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However, CNS tissues and barriers compartmentalize the brain, spinal cord, and adjacent spaces, facilitating the transmittal of fluids, metabolic wastes, immune cells, and vital signals, while more conventional lymphatic pathways in the meninges, cervicofacial\u00a0and paraspinal regions transmit efflux fluid and molecules to peripheral lymph and lymph nodes. Thus, a unique and highly organized fluid circulation network encompassing intraparenchymal, subarachnoid, dural, and extradural segments functions in unison to maintain CNS homeostasis. Pathways involved in this system have been under investigation for centuries and continue to be the source of considerable interest and debate. Modern imaging and microscopy technologies have led to important breakthroughs pertaining to various elements of CNS fluid circuitry and exchange over the past decade, thus enhancing knowledge on mechanisms of mammalian CNS maintenance and disease. Yet, to better understand precise anatomical routes, the physiology and clinical significance of these CNS pathways, and potential therapeutic targets in humans, fluid conduits, flow\u2010regulating factors, and tissue effects must be analyzed systematically and in a global manner in persons across age, demographical factors, and disease states. Here, we illustrate the system\u2010wide nature of intermixing CNS fluid networks, summarize historical and clinical studies, and discuss anatomical and physiological similarities and differences that are relevant for translation of evidence from mice to humans. We also review Cushing's classical model of cerebrospinal fluid flow and present a new framework of this \u201cthird circulation\u201d that emphasizes previously unexplained complexities of CNS fluid circulation in humans. Finally, we review future directions in the field, including emerging theranostic techniques and MRI studies required in humans.<\/jats:p>","DOI":"10.1002\/nbm.5149","type":"journal-article","created":{"date-parts":[[2024,4,7]],"date-time":"2024-04-07T21:45:25Z","timestamp":1712526325000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Understanding central nervous system fluid networks: Historical perspectives and a revised model for clinical neurofluid imaging"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4917-6907","authenticated-orcid":false,"given":"Rupal I.","family":"Mehta","sequence":"first","affiliation":[{"name":"Department of Pathology Rush University Medical Center  Chicago Illinois USA"},{"name":"Rush Alzheimer's Disease Center Rush University Medical Center  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2532-7435","authenticated-orcid":false,"given":"Rashi I.","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, Rockefeller Neuroscience Institute West Virginia University  Morgantown West Virginia USA"},{"name":"Department of Neuroscience, Rockefeller Neuroscience Institute West Virginia University  Morgantown West Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,7]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/2045\u20108118\u20108\u20104"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13469"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3265"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1517\/17425247.2016.1171315"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/394447"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14432"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20142290"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003748"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11064\u2010015\u20101581\u20106"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018\u2010020\u201003706\u20105"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010019\u20100417\u20103"},{"key":"e_1_2_13_13_1","unstructured":"The Edwin Smith Surgical Papyrus: Published in Facsimile and Hieroglyphic Transliteration with Translation and Commentary in Two Volumes. University of Chicago Oriental Institute.1930. ISBN 978\u20100\u2010918986\u201073\u20103 fulltext of translation with original hieroglyphics (printed) and commentary.https:\/\/isac.uchicago.edu\/research\/publications\/oip\/edwin-smith-surgical-papyrus-volume-1-hieroglyphic-transliteration"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11999\u2010014\u20103909\u2010y"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.17077\/0006-7474.1451"},{"key":"e_1_2_13_16_1","unstructured":"MascagniP.Vasorum lymphaticorum Corporis Humani Historia et Ichnographia auctore Paulo Mascagni in Regio Senarum Lyceo Publico Anatomes Professore. 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