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Human brain solute transport quantified by glymphatic MRI-informed biophysics during sleep and sleep deprivation

Vinje, Vegard, Zapf, Bastian, Ringstad, Geir, Eide, Per Kristian, Rognes, Marie E., Mardal, Kent-Andre·2023·Fluids and Barriers of the CNS
DOI 10.1186/s12987-023-00459-8PMC PMC10439559

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Abstract

Whether you are reading, running or sleeping, your brain and its fluid environment continuously interacts to distribute nutrients and clear metabolic waste. Yet, the precise mechanisms for solute transport within the human brain have remained hard to quantify using imaging techniques alone. From multi-modal human brain MRI data sets in sleeping and sleep-deprived subjects, we identify and quantify CSF tracer transport parameters using forward and inverse subject-specific computational modelling. Our findings support the notion that extracellular diffusion alone is not sufficient as a brain-wide tracer transport mechanism. Instead, we show that human MRI observations align well with transport by either by an effective diffusion coefficent 3.5 $$\times $$ × that of extracellular diffusion in combination with local clearance rates corresponding to a tracer half-life of up to 5 h, or by extracellular diffusion augmented by advection with brain-wide average flow speeds on the order of 1–9 $$\mu $$ μ m/min. Reduced advection fully explains reduced tracer clearance after sleep-deprivation, supporting the role of sleep and sleep deprivation on human brain clearance.

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  • Almost all experiments that have been interpreted as showing that sleep or anesthesia change brain clearance have involved introducing markers into the CSF, which then move into the brain parenchyma, confounding quantification of clearance.

    “Indeed, almost all the experiments that have been interpreted as showing that sleep or anesthesia change brain clearance have involved introducing markers into the CSF, which then move into the brain parenchyma14,26–30. Under these circumstances, entry, exit and redistribution of the marker are all occurring simultaneously, greatly confounding any quantification of clearance.”

    From Brain clearance is reduced during sleep and anesthesia (2024) · cites this paper as [29]

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  1. [1]Tarasoff-Conway JM Clearance systems in the brain-implications for Alzheimer disease Nat Rev Neurol 2015 11 457 470 10.1038/nrneurol.2015.119 26195256 PMC4694579 · DOI · Paper page
  2. [2]Matsumae M Research into the physiology of cerebrospinal fluid reaches a new horizon: intimate exchange between cerebrospinal fluid and interstitial fluid may contribute to maintenance of homeostasis in the central nervous system Neurol Med-Chir 2016 56 416 441 10.2176/nmc.ra.2016-0020 PMC4945600 27245177 · DOI
  3. [3]Louveau A Understanding the functions and relationships of the glymphatic system and meningeal lymphatics J Clin invest 2017 127 3210 3219 10.1172/JCI90603 28862640 PMC5669566 · DOI · Paper page
  4. [4]Nicholson C Diffusion and related transport mechanisms in brain tissue Rep Progress Phys 2001 64 815 10.1088/0034-4885/64/7/202 · DOI
  5. [5]Smith AJ Verkman AS Going against the flow: Interstitial solute transport in brain is diffusive and aquaporin-4 independent J Physiol 2019 597 4421 10.1113/JP277636 31389038 PMC6717017 · DOI
  6. [6]Cserr HF Ostrach L Bulk flow of interstitial fluid after intracranial injection of blue dextran 2000 Exp Neurol 1974 45 50 60 10.1016/0014-4886(74)90099-5 4137563 · DOI
  7. [7]Rennels ML Gregory TF Blaumanis OR Fujimoto K Grady PA Evidence for a ‘paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space Brain Res 1985 326 47 63 10.1016/0006-8993(85)91383-6 3971148 · DOI · Paper page
  8. [9]Harrison IF Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model Brain 2020 143 2576 2593 10.1093/brain/awaa179 32705145 PMC7447521 · DOI
  9. [11]Gaberel T Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis? Stroke 2014 45 3092 3096 10.1161/STROKEAHA.114.006617 25190438 · DOI
  10. [12]Thrane AS Thrane VR Nedergaard M Drowning stars: reassessing the role of astrocytes in brain edema Trends Neurosci 2014 37 620 628 10.1016/j.tins.2014.08.010 25236348 PMC4253572 · DOI
  11. [13]Mehta AI Linninger A Lesniak MS Engelhard HH Current status of intratumoral therapy for glioblastoma J Neuro-oncol 2015 125 1 7 10.1007/s11060-015-1875-1 26233248 · DOI
  12. [14]Lohela TJ Lilius TO Nedergaard M The glymphatic system: implications for drugs for central nervous system diseases Nat Rev Drug Discov 2022 21 763 779 10.1038/s41573-022-00500-9 35948785 · DOI · Paper page
  13. [16]Ma Q Rapid lymphatic efflux limits cerebrospinal fluid flow to the brain Acta Neuropathol 2019 137 151 165 10.1007/s00401-018-1916-x 30306266 PMC6338719 · DOI · Paper page
  14. [17]Eide PK Vinje V Pripp AH Mardal K-A Ringstad G Sleep deprivation impairs molecular clearance from the human brain Brain 2021 144 863 874 10.1093/brain/awaa443 33829232 · DOI · Paper page
  15. [18]Wardlaw JM Perivascular spaces in the brain: anatomy, physiology and pathology Nat Rev Neurol 2020 16 137 153 10.1038/s41582-020-0312-z 32094487 · DOI · Paper page
  16. [19]Hladky SB Barrand MA The glymphatic hypothesis: the theory and the evidence Fluids Barriers CNS 2022 19 1 33 10.1186/s12987-021-00282-z 35115036 PMC8815211 · DOI
  17. [20]Rasmussen MK Mestre H Nedergaard M Fluid transport in the brain Physiol Rev 2022 102 1025 1151 10.1152/physrev.00031.2020 33949874 PMC8897154 · DOI
  18. [21]Bohr T The glymphatic system: current understanding and modeling iScience 2022 25 104987 10.1016/j.isci.2022.104987 36093063 PMC9460186 · DOI
  19. [24]Holter KE Kehlet B Devor A Sejnowski TJ Dale AM Omholt SW Ottersen OP Nagelhus EA Mardal K-A Pettersen KH Interstitial solute transport in 3D reconstructed neuropil occurs by diffusion rather than bulk flow Proc Natl Acad Sci 2017 114 37 9894 9899 10.1073/pnas.1706942114 28847942 PMC5604020 · DOI · Paper page
  20. [25]Wentland AL Wieben O Korosec FR Haughton VM Accuracy and reproducibility of phase-contrast MR imaging measurements for CSF flow Am J Neuroradiol 2010 31 1331 1336 10.3174/ajnr.A2039 20203113 PMC3818526 · DOI
  21. [26]Mestre H Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension Nat Commun 2018 9 1 9 10.1038/s41467-018-07318-3 30451853 PMC6242982 · DOI · Paper page
  22. [28]Ray LA Pike M Simon M Iliff JJ Heys JJ Quantitative analysis of macroscopic solute transport in the murine brain Fluids Barriers CNS 2021 18 1 19 10.1186/s12987-021-00290-z 34876169 PMC8650464 · DOI
  23. [29]Ringstad G Non-invasive assessment of pulsatile intracranial pressure with phase-contrast magnetic resonance imaging PLoS ONE 2017 12 e0188896 10.1371/journal.pone.0188896 29190788 PMC5708728 · DOI
  24. [30]Watts R Steinklein J Waldman L Zhou X Filippi C Measuring glymphatic flow in man using quantitative contrast-enhanced MRI Am J Neuroradiol 2019 40 648 651 30679221 PMC7048502
  25. [31]Eide PK Valnes LM Lindstrøm EK Mardal K-A Ringstad G Direction and magnitude of cerebrospinal fluid flow vary substantially across central nervous system diseases Fluids Barriers CNS 2021 18 1 18 10.1186/s12987-021-00251-6 33794929 PMC8017867 · DOI
  26. [32]Eide PK Altered glymphatic enhancement of cerebrospinal fluid tracer in individuals with chronic poor sleep quality J Cereb Blood Flow Metab 2022 10.1177/0271678X221090747 35350917 PMC9441729 · DOI
  27. [33]Croci M Vinje V Rognes ME Uncertainty quantification of parenchymal tracer distribution using random diffusion and convective velocity fields Fluids Barriers CNS 2019 16 1 21 10.1186/s12987-019-0152-7 31564250 PMC6767654 · DOI
  28. [34]Valnes LM Apparent diffusion coefficient estimates based on 24 hours tracer movement support glymphatic transport in human cerebral cortex Sci Rep 2020 10 1 12 10.1038/s41598-020-66042-5 32514105 PMC7280526 · DOI
  29. [35]Kinney JP Extracellular sheets and tunnels modulate glutamate diffusion in hippocampal neuropil J Comp Neurol 2013 521 448 464 10.1002/cne.23181 22740128 PMC3540825 · DOI
  30. [36]Daversin-Catty C Vinje V Mardal K-A Rognes ME The mechanisms behind perivascular fluid flow Plos one 2020 15 12 e0244442 10.1101/2020.06.17.157917 33373419 PMC7771676 · DOI
  31. [37]Sharp MK Carare RO Martin BA Dispersion in porous media in oscillatory flow between flat plates: applications to intrathecal, periarterial and paraarterial solute transport in the central nervous system Fluids Barriers CNS 2019 16 13 10.1186/s12987-019-0132-y 31056079 PMC6512764 · DOI
  32. [38]Kedarasetti RT Drew PJ Costanzo F Arterial pulsations drive oscillatory flow of CSF but not directional pumping Sci Rep 2020 10 1 12 10.1038/s41598-020-66887-w 32572120 PMC7308311 · DOI
  33. [39]Kedarasetti RT Functional hyperemia drives fluid exchange in the paravascular space Fluids Barriers CNS 2020 17 1 25 10.1186/s12987-020-00214-3 32819402 PMC7441569 · DOI
  34. [40]Thomas JH Fluid dynamics of cerebrospinal fluid flow in perivascular spaces J R Soc Interface 2019 16 20190572 10.1098/rsif.2019.0572 31640500 PMC6833335 · DOI · Paper page
  35. [41]Tithof J Kelley DH Mestre H Nedergaard M Thomas JH Hydraulic resistance of periarterial spaces in the brain Fluids Barriers CNS 2019 16 19 10.1186/s12987-019-0140-y 31217012 PMC6585017 · DOI
  36. [42]Troyetsky DE Tithof J Thomas JH Kelley DH Dispersion as a waste-clearance mechanism in flow through penetrating perivascular spaces in the brain Sci Rep 2021 11 1 12 33633194 PMC7907360
  37. [43]Ratner V Cerebrospinal and interstitial fluid transport via the glymphatic pathway modeled by optimal mass transport Neuroimage 2017 152 530 537 10.1016/j.neuroimage.2017.03.021 28323163 PMC5490081 · DOI
  38. [44]Koundal S Optimal mass transport with Lagrangian workflow reveals advective and diffusion driven solute transport in the glymphatic system Sci Rep 2020 10 1 18 32029859 PMC7004986
  39. [45]Benveniste H Glymphatic cerebrospinal fluid and solute transport quantified by MRI and pet imaging Neuroscience 2021 474 63 79 10.1016/j.neuroscience.2020.11.014 33248153 PMC8149482 · DOI
  40. [46]Nicholson C Diffusion and related transport mechanisms in brain tissue Rep Progress Phys 2001 64 815 10.1088/0034-4885/64/7/202 · DOI
  41. [47]Hovd MH Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders Fluids Barriers CNS 2022 19 1 14 10.1186/s12987-022-00352-w 35778719 PMC9250213 · DOI
  42. [48]Bedussi B Almasian M de Vos J VanBavel E Bakker EN Paravascular spaces at the brain surface: Low resistance pathways for cerebrospinal fluid flow J Cereb Blood Flow Metab 2018 38 719 726 10.1177/0271678X17737984 29039724 PMC5888857 · DOI · Paper page
  43. [49]Hinze M Pinnau R Ulbrich M Ulbrich S Optimization with PDE constraints 2008 Berlin Springer Science & Business Media
  44. [51]Edsbagge M Tisell M Jacobsson L Wikkelso C Spinal CSF absorption in healthy individuals Am J Physiol-Regul Integr Comp Physiol 2004 287 R1450 R1455 10.1152/ajpregu.00215.2004 15308484 · DOI
  45. [52]Marmarou A Shulman K Lamorgese J Compartmental analysis of compliance and outflow resistance of the cerebrospinal fluid system J Neurosurg 1975 43 523 534 10.3171/jns.1975.43.5.0523 1181384 · DOI
  46. [53]Bozanovic-Sosic R Mollanji R Johnston M Spinal and cranial contributions to total cerebrospinal fluid transport Am J Physiol-Regul Integr Comp Physiol 2001 281 R909 R916 10.1152/ajpregu.2001.281.3.R909 11507008 · DOI
  47. [54]Proulx ST Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics Cell Mol Life Sci 2021 78 2429 2457 10.1007/s00018-020-03706-5 33427948 PMC8004496 · DOI
  48. [55]Lee H Quantitative Gd-DOTA uptake from cerebrospinal fluid into rat brain using 3D VFA-SPGR at 9.4T Magn Reson Med 2018 79 1568 1578 10.1002/mrm.26779 28627037 PMC5736474 · DOI · Paper page
  49. [57]Hornkjøl M Valnes LM Ringstad G Rognes ME Eide P-K Mardal K-A Vinje V CSF circulation and dispersion yield rapid clearance from intracranial compartments Front Bioeng Biotechnol 2022 10 932469 10.1101/2022.05.02.490257 36172015 PMC9510842 · DOI
  50. [58]Chagnot A Barnes SR Montagne A Magnetic resonance imaging of blood–brain barrier permeability in dementia Neuroscience 2021 474 14 29 10.1016/j.neuroscience.2021.08.003 34400249 PMC8528227 · DOI
  51. [59]Cserr H Cooper D Suri P Patlak C Efflux of radiolabeled polyethylene glycols and albumin from rat brain Am J Physiol-Renal Physiol 1981 240 F319 F328 10.1152/ajprenal.1981.240.4.F319 7223889 · DOI · Paper page
  52. [60]Bradbury M Cserr H Westrop R Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit Am J Physiol-Renal Physiol 1981 240 F329 F336 10.1152/ajprenal.1981.240.4.F329 7223890 · DOI · Paper page
  53. [61]Szentistvanyi I Patlak CS Ellis RA Cserr HF Drainage of interstitial fluid from different regions of rat brain Am J Physiol-Renal Physiol 1984 246 F835 F844 10.1152/ajprenal.1984.246.6.F835 6742132 · DOI
  54. [63]Ray L Iliff JJ Heys JJ Analysis of convective and diffusive transport in the brain interstitium Fluids Barriers CNS 2019 16 1 18 10.1186/s12987-019-0126-9 30836968 PMC6402182 · DOI
  55. [64]Bulat M Klarica M Recent insights into a new hydrodynamics of the cerebrospinal fluid Brain Res Rev 2011 65 99 112 10.1016/j.brainresrev.2010.08.002 20817024 · DOI
  56. [65]Sakka L Coll G Chazal J Anatomy and physiology of cerebrospinal fluid Eur Ann Otorhinolaryngol Head Neck Dis 2011 128 309 316 10.1016/j.anorl.2011.03.002 22100360 · DOI
  57. [66]Cserr HF Kovàch AGB Hamar J Szabó L Convection of brain interstitial fluid Cardiovascular physiology microcirculation and capillary exchange 1981 Amsterdam Elsevier 337 341
  58. [67]Myung J The choroid plexus is an important circadian clock component Nat Commun 2018 9 1 13 10.1038/s41467-018-03507-2 29540683 PMC5852131 · DOI
  59. [70]Lee H The effect of body posture on brain glymphatic transport J Neurosci 2015 35 11034 11044 10.1523/JNEUROSCI.1625-15.2015 26245965 PMC4524974 · DOI · Paper page
  60. [71]Fultz NE Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep Science 2019 366 628 631 10.1126/science.aax5440 31672896 PMC7309589 · DOI · Paper page
  61. [72]Elvsåshagen T Widespread changes in white matter microstructure after a day of waking and sleep deprivation PLoS ONE 2015 10 e0127351 10.1371/journal.pone.0127351 26020651 PMC4447359 · DOI
  62. [73]Nilsson C Stahlberg F Gideon P Thomsen C Henriksen O The nocturnal increase in human cerebrospinal fluid production is inhibited by a beta 1-receptor antagonist Am J Physiol-Regul Integr Comp Physiol 1994 267 R1445 R1448 10.1152/ajpregu.1994.267.6.R1445 7810751 · DOI
  63. [74]Glowinski R Song Y Yuan X Yue H Bilinear optimal control of an advection-reaction-diffusion system SIAM Rev 2022 64 392 421 10.1137/21M1389778 · DOI
  64. [75]Poulain A Riseth J Vinje V Multi-compartmental model of glymphatic clearance of solutes in brain tissue PLoS ONE 2023 18 e0280501 10.1371/journal.pone.0280501 36881576 PMC9990927 · DOI
  65. [76]Shipley RJ Sweeney PW Chapman SJ Roose T A four-compartment multiscale model of fluid and drug distribution in vascular tumours Int J Numer Methods Biomed Eng 2020 36 e3315 10.1002/cnm.3315 PMC7187161 32031302 · DOI
  66. [77]Eide PK Hansson H-A Blood–brain barrier leakage of blood proteins in idiopathic normal pressure hydrocephalus Brain Res 2020 1727 146547 10.1016/j.brainres.2019.146547 31712085 · DOI
  67. [78]Van De Haar HJ Blood–brain barrier leakage in patients with early Alzheimer disease Radiology 2016 281 527 535 10.1148/radiol.2016152244 27243267 · DOI · Paper page
  68. [79]Dembitskaya Y Shadow imaging for panoptical visualization of brain tissue in vivo Res Gate 2022 10.21203/rs.3.rs-2198041/v1 PMC10570379 37828018 · DOI
  69. [80]Fischl B Freesurfer Neuroimage 2012 62 774 781 10.1016/j.neuroimage.2012.01.021 22248573 PMC3685476 · DOI · Paper page
  70. [81]Mardal K-A Rognes ME Thompson TB Valnes LM Mathematical modeling of the human brain: from magnetic resonance images to finite element simulation 2022 Berlin Springer
  71. [82]Vinje V, et al. Example meshes for ‘Human brain solute transport quantified by glymphatic MRI-informed biophysics during sleep and sleep deprivation’, version 1, dated July 14, 2023. 10.5281/zenodo.8036492. PMC10439559 37596635 · DOI
  72. [84]Alnæs M The FEniCS project version 1.5 Arch Numer Softw 2015 10.11588/ans.2015.100.20553 · DOI
  73. [87]Liu DC Nocedal J On the limited memory BFGS method for large scale optimization Math Progr 1989 45 503 528 10.1007/BF01589116 · DOI
  74. [88]Farrell PE Ham DA Funke SW Rognes ME Automated derivation of the adjoint of high-level transient finite element programs SIAM J Sci Comput 2013 35 C369 C393 10.1137/120873558 · DOI
  75. [89]Virtanen P Scipy 1.0: fundamental algorithms for scientific computing in python Nat Methods 2020 17 261 272 10.1038/s41592-019-0686-2 32015543 PMC7056644 · DOI · Paper page

Cited by

Sorted by citations

Authors
Vinje, V., Zapf, B., Ringstad, G., Eide, P. K., Rognes, M. E., & Mardal, K.-A.
Venue
Fluids and Barriers of the CNS
Publisher
Springer Science and Business Media LLC
Published
2023-08-18
Volume
20
Issue
1
ISSN
2045-8118
DOI
10.1186/s12987-023-00459-8
PMC
PMC10439559
Cited by
81
References
10
Language
en
Licence
Funders
  • Research Council of Norway (301013, 324239)
  • national infrastructure for computational science in Norway, Sigma2 (NN9279K)
  • European Research Council (714892)
  • University of Oslo

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