The roles of cerebral blood flow, capillary transit time heterogeneity, and oxygen tension in brain oxygenation and metabolism
Sune N Jespersen, Leif Østergaard, Sune N Jespersen, Leif Østergaard
Abstract
Normal brain function depends critically on moment-to-moment regulation of oxygen supply by the bloodstream to meet changing metabolic needs. Neurovascular coupling, a range of mechanisms that converge on arterioles to adjust local cerebral blood flow (CBF), represents our current framework for understanding this regulation. We modeled the combined effects of CBF and capillary transit time heterogeneity (CTTH) on the maximum oxygen extraction fraction (OEF(max)) and metabolic rate of oxygen that can biophysically be supported, for a given tissue oxygen tension. Red blood cell velocity recordings in rat brain support close hemodynamic-metabolic coupling by means of CBF and CTTH across a range of physiological conditions. The CTTH reduction improves tissue oxygenation by counteracting inherent reductions in OEF(max) as CBF increases, and seemingly secures sufficient oxygenation during episodes of hyperemia resulting from cortical activation or hypoxemia. In hypoperfusion and states of blocked CBF, both lower oxygen tension and CTTH may secure tissue oxygenation. Our model predicts that disturbed capillary flows may cause a condition of malignant CTTH, in which states of higher CBF display lower oxygen availability. We propose that conditions with altered capillary morphology, such as amyloid, diabetic or hypertensive microangiopathy, and ischemia-reperfusion, may disturb CTTH and thereby flow-metabolism coupling and cerebral oxygen metabolism.
Figures
References
- Abounader R, Vogel J, Kuschinsky W. Patterns of capillary plasma perfusion in brains in conscious rats during normocapnia and hypercapnia. Circ Res. 1995;76:120–126.
- Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA. Glial and neuronal control of brain blood flow. Nature. 2010;468:232–243.
- Buxton RB. Interpreting oxygenation-based neuroimaging signals: the importance and the challenge of understanding brain oxygen metabolism. Front Neuroenergetics. 2010;2:8.
- Buxton RB, Frank LR. A model for the coupling between cerebral blood flow and oxygen metabolism during neural stimulation. J Cereb Blood Flow Metab. 1997;17:64–72.
- Buxton RB, Wong EC, Frank LR. Dynamics of blood flow and oxygenation changes during brain activation: the balloon model. Magn Reson Med. 1998;39:855–864.
- Cousineau D, Rose CP, Lamoureux D, Goresky CA. Changes in cardiac transcapillary exchange with metabolic coronary vasodilation in the intact dog. Circ Res. 1983;53:719–730.
- Crone C. The permeability of capillaries in various organs as determined by use of the ‘indicator diffusion' method. Acta Physiol Scand. 1963;58:292–305.
- Dash RK, Bassingthwaighte JB. Simultaneous blood-tissue exchange of oxygen, carbon dioxide, bicarbonate, and hydrogen ion. Ann Biomed Eng. 2006;34:1129–1148.
- Davis TL, Kwong KK, Weisskoff RM, Rosen BR. Calibrated functional MRI: mapping the dynamics of oxidative metabolism. Proc Natl Acad Sci USA. 1998;95:1834–1839.
- Derdeyn CP, Videen TO, Yundt KD, Fritsch SM, Carpenter DA, Grubb RL, Powers WJ. Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited. Brain. 2002;125:595–607.
- Donahue MJ, Stevens RD, de Boorder M, Pekar JJ, Hendrikse J, van Zijl PC. Hemodynamic changes after visual stimulation and breath holding provide evidence for an uncoupling of cerebral blood flow and volume from oxygen metabolism. J Cereb Blood Flow Metab. 2009;29:176–185.
- Dore-Duffy P, LaManna JC. Physiologic angiodynamics in the brain. Antioxid Redox Signal. 2007;9:1363–1371.
- Fernandez-Klett F, Offenhauser N, Dirnagl U, Priller J, Lindauer U. Pericytes in capillaries are contractile in vivo, but arterioles mediate functional hyperemia in the mouse brain. Proc Natl Acad Sci USA. 2010;107:22290–22295.
- Fox PT, Raichle ME. Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proc Natl Acad Sci USA. 1986;83:1140–1144.
- Girouard H, Iadecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol. 2006;100:328–335.
- Grubb RL, Jr, Raichle ME, Eichling JO, Ter-Pogossian MM. The effects of changes in PaCO2 on cerebral blood volume, blood flow, and vascular mean transit time. Stroke. 1974;5:630–639.
- Hayashi T, Watabe H, Kudomi N, Kim KM, Enmi J, Hayashida K, Iida H. A theoretical model of oxygen delivery and metabolism for physiologic interpretation of quantitative cerebral blood flow and metabolic rate of oxygen. J Cereb Blood Flow Metab. 2003;23:1314–1323.
- Hudetz AG, Biswal BB, Feher G, Kampine JP. Effects of hypoxia and hypercapnia on capillary flow velocity in the rat cerebral cortex. Microvasc Res. 1997;54:35–42.
- Hudetz AG, Feher G, Kampine JP. Heterogeneous autoregulation of cerebrocortical capillary flow: evidence for functional thoroughfare channels. Microvasc Res. 1996;51:131–136.
- Hudetz AG, Feher G, Weigle CG, Knuese DE, Kampine JP. Video microscopy of cerebrocortical capillary flow: response to hypotension and intracranial hypertension. Am J Physiol. 1995;268:H2202–H2210.
- Hyder F, Shulman RG, Rothman DL. A model for the regulation of cerebral oxygen delivery. J Appl Physiol. 1998;85:554–564.
- Kalliokoski KK, Knuuti J, Nuutila P. Blood transit time heterogeneity is associated to oxygen extraction in exercising human skeletal muscle. Microvasc Res. 2004;67:125–132.
- King RB, Raymond GM, Bassingthwaighte JB. Modeling blood flow heterogeneity. Ann Biomed Eng. 1996;24:352–372.
- Kleinfeld D, Mitra PP, Helmchen F, Denk W. Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. Proc Natl Acad Sci USA. 1998;95:15741–15746.
- Krogh A. The supply of oxygen to the tissues and the regulation of the capillary circulation. J Physiol (London) 1919;52:457–474.
- Krolo I, Hudetz AG. Hypoxemia alters erythrocyte perfusion pattern in the cerebral capillary network. Microvasc Res. 2000;59:72–79.
- Kruger G, Kleinschmidt A, Frahm J. Dynamic MRI sensitized to cerebral blood oxygenation and flow during sustained activation of human visual cortex. Magn Reson Med. 1996;35:797–800.
- Kuschinsky W, Paulson OB. Capillary circulation in the brain. Cerebrovasc Brain Metab Rev. 1992;4:261–286.
- Lassen NA. The luxury-perfusion syndrome and its possible relation to acute metabolic acidosis localised within the brain. Lancet. 1966;2:1113–1115.
- Leithner C, Royl G, Offenhauser N, Fuchtemeier M, Kohl-Bareis M, Villringer A, Dirnagl U, Lindauer U. Pharmacological uncoupling of activation induced increases in CBF and CMRO2. J Cereb Blood Flow Metab. 2010;30:311–322.
- Li Z, Yipintsoi T, Bassingthwaighte JB. Nonlinear model for capillary-tissue oxygen transport and metabolism. Ann Biomed Eng. 1997;25:604–619.
- Lin AL, Fox PT, Hardies J, Duong TQ, Gao JH. Nonlinear coupling between cerebral blood flow, oxygen consumption, and ATP production in human visual cortex. Proc Natl Acad Sci USA. 2010;107:8446–8451.
- Malonek D, Dirnagl U, Lindauer U, Yamada K, Kanno I, Grinvald A. Vascular imprints of neuronal activity: relationships between the dynamics of cortical blood flow, oxygenation, and volume changes following sensory stimulation. Proc Natl Acad Sci USA. 1997;94:14826–14831.
- Mandeville JB, Marota JJ, Ayata C, Zaharchuk G, Moskowitz MA, Rosen BR, Weisskoff RM. Evidence of a cerebrovascular postarteriole windkessel with delayed compliance. J Cereb Blood Flow Metab. 1999;19:679–689.
- Masamoto K, Vazquez A, Wang P, Kim SG. Brain tissue oxygen consumption and supply induced by neural activation: determined under suppressed hemodynamic response conditions in the anesthetized rat cerebral cortex. Adv Exp Med Biol. 2009;645:287–292.
- Mintun MA, Lundstrom BN, Snyder AZ, Vlassenko AG, Shulman GL, Raichle ME. Blood flow and oxygen delivery to human brain during functional activity: theoretical modeling and experimental data. Proc Natl Acad Sci USA. 2001;98:6859–6864.
- Mouridsen K, Østergaard L, Christensen S, Jespersen SN.2011Reliable estimation of capillary transit time distributions at voxel-level using DSC-MRI Proceedings of the International Society for Magnetic Resonance in Medicines 19th Annual Meeting and Exhibition3915
- Ndubuizu O, LaManna JC. Brain tissue oxygen concentration measurements. Antioxid Redox Signal. 2007;9:1207–1219.
- Østergaard L, Chesler DA, Weisskoff RM, Sorensen AG, Rosen BR. Modeling cerebral blood flow and flow heterogeneity from magnetic resonance residue data. J Cereb Blood Flow Metab. 1999;19:690–699.
- Østergaard L, Sorensen AG, Chesler DA, Weisskoff RM, Koroshetz WJ, Wu O, Gyldensted C, Rosen BR. Combined diffusion-weighted and perfusion-weighted flow heterogeneity magnetic resonance imaging in acute stroke. Stroke. 2000;31:1097–1103.
- Pawlik G, Rackl A, Bing RJ. Quantitative capillary topography and blood flow in the cerebral cortex of cats: an in vivo microscopic study. Brain Res. 1981;208:35–58.
- Peppiatt CM, Howarth C, Mobbs P, Attwell D. Bidirectional control of CNS capillary diameter by pericytes. Nature. 2006;443:700–704.
- Pittman RN. Oxygen gradients in the microcirculation. Acta Physiol (Oxf) 2011;202:311–322.
- Pries AR, Secomb TW, Gaehtgens P. Structure and hemodynamics of microvascular networks: heterogeneity and correlations. Am J Physiol. 1995;269:H1713–H1722.
- Pries AR, Secomb TW, Gaehtgens P. Relationship between structural and hemodynamic heterogeneity in microvascular networks. Am J Physiol. 1996;270:H545–H553.
- Roy CS, Sherrington CS. On the regulation of the blood-supply of the brain. J Physiol. 1890;11:85–158.17.
- Schulte ML, Wood JD, Hudetz AG. Cortical electrical stimulation alters erythrocyte perfusion pattern in the cerebral capillary network of the rat. Brain Res. 2003;963:81–92.
- Shulman RG, Hyder F, Rothman DL. Biophysical basis of brain activity: implications for neuroimaging. Q Rev Biophys. 2002;35:287–325.
- Stefanovic B, Hutchinson E, Yakovleva V, Schram V, Russell JT, Belluscio L, Koretsky AP, Silva AC. Functional reactivity of cerebral capillaries. J Cereb Blood Flow Metab. 2008;28:961–972.
- Stewart GN. Researches on the circulation time in organs and on the influences which affect it. Parts I–III. J Physiol. 1894;15:1–89.
- Tomita Y, Tomita M, Schiszler I, Amano T, Tanahashi N, Kobari M, Takeda H, Ohtomo M, Fukuuchi Y. Moment analysis of microflow histogram in focal ischemic lesion to evaluate microvascular derangement after small pial arterial occlusion in rats. J Cereb Blood Flow Metab. 2002;22:663–669.
- Vafaee MS, Gjedde A. Model of blood-brain transfer of oxygen explains nonlinear flow-metabolism coupling during stimulation of visual cortex. J Cereb Blood Flow Metab. 2000;20:747–754.
- Villringer A, Them A, Lindauer U, Einhaupl K, Dirnagl U. Capillary perfusion of the rat brain cortex. An in vivo confocal microscopy study. Circ Res. 1994;75:55–62.
- Vimtrup B. Beiträge zur Anatomie der Capillaren. I. Über contraktile Elemente in der Gefasswand der Blutkapillaren. Zeitschr Anat Entwickl. 1922;65:150–182.
- Vogel J, Abounader R, Schrock H, Zeller K, Duelli R, Kuschinsky W. Parallel changes of blood flow and heterogeneity of capillary plasma perfusion in rat brains during hypocapnia. Am J Physiol. 1996;270:H1441–H1445.
- Vogel J, Kuschinsky W. Decreased heterogeneity of capillary plasma flow in the rat whisker-barrel cortex during functional hyperemia. J Cereb Blood Flow Metab. 1996;16:1300–1306.
- Yamanishi S, Katsumura K, Kobayashi T, Puro DG. Extracellular lactate as a dynamic vasoactive signal in the rat retinal microvasculature. Am J Physiol Heart Circ Physiol. 2006;290:H925–H934.
- Zheng Y, Martindale J, Johnston D, Jones M, Berwick J, Mayhew J. A model of the hemodynamic response and oxygen delivery to brain. Neuroimage. 2002;16:617–637.
Source: PubMed