, Nadeem S, et al. Optimal mass transport with Lagrangian Workflow reveals advective and diffusion driven solute transport in the glymphatic system. Sci Rep 2020;10(1):1990. DOI: 10.1038/s41598-020-59045-9
  46. Ray L, Iliff JJ, Heys JJ. Analysis of convective and diffusive transport in the brain interstitium. Fluids Barriers CNS 2019;16(1):6. DOI: 10.1186/s12987-019-0126-9
  47. Ren Z, Iliff JJ, Yang L, et al. ‘Hit & Run’ model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. J Cereb Blood Flow Metab 2013;33(6):834–845. DOI: 10.1038/jcbfm.2013.30
  48. Iliff JJ, Chen MJ, Plog BA, et al. Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury. J Neurosci 2014;34(49):16180–93. DOI: 10.1523/JNEUROSCI.3020-14.2014
  49. Cherian I, Burhan H, Dashevskiy G, et al. Cisternostomy: a timely intervention in moderate to severe traumatic brain injuries: rationale, indications, and prospects. World Neurosurg 2019;131:385–390. DOI: 10.1016/j.wneu.2019.07.082
  50. Cherian I, Bernardo A, Grasso G. Cisternostomy for Traumatic brain injury: pathophysiologic mechanisms and surgical technical notes. World Neurosurg 2016;89:51–57. DOI: 10.1016/j.wneu.2016.01.072
  51. Kanmounye US. The rise of inflow cisternostomy in resource-limited settings: rationale, limitations, and future challenges. Emerg Med Int 2021;2021:6630050. DOI: 10.1155/2021/6630050
  52. Cherian I, Yi G, Munakomi S. Cisternostomy: replacing the age old decompressive hemicraniectomy? Asian J Neurosurg 2013;8(3):132–138. DOI: 10.4103/1793-5482.121684
  53. Henry RJ, Ritzel RM, Barrett JP, et al. Microglial depletion with CSF1R Inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits. J Neurosci 2020;40(14):2960–2974. DOI: 10.1523/JNEUROSCI.2402-19.2020
  54. Kratz SV. Case report: manual therapies promote resolution of persistent post-concussion symptoms in a 24-year-old athlete. SAGE Open Med Case Rep 2021;9:2050313X20952224. DOI: 10.1177/2050313X20952224
  55. Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiol Dis 2016;93:215–225. DOI: 10.1016/j.nbd.2016.05.015
  56. Doustar J, Danan IJ. Glymphatic system dysfunction in mild traumatic brain injury. Neurology 2022;98(1 Supplement 1):S24. DOI: 10.1212/01.wnl.0000801968.87371.4e
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