The Role of Oxygen in Brain Tissue Function
Weili Lin1 and William J Powers2

1Biomedical Research Imaging Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States, 2Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Synopsis

While our brains utilize oxygen and glucose at rapid rates, they have little energy reserves and require constant supplies of glucose and oxygen to maintain normal brain function. Cerebral blood flow serves as the means through which these energy sources are delivered to the brain. This presentation will introduce the concepts of cerebral oxygen metabolism, the approaches to measure it, and the applications of these approaches to discern the interplay between CBF, OEF, and CMRO2 in both normal and pathophysiological conditions. Emphases will be made, when possible, to compare PET and MR approaches that provide similar physiological measures and their in vivo results.

Introduction

The human brain compromises 2% of the total body weight but receives a disproportionally high cardiac output (15%) and consumes 1/5 of the oxygen and 1/4 of the glucose of the entire body. The brain utilizes oxygen and glucose at rapid rates. Yet, our brains have little energy reserves and require consistent and constant supplies of glucose and oxygen in order to maintain normal brain function. Cerebral blood flow (CBF) serves as the means through which energy sources are delivered to the brain. Therefore, CBF and brain oxygen metabolism are tightly coupled under normal physiological conditions as has been widely recognized. The normal resting brain relies mostly on oxidative metabolism of glucose for its energy needs (generating 36 molecules of ATP) and only about 5-10% of glucose is metabolized non-oxidatively (generating 2 molecules of ATP) to lactate (1). As a result, oxygen plays a pivotal role in maintaining normal brain function. While the importance of oxygen was well recognized, it was only until the development of Kety-Schmidt method, based on the Fick Principle, that quantitative measures of whole brain CBF and energy metabolism became possible (2). Results from the applications of Kety-Schmidt approach to a wide array of experimental conditions had provided much of our current understanding of the interplay between CBF and oxygen metabolism. However, the lack of regional information using the Kety-Schmidt approach had hampered our ability to discern regional changes of oxygen metabolism and/or CBF responding to brain functional activation or cerebrovascular diseases. Nevertheless, this difficulty was later overcome with the development of the autoradiolographic 131I-trifluoroiodomethane approach offering regional measures of CBF in animals (3). The discovery of positron emission tomography (PET) in late 70’s further enabled direct and quantitative measures of cerebral hemodynamics in human subjects (4-6). Specifically, using intravenous infusion of H215O, CBF can be obtained (7); following a brief inhalation of C15O, which binds to hemoglobin and remains intravascularly, cerebral blood volume can be computed (8). A brief inhalation of O15O, together with a two compartment model (intravascular space and distribution space for free water) and arterial blood samples, oxygen extraction fraction (OEF) can be calculated (9, 10). Finally, cerebral metabolic rate of oxygen utilization (CMRO2) can be calculated as the product of CBF, OEF and arterial oxygen content (10). OEF reflects the balance between oxygen supply (CBF) and demand (CMRO2) (11). With these approaches, extensive studies have been conducted providing important insights into alterations of cerebral oxygen metabolism in response to external sensory stimuli (12, 13) and a wide array of cerebrovascular diseases (11, 14-19). While PET is an indispensable tool characterizing cerebral oxygen metabolism, its wide applicability has been substantially limited owing to the need of an onsite cyclotron since 15O-based tracers have a relatively short half-life, 2 min. In addition, complex and dedicated set-up is needed to conduct 15O experiments. Therefore, alternative approaches capable of providing similar physiological information but without the shortcomings associated with PET are needed. To this end, recent discovery of blood oxygen level dependent (BOLD) contrast (20) had offered a means to potentially provide quantitative measures of cerebral oxygen metabolism (21-51). This concept was first recognized by Thulborn et al (52), where they reported a linear relation between R2 and (Hb/(Hb+HbO2))2. This relationship was later confirmed and applied in vivo by Wright et al (47). Subsequently, Yablonskiy and Haacke (53) proposed the theoretical basis of BOLD effects, which has been used by numerous groups for the estimates of cerebral oxygen metabolism (22, 23, 25-29, 31-33, 36, 39, 40).

Key Areas

This presentation will focus on several key areas delineating the importance of oxygen in brain function. First, a brief introduction regarding the Kety-Schmidt approach and its applications to a wide array of experimental conditions establishing fundamental relations between CBF and oxygen metabolism will be provided. Second, the PET approaches to obtain quantitative measures of CBF, CBV, OEF and CMRO2 will be discussed in parallel with the MR approaches capable of obtaining similar physiological information. In addition, we will discuss how PET and MR approaches for measuring cerebral oxygen metabolism were validated. Third, cerebral oxygen metabolism in relation to brain functional activation will be addressed. In particular, the concept of the neurovascular unit (54) will be introduced, and through which the links between the underlying mechanisms of BOLD functional MRI and PET findings of oxygen metabolism alterations during external sensory stimuli will be addressed. Fourth, the applications of PET and MR approaches for measuring oxygen metabolism to characterize disease conditions will be discussed. In particular, one of the most commonly observed abnormalities in cerebrovascular diseases is reduced CBF. However, the underlying mechanisms leading to reduced CBF can be categorized into two fundamentally different situations, primary or secondary reduction of CBF; each has completely different implications in cerebral oxygen metabolism. One of the most representative examples for the primary reduction of CBF is cerebral ischemia where blockage of an artery leads to a reduction of CBF, which in turn, if severe enough, results in cascade of cellular and neuronal dysfunction and death if normal CBF is not restored in a timely manner. Specifically, initial reduction of CBF can potentially be compensated by an increased OEF, which in turn preserves normal CMRO2 and brain function (11). However, when the increased OEF exhausts its capacity for compensating continuing reduction of CBF, CMRO2 will reduce, leading to, potentially, tissue infarction. In contrast, CBF reduction may be secondary to a reduced CMRO2. No changes of OEF will be observed despite the reduced CBF. A representative example for secondary reduction of CBF due to reduced CMRO2 is anesthesia. Additional clinical examples on primary and secondary CBF reduction will be further discussed in this presentation. Finally, how MR and PET measured CMRO2 may provide insights into brain tissue viability during acute cerebral ischemia will be discussed.

Conclusions

In summary, this lecture will introduce the concepts of cerebral oxygen metabolism, the approaches to measures them, and the applications of these approaches to discern the interplay between CBF, OEF, and CMRO2 in both normal and pathophysiological conditions. Emphases will be made, when possible, to compare PET and MR approaches that provide similar physiological measures and their in vivo results.

Acknowledgements

No acknowledgement found.

References

1. Gottstein U, Bernsmeier A, & Sedlmeyer I (1963) [the Carbohydrate Metabolism of the Human Brain. I. Studies with Substrate-Specific Enzymatic Methods in Normal Brain Circulation]. Klinische Wochenschrift 41:943-948.

2. Kety SS & Schmidt CF (1948) The Nitrous Oxide Method for the Quantitative Determination of Cerebral Blood Flow in Man: Theory, Procedure and Normal Values. The Journal of clinical investigation 27(4):476-483.

3. Landau WM, Freygang WH, Jr., Roland LP, Sokoloff L, & Kety SS (1955) The local circulation of the living brain; values in the unanesthetized and anesthetized cat. Trans Am Neurol Assoc (80th Meeting):125-129.

4. Hoffmann EJ, Phelps ME, Mullani NA, Higgins CS, & Ter-Pogossian MM (1976) Design and performance characteristics of a whole-body positron transaxial tomograph. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 17(6):493-502.

5. Phelps ME, Hoffman EJ, Mullani NA, & Ter-Pogossian MM (1975) Application of annihilation coincidence detection to transaxial reconstruction tomography. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 16(3):210-224.

6. Ter-Pogossian MM, Phelps ME, Hoffman EJ, & Mullani NA (1975) A positron-emission transaxial tomograph for nuclear imaging (PETT). Radiology 114(1):89-98.

7. Raichle ME, Martin WR, Herscovitch P, Mintun MA, & Markham J (1983) Brain blood flow measured with intravenous H2(15)O. II. Implementation and validation. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 24(9):790-798.

8. Eichling JO, Raichle ME, Grubb RL, Jr., Larson KB, & Ter-Pogossian MM (1975) In vivo determination of cerebral blood volume with radioactive oxygen-15 in the monkey. Circulation research 37(6):707-714.

9. Altman DI, Lich LL, & Powers WJ (1991) Brief inhalation method to measure cerebral oxygen extraction fraction with PET: accuracy determination under pathologic conditions. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 32(9):1738-1741.

10. Mintun MA, Raichle ME, Martin WR, & Herscovitch P (1984) Brain oxygen utilization measured with O-15 radiotracers and positron emission tomography. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 25(2):177-187.

11. Powers WJ & Raichle ME (1985) Positron emission tomography and its application to the study of cerebrovascular disease in man. Stroke 16(3):361-376.

12. Fox PT & Raichle ME (1986) Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects. Proceedings of the National Academy of Sciences of the United States of America 83(4):1140-1144.

13. Fox PT, Raichle ME, & Thach WT (1985) Functional mapping of the human cerebellum with positron emission tomography. Proceedings of the National Academy of Sciences of the United States of America 82(21):7462-7466.

14. Powers WJ, Grubb RL, Jr., Darriet D, & Raichle ME (1985) Cerebral blood flow and cerebral metabolic rate of oxygen requirements for cerebral function and viability in humans. J Cereb Blood Flow Metab 5(4):600-608.

15. Powers WJ, Grubb RL, Jr., Baker RP, Mintun MA, & Raichle ME (1985) Regional cerebral blood flow and metabolism in reversible ischemia due to vasospasm. Determination by positron emission tomography. Journal of neurosurgery 62(4):539-546.

16. Powers WJ, Grubb RL, Jr., & Raichle ME (1989) Clinical results of extracranial-intracranial bypass surgery in patients with hemodynamic cerebrovascular disease. Journal of neurosurgery 70(1):61-67.

17. Powers WJ, Press GA, Grubb RL, Jr., Gado M, & Raichle ME (1987) The effect of hemodynamically significant carotid artery disease on the hemodynamic status of the cerebral circulation. Annals of internal medicine 106(1):27-34.

18. Powers WJ, Grubb RL, Jr., & Raichle ME (1984) Physiological responses to focal cerebral ischemia in humans. Ann Neurol 16(5):546-552.

19. Powers WJ & Raichle ME (1983) Positron emission tomography in cerebrovascular disease. Clin Neurosurg 31:107-116.

20. Ogawa S, Lee TM, Kay AR, & Tank DW (1990) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proceedings of the National Academy of Sciences of the United States of America 87(24):9868-9872.

21. Haacke EM, et al. (1997) In vivo measurement of blood oxygen saturation using magnetic resonance imaging: a direct validation of the blood oxygen level-dependent concept in functional brain imaging. Human brain mapping 5(5):341-346.

22. Golay X, et al. (2001) Measurement of tissue oxygen extraction ratios from venous blood T(2): increased precision and validation of principle. Magn Reson Med 46(2):282-291.

23. Christen T, et al. (2011) Evaluation of a quantitative blood oxygenation level-dependent (qBOLD) approach to map local blood oxygen saturation. NMR Biomed 24(4):393-403.

24. Christen T, et al. (2012) Is T2* enough to assess oxygenation? Quantitative blood oxygen level-dependent analysis in brain tumor. Radiology 262(2):495-502.

25. An H & Lin W (2000) Quantitative measurements of cerebral blood oxygen saturation using magnetic resonance imaging. J Cereb Blood Flow Metab 20(8):1225-1236.

26. An H & Lin W (2002) Cerebral oxygen extraction fraction and cerebral venous blood volume measurements using MRI: effects of magnetic field variation. Magn Reson Med 47(5):958-966.

27. An H & Lin W (2003) Impact of intravascular signal on quantitative measures of cerebral oxygen extraction and blood volume under normo- and hypercapnic conditions using an asymmetric spin echo approach. Magn Reson Med 50(4):708-716.

28. An H, Liu Q, Chen Y, & Lin W (2009) Evaluation of MR-derived cerebral oxygen metabolic index in experimental hyperoxic hypercapnia, hypoxia, and ischemia. Stroke 40(6):2165-2172.

29. An H, Sen S, Chen Y, Powers WJ, & Lin W (2012) Noninvasive Measurements of Cerebral Blood Flow, Oxygen Extraction Fraction, and Oxygen Metabolic Index in Human with Inhalation of Air and Carbogen using Magnetic Resonance Imaging. Transl Stroke Res 3(2):246-254.

30. Lin W, et al. (2013) MR imaging of oxygen extraction and neurovascular coupling. Stroke 44(6 Suppl 1):S61-64.

31. An H, et al. (2014) Imaging Oxygen Metabolism In Acute Stroke Using MRI. Current radiology reports 2(3):39.

32. An H, et al. (2015) Defining the ischemic penumbra using magnetic resonance oxygen metabolic index. Stroke 46(4):982-988.

33. Christen T, et al. (2014) Tissue oxygen saturation mapping with magnetic resonance imaging. J Cereb Blood Flow Metab 34(9):1550-1557.

34. Christen T, et al. (2014) MR vascular fingerprinting: A new approach to compute cerebral blood volume, mean vessel radius, and oxygenation maps in the human brain. Neuroimage 89:262-270.

35. Lemasson B, et al. (2012) Evaluation of the relationship between MR estimates of blood oxygen saturation and hypoxia: effect of an antiangiogenic treatment on a gliosarcoma model. Radiology 265(3):743-752.

36. Christen T, Bolar DS, & Zaharchuk G (2013) Imaging brain oxygenation with MRI using blood oxygenation approaches: methods, validation, and clinical applications. AJNR. American journal of neuroradiology 34(6):1113-1123.

37. Christen T, et al. (2012) Quantitative MR estimates of blood oxygenation based on T2*: a numerical study of the impact of model assumptions. Magn Reson Med 67(5):1458-1468.

38. Christen T, Schmiedeskamp H, Straka M, Bammer R, & Zaharchuk G (2012) Measuring brain oxygenation in humans using a multiparametric quantitative blood oxygenation level dependent MRI approach. Magn Reson Med 68(3):905-911.

39. He X & Yablonskiy DA (2007) Quantitative BOLD: mapping of human cerebral deoxygenated blood volume and oxygen extraction fraction: default state. Magn Reson Med 57(1):115-126.

40. He X, Zhu M, & Yablonskiy DA (2008) Validation of oxygen extraction fraction measurement by qBOLD technique. Magn Reson Med 60(4):882-888.

41. Nield LE, et al. (2005) In vivo MRI measurement of blood oxygen saturation in children with congenital heart disease. Pediatric radiology 35(2):179-185.

42. Nield LE, et al. (2002) MRI-based blood oxygen saturation measurements in infants and children with congenital heart disease. Pediatric radiology 32(7):518-522.

43. Stainsby JA & Wright GA (2001) Monitoring blood oxygen state in muscle microcirculation with transverse relaxation. Magn Reson Med 45(4):662-672.

44. Foltz WD, Merchant N, Downar E, Stainsby JA, & Wright GA (1999) Coronary venous oximetry using MRI. Magn Reson Med 42(5):837-848.

45. Li KC, et al. (1997) In vivo magnetic resonance evaluation of blood oxygen saturation in the superior mesenteric vein as a measure of the degree of acute flow reduction in the superior mesenteric artery: findings in a canine model. Academic radiology 4(1):21-25.

46. Li KC, et al. (1995) Oxygen saturation of blood in the superior mesenteric vein: in vivo verification of MR imaging measurements in a canine model. Work in progress. Radiology 194(2):321-325.

47. Wright GA, Hu BS, & Macovski A (1991) 1991 I.I. Rabi Award. Estimating oxygen saturation of blood in vivo with MR imaging at 1.5 T. J Magn Reson Imaging 1(3):275-283.

48. Lu H, et al. (2012) Calibration and validation of TRUST MRI for the estimation of cerebral blood oxygenation. Magn Reson Med 67(1):42-49.

49. Qin Q, Grgac K, & van Zijl PC (2011) Determination of whole-brain oxygen extraction fractions by fast measurement of blood T(2) in the jugular vein. Magn Reson Med 65(2):471-479.

50. Cheng Y, van Zijl PC, & Hua J (2015) Measurement of parenchymal extravascular R2* and tissue oxygen extraction fraction using multi-echo vascular space occupancy MRI at 7 T. NMR Biomed 28(2):264-271.

51. Lu H & van Zijl PC (2005) Experimental measurement of extravascular parenchymal BOLD effects and tissue oxygen extraction fractions using multi-echo VASO fMRI at 1.5 and 3.0 T. Magn Reson Med 53(4):808-816.

52. Thulborn KR, Waterton JC, Matthews PM, & Radda GK (1982) Oxygenation dependence of the transverse relaxation time of water protons in whole blood at high field. Biochimica et biophysica acta 714(2):265-270.

53. Yablonskiy DA & Haacke EM (1994) Theory of NMR signal behavior in magnetically inhomogeneous tissues: the static dephasing regime. Magn Reson Med 32(6):749-763. 54. Petzold GC & Murthy VN (2011) Role of astrocytes in neurovascular coupling. Neuron 71(5):782-797.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)