{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:39:24Z","timestamp":1760146764679,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T00:00:00Z","timestamp":1733875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background\/objectives: Cerebrospinal infusion studies indicate that cerebrospinal fluid outflow resistance (Rout) is elevated in normal pressure hydrocephalus (NPH). These studies assume that the cerebrospinal formation rate (CSFfr) does not vary during the infusion. If the CSFfr were to increase during the infusion then the Rout would be overestimated. Previous estimates of the CSFfr in NPH have suggested a low figure. More recent estimates of the CSFfr suggest that it is increased, indicating it probably varies with measurement technique. This would bring the estimation of Rout into doubt. A previous paper using a lumped parameter model suggested the CSFfr could vary with the capillary transmural pressure (TMP) in this disease, suggesting a possible solution to this problem. The current study investigates the possibility that the intracranial pressure manipulation occurring during an infusion study may vary the capillary TMP and CSFfr. Methods: A lumped parameter model previously developed to describe the hydrodynamics of NPH was modified to investigate the effect of CSF pressure manipulation during infusion studies and to describe how the CSFfr could vary depending on the technique used. Results: The model indicates the capillary transmural pressure is normal in NPH and increases during an infusion study. CSF drainage at the end of an infusion study similarly increases the capillary TMP and, presumably, the CSFfr by increasing the interstitial fluid production. Conclusions: The model suggests that infusion studies and draining CSF increases the CSFfr in NPH compared to earlier techniques. Allowing for an increase in the CSFfr suggests that infusion overestimates the Rout by between 23 and 33%. This study indicates that further research may be required into the utility and accuracy of infusion studies and their ability to diagnose NPH.<\/jats:p>","DOI":"10.3390\/brainsci14121242","type":"journal-article","created":{"date-parts":[[2024,12,11]],"date-time":"2024-12-11T12:38:56Z","timestamp":1733920736000},"page":"1242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Lumped Parameter Model Suggests That Infusion Studies Overestimate the Cerebrospinal Fluid Outflow Resistance in Normal Pressure Hydrocephalus"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3095-9047","authenticated-orcid":false,"given":"Grant A.","family":"Bateman","sequence":"first","affiliation":[{"name":"Department of Medical Imaging, John Hunter Hospital, Newcastle, NSW 2310, Australia"},{"name":"Faculty of Health, Newcastle University, Callaghan Campus, Newcastle, NSW 2308, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6090-5344","authenticated-orcid":false,"given":"Alexander R.","family":"Bateman","sequence":"additional","affiliation":[{"name":"School of Mechanical Engineering, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1056\/NEJM196507152730301","article-title":"Symptomatic Occult Hydrocephalus with \u201cNormal\u201d Cerebrospinal-Fluid Pressure. A Treatable Syndrome","volume":"273","author":"Adams","year":"1965","journal-title":"N. Engl. J. Med."},{"key":"ref_2","unstructured":"Davson, H., Welch, K., and Segal, M.B. (1987). Physiology and Pathophysiology of the Cerebrospinal Fluid, Churchill Livingstone."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"102837","DOI":"10.1016\/j.bas.2024.102837","article-title":"Embracing uncertainty in cerebrospinal fluid dynamics: A Bayesian approach to analysing infusion studies","volume":"4","author":"Chabros","year":"2024","journal-title":"Brain Spine"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.wneu.2024.05.131","article-title":"Assessment of CSF Dynamics Using Infusion Study: Tips and Tricks","volume":"189","author":"Jannelli","year":"2024","journal-title":"World Neurosurg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.3171\/jns.2002.97.6.1271","article-title":"Downregulation of cerebrospinal fluid production in patients with chronic hydrocephalus","volume":"97","author":"Silverberg","year":"2002","journal-title":"J. Neurosurg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1001\/archneurpsyc.1934.02250090060006","article-title":"Cerebrospinal Hydrodynamics: IV. Clinical Experimental Studies","volume":"32","author":"Masserman","year":"1934","journal-title":"Arch. Neurol. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12987-024-00560-6","article-title":"CSF formation rate-a potential glymphatic flow parameter in hydrocephalus?","volume":"21","author":"Qvarlander","year":"2024","journal-title":"Fluids Barriers CNS"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.1007\/s00701-023-05650-2","article-title":"Cerebrospinal fluid production rate in various pathological conditions: A preliminary study","volume":"165","author":"Tariq","year":"2023","journal-title":"Acta Neurochir."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fleischman, D., Berdahl, J.P., Zaydlarova, J., Stinnett, S., Fautsch, M.P., and Allingham, R.R. (2012). Cerebrospinal fluid pressure decreases with older age. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052664"},{"key":"ref_10","first-page":"623","article-title":"Cerebral venous pressure, sinus pressure and intracranial pressure","volume":"20","author":"Benabid","year":"1974","journal-title":"Neurochirurgie"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/2045-8118-11-11","article-title":"Cerebrospinal fluid absorption block at the vertex in chronic hydrocephalus: Obstructed arachnoid granulations or elevated venous pressure?","volume":"11","author":"Bateman","year":"2014","journal-title":"Fluids Barriers CNS"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3171\/jns.2001.94.3.0482","article-title":"Age dependence of cerebrospinal pressure-volume compensation in patients with hydrocephalus","volume":"94","author":"Czosnyka","year":"2001","journal-title":"J. Neurosurg."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"687","DOI":"10.3171\/jns.1997.87.5.0687","article-title":"Dutch normal-pressure hydrocephalus study: Prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid","volume":"87","author":"Boon","year":"1997","journal-title":"J. Neurosurg."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bateman, G.A., and Bateman, A.R. (2024). A lumped parameter modelling study of cerebral autoregulation in normal pressure hydrocephalus suggests the brain chooses to be ischemic. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-75214-6"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zislin, V., and Rosenfeld, M. (2018). Impedance Pumping and Resonance in a Multi-Vessel System. Bioengineering, 5.","DOI":"10.3390\/bioengineering5030063"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1038\/jcbfm.2011.93","article-title":"Heterogeneity in the penumbra","volume":"31","author":"Sharp","year":"2011","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/BF02364625","article-title":"A mathematical study of human intracranial hydrodynamics. Part 1\u2014The cerebrospinal fluid pulse pressure","volume":"16","author":"Ursino","year":"1988","journal-title":"Ann. Biomed. Eng."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1136\/jnnp.34.6.687","article-title":"Effect of intracranial hypotension on cerebral blood flow","volume":"34","author":"Salmon","year":"1971","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1007\/BF02345321","article-title":"Mathematical study of the role of non-linear venous compliance in the cranial volume-pressure test","volume":"41","author":"Cirovic","year":"2003","journal-title":"Med. Biol. Eng. Comput."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1136\/jnnp.37.4.392","article-title":"Raised intracranial pressure and cerebral blood flow. 3. Venous outflow tract pressures and vascular resistances in experimental intracranial hypertension","volume":"37","author":"Johnston","year":"1974","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.neuroimage.2018.02.027","article-title":"MRI techniques to measure arterial and venous cerebral blood volume","volume":"187","author":"Hua","year":"2019","journal-title":"Neuroimage"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Men\u00e9ndez Gonz\u00e1lez, M. (2023). CNS Compartments: The Anatomy and Physiology of the Cerebrospinal Fluid. Liquorpheresis: Cerebrospinal Fluid Filtration to Treat CNS Conditions, Springer Nature.","DOI":"10.1007\/978-3-031-43482-2"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3171\/jns.1998.89.2.0275","article-title":"Age dependency of resistance to cerebrospinal fluid outflow","volume":"89","author":"Albeck","year":"1998","journal-title":"J. Neurosurg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1136\/jnnp.41.4.345","article-title":"CSF hydrodynamic studies in man. 2. Normal hydrodynamic variables related to CSF pressure and flow","volume":"41","author":"Ekstedt","year":"1978","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1152\/physrev.00022.2020","article-title":"Regulation of cerebral blood flow in humans: Physiology and clinical implications of autoregulation","volume":"101","author":"Claassen","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1038\/jcbfm.1993.129","article-title":"Changes in brain capillary diameter during hypocapnia and hypercapnia","volume":"13","author":"Duelli","year":"1993","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_27","first-page":"76","article-title":"Starling resistors, autoregulation of cerebral perfusion and the pathogenesis of idiopathic intracranial hypertension","volume":"59","author":"Ranieri","year":"2017","journal-title":"Panminerva Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1093\/brain\/awh131","article-title":"Pattern of white matter regional cerebral blood flow and autoregulation in normal pressure hydrocephalus","volume":"127","author":"Momjian","year":"2004","journal-title":"Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1034\/j.1600-0404.2001.00092.x","article-title":"Normal pressure hydrocephalus and cerebral blood flow: A review","volume":"104","author":"Owler","year":"2001","journal-title":"Acta Neurol. Scand."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s12987-017-0072-3","article-title":"The role of perfusion and diffusion MRI in the assessment of patients affected by probable idiopathic normal pressure hydrocephalus. A cohort-prospective preliminary study","volume":"14","author":"Tuniz","year":"2017","journal-title":"Fluids Barriers CNS"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.3171\/2010.8.JNS10157","article-title":"Comparison between 3 infusion methods to measure cerebrospinal fluid outflow conductance","volume":"113","author":"Sundstrom","year":"2010","journal-title":"J. Neurosurg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.3174\/ajnr.A5642","article-title":"CSF Pressure Change in Relation to Opening Pressure and CSF Volume Removed","volume":"39","author":"Griffith","year":"2018","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1001\/archneur.1978.00500320047010","article-title":"Modulation of CSF production by alterations in cerebral perfusion pressure","volume":"35","author":"Weiss","year":"1978","journal-title":"Arch. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1152\/physrev.1971.51.2.273","article-title":"Physiology of the choroid plexus","volume":"51","author":"Cserr","year":"1971","journal-title":"Physiol. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.neuroscience.2004.07.033","article-title":"Water homeostasis in the brain: Basic concepts","volume":"129","author":"Kimelberg","year":"2004","journal-title":"Neuroscience"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s10877-006-9047-7","article-title":"Comparison of intracranial pressure measured simultaneously within the brain parenchyma and cerebral ventricles","volume":"20","author":"Brean","year":"2006","journal-title":"J. Clin. Monit. Comput."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1227\/01.NEU.0000156609.95596.24","article-title":"Clinical experience with the intraparenchymal intracranial pressure monitoring Codman MicroSensor system","volume":"56","author":"Koskinen","year":"2005","journal-title":"Neurosurgery"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Xiang, J., Hua, Y., Xi, G., and Keep, R.F. (2023). Mechanisms of cerebrospinal fluid and brain interstitial fluid production. Neurobiol. Dis., 183.","DOI":"10.1016\/j.nbd.2023.106159"},{"key":"ref_39","first-page":"159","article-title":"Submicroscopic pathology of human and experimental hydrocephalic cerebral cortex","volume":"48","author":"Castejon","year":"2010","journal-title":"Folia Neuropathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"146547","DOI":"10.1016\/j.brainres.2019.146547","article-title":"Blood-brain barrier leakage of blood proteins in idiopathic normal pressure hydrocephalus","volume":"1727","author":"Eide","year":"2020","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Schmidt, M.J., Kolecka, M., Kirberger, R., and Hartmann, A. (2017). Dynamic Susceptibility Contrast Perfusion Magnetic Resonance Imaging Demonstrates Reduced Periventricular Cerebral Blood Flow in Dogs with Ventriculomegaly. Front. Vet. Sci., 4.","DOI":"10.3389\/fvets.2017.00137"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1006\/nimg.2001.0857","article-title":"Cerebral asymmetry and the effects of sex and handedness on brain structure: A voxel-based morphometric analysis of 465 normal adult human brains","volume":"14","author":"Good","year":"2001","journal-title":"Neuroimage"},{"key":"ref_43","first-page":"H847","article-title":"Sex differences in gray matter, white matter, and regional brain perfusion in young, healthy adults","volume":"327","author":"Muer","year":"2024","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"398","DOI":"10.3171\/2017.9.JNS171100","article-title":"Usefulness of the convexity apparent hyperperfusion sign in 123I-iodoamphetamine brain perfusion SPECT for the diagnosis of idiopathic normal pressure hydrocephalus","volume":"130","author":"Ohmichi","year":"2019","journal-title":"J. Neurosurg."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.nicl.2018.09.006","article-title":"Cerebrospinal fluid volumetric net flow rate and direction in idiopathic normal pressure hydrocephalus","volume":"20","author":"Lindstrom","year":"2018","journal-title":"Neuroimage Clin."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Rau, A., Reisert, M., Kellner, E., Hosp, J.A., Urbach, H., and Demerath, T. (2021). Increased interstitial fluid in periventricular and deep white matter hyperintensities in patients with suspected idiopathic normal pressure hydrocephalus. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-98054-0"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/01616412.2000.11741045","article-title":"Magnetic resonance imaging study of extracellular fluid tracer movement in brains of immature rats with hydrocephalus","volume":"22","author":"Shoesmith","year":"2000","journal-title":"Neurol. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1126\/science.1240514","article-title":"Neuroscience. Garbage truck of the brain","volume":"340","author":"Nedergaard","year":"2013","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"fcaa187","DOI":"10.1093\/braincomms\/fcaa187","article-title":"Magnetic resonance imaging biomarkers of cerebrospinal fluid tracer dynamics in idiopathic normal pressure hydrocephalus","volume":"2","author":"Eide","year":"2020","journal-title":"Brain Commun."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Bateman, G.A., and Bateman, A.R. (2023). Syringomyelia Is Associated with a Reduction in Spinal Canal Compliance, Venous Outflow Dilatation and Glymphatic Fluid Obstruction. J. Clin. Med., 12.","DOI":"10.3390\/jcm12206646"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"105136","DOI":"10.1016\/j.msard.2023.105136","article-title":"The dilated cortical veins found in multiple sclerosis can explain the reduction in glymphatic flow","volume":"81","author":"Bateman","year":"2024","journal-title":"Mult. Scler. Relat. Disord."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"120517","DOI":"10.1016\/j.neuroimage.2024.120517","article-title":"The dilated veins surrounding the cord in multiple sclerosis suggest elevated pressure and obstruction of the glymphatic system","volume":"286","author":"Bateman","year":"2024","journal-title":"Neuroimage"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Bonney, P.A., Briggs, R.G., Wu, K., Choi, W., Khahera, A., Ojogho, B., Shao, X., Zhao, Z., Borzage, M., and Wang, D.J.J. (2022). Pathophysiological Mechanisms Underlying Idiopathic Normal Pressure Hydrocephalus: A Review of Recent Insights. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.866313"},{"key":"ref_54","unstructured":"Tariq, K., Toma, A., Khawari, S., Amarouche, M., Elborady, M.A., and Thorne, L. (2024, January 13\u201316). Normal cerebrospinal fluid production rate in normal pressure hydrocephalus patients post lumbar infusion test. Proceedings of the Hydrocephalus 2024, Nagoya, Japan."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/978-3-7091-0923-6_11","article-title":"Hydrocephalus and aquaporins: The role of aquaporin-1","volume":"113","author":"Kalani","year":"2012","journal-title":"Acta Neurochir. Suppl."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.bpj.2012.11.3818","article-title":"Human AQP1 is a constitutively open channel that closes by a membrane-tension-mediated mechanism","volume":"104","author":"Ozu","year":"2013","journal-title":"Biophys. J."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/12\/1242\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:52:32Z","timestamp":1760115152000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/12\/1242"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,11]]},"references-count":56,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["brainsci14121242"],"URL":"https:\/\/doi.org\/10.3390\/brainsci14121242","relation":{},"ISSN":["2076-3425"],"issn-type":[{"type":"electronic","value":"2076-3425"}],"subject":[],"published":{"date-parts":[[2024,12,11]]}}}