Oxygenation Imaging by Nuclear Magnetic Resonance Methods

  • Heling Zhou
  • Nuria Arias-Ramos
  • Pilar López-Larrubia
  • Ralph P. Mason
  • Sebastián Cerdán
  • Jesús Pacheco-TorresEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1718)


Oxygen monitoring is a topic of exhaustive research due to its central role in many biological processes, from energy metabolism to gene regulation. The ability to monitor in vivo the physiological distribution and the dynamics of oxygen from subcellular to macroscopic levels is a prerequisite to better understand the mechanisms associated with both normal and disease states (cancer, neurodegeneration, stroke, etc.). This chapter focuses on magnetic resonance imaging (MRI) based techniques to assess oxygenation in vivo. The first methodology uses injected fluorinated agents to provide quantitative pO2 measurements with high precision and suitable spatial and temporal resolution for many applications. The second method exploits changes in endogenous contrasts, i.e., deoxyhemoglobin and oxygen molecules through measurements of T2* and T1, in response to an intervention to qualitatively evaluate hypoxia and its potential modulation.

Key words

MRI Oximetry pO2 BOLD Hypoxia Perfluorocarbons Quantification 



Method development and application supported in part by CPRIT RP140399, RP120670-03, P30 CA142543, and P41 EB015908.


  1. 1.
    Lassmann H (2016) Demyelination and neurodegeneration in multiple sclerosis: The role of hypoxia. Ann Neurol 79(4):520–521. CrossRefPubMedGoogle Scholar
  2. 2.
    Peers C, Dallas ML, Boycott HE, Scragg JL, Pearson HA, Boyle JP (2009) Hypoxia and neurodegeneration. Ann N Y Acad Sci 1177:169–177. CrossRefPubMedGoogle Scholar
  3. 3.
    Figueroa XA, Wright JK (2016) Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials. Neurology 87(13):1400–1406. CrossRefPubMedGoogle Scholar
  4. 4.
    Kones R (2011) Oxygen therapy for acute myocardial infarction-then and now. A century of uncertainty. Am J Med 124(11):1000–1005. CrossRefPubMedGoogle Scholar
  5. 5.
    Rink C, Khanna S (2011) Significance of brain tissue oxygenation and the arachidonic acid cascade in stroke. Antioxid Redox Signal 14(10):1889–1903. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Pacheco-Torres J, Lopez-Larrubia P, Ballesteros P, Cerdan S (2011) Imaging tumor hypoxia by magnetic resonance methods. NMR Biomed 24(1):1–16. CrossRefPubMedGoogle Scholar
  7. 7.
    Mason RP, Zhao D, Pacheco-Torres J, Cui W, Kodibagkar VD, Gulaka PK, Hao G, Thorpe P, Hahn EW, Peschke P (2010) Multimodality imaging of hypoxia in preclinical settings. Q J Nucl Med Mol Imaging 54(3):259–280PubMedPubMedCentralGoogle Scholar
  8. 8.
    Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC (1953) The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 26(312):638–648CrossRefPubMedGoogle Scholar
  9. 9.
    Overgaard J (2007) Hypoxic radiosensitization: adored and ignored. J Clin Oncol 25(26):4066–4074. CrossRefPubMedGoogle Scholar
  10. 10.
    Tredan O, Grantab R, Dumontet C (2008) Can tumor hypoxia be turned into a chemotherapeutic advantage? Bull Cancer 95(5):528–534. PubMedGoogle Scholar
  11. 11.
    Hay MP, Hicks KO, Wang J (2014) Hypoxia-directed drug strategies to target the tumor microenvironment. Adv Exp Med Biol 772:111–145. CrossRefPubMedGoogle Scholar
  12. 12.
    Tatum JL, Kelloff GJ, Gillies RJ, Arbeit JM, Brown JM, Chao KS, Chapman JD, Eckelman WC, Fyles AW, Giaccia AJ, Hill RP, Koch CJ, Krishna MC, Krohn KA, Lewis JS, Mason RP, Melillo G, Padhani AR, Powis G, Rajendran JG, Reba R, Robinson SP, Semenza GL, Swartz HM, Vaupel P, Yang D, Croft B, Hoffman J, Liu G, Stone H, Sullivan D (2006) Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol 82(10):699–757. CrossRefPubMedGoogle Scholar
  13. 13.
    Overgaard J, Horsman MR (1996) Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol 6:10–21CrossRefPubMedGoogle Scholar
  14. 14.
    Matsuo M, Matsumoto S, Mitchell JB, Krishna MC, Camphausen K (2014) Magnetic resonance imaging of the tumor microenvironment in radiotherapy: perfusion, hypoxia, and metabolism. Semin Radiat Oncol 24(3):210–217. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, Terris DJ, Overgaard J (2005) Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 77(1):18–24CrossRefPubMedGoogle Scholar
  16. 16.
    Vaupel P, Höckel M, Mayer A (2007) Detection and characterization of tumor hypoxia using pO2 histography. Antioxid Redox Signal 9(8):1221–1236. CrossRefPubMedGoogle Scholar
  17. 17.
    Griffiths JR, Robinson SP (1999) The OxyLite: a fibre-optic oxygen sensor. Br J Radiol 72(859):627–630CrossRefPubMedGoogle Scholar
  18. 18.
    Peeters SG, Zegers CM, Yaromina A, Van Elmpt W, Dubois L, Lambin P (2015) Current preclinical and clinical applications of hypoxia PET imaging using 2-nitroimidazoles. Q J Nucl Med Mol Imaging 59(1):39–57PubMedGoogle Scholar
  19. 19.
    Peeters SG, Zegers CM, Lieuwes NG, van Elmpt W, Eriksson J, van Dongen GA, Dubois L, Lambin P (2015) A comparative study of the hypoxia PET tracers [(1)(8)F]HX4, [(1)(8)F]FAZA, and [(1)(8)F]FMISO in a preclinical tumor model. Int J Radiat Oncol Biol Phys 91(2):351–359. CrossRefPubMedGoogle Scholar
  20. 20.
    Krohn KA, Link JM, Mason RP (2008) Molecular imaging of hypoxia. J Nucl Med 49(Suppl 2):129S–148S. CrossRefPubMedGoogle Scholar
  21. 21.
    Padhani AR, Krohn KA, Lewis JS, Alber M (2007) Imaging oxygenation of human tumours. Eur Radiol 17(4):861–872CrossRefPubMedGoogle Scholar
  22. 22.
    Foo SS, Abbott DF, Lawrentschuk N, Scott AM (2004) Functional imaging of intratumoral hypoxia. Mol Imaging Biol 6(5):291–305CrossRefPubMedGoogle Scholar
  23. 23.
    Ljungkvist AS, Bussink J, Kaanders JH, van der Kogel AJ (2007) Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat Res 167(2):127–145CrossRefPubMedGoogle Scholar
  24. 24.
    Vikram DS, Zweier JL, Kuppusamy P (2007) Methods for noninvasive imaging of tissue hypoxia. Antioxid Redox Signal 9(10):1745–1756CrossRefPubMedGoogle Scholar
  25. 25.
    Liu H, Gu Y, Kim JG, Mason RP (2004) Near infrared spectroscopy and imaging of tumor vascular oxygenation. Methods Enzymol 386:349–378CrossRefPubMedGoogle Scholar
  26. 26.
    Roussakis E, Li Z, Nichols AJ, Evans CL (2015) Oxygen-sensing methods in biomedicine from the macroscale to the microscale. Angew Chem 54(29):8340–8362. CrossRefGoogle Scholar
  27. 27.
    Mason RP (2017) Oxygen breathing challenge—the simplest theranostics. Theranostics 7(16):3873–3875. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Charnley N, Donaldson S, Price P (2009) Imaging angiogenesis. Methods Mol Biol 467:25–51CrossRefPubMedGoogle Scholar
  29. 29.
    Jordan BF, Runquist M, Raghunand N, Baker A, Williams R, Kirkpatrick L, Powis G, Gillies RJ (2005) Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1alpha using PX-478. Neoplasia 7(5):475–485CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Shukla HP, Mason RP, Woessner DE, Antich PP (1995) A comparison of three commercial perfluorocarbon emulsions as high-field 19F NMR probes of oxygen tension and temperature. J Magn Reson B 106(2):131–141. CrossRefGoogle Scholar
  31. 31.
    Ali Hamza MH, Serratrice G, Stébé M-J, Delpuech J-J (1981) Fluorocarbons as oxygen carriers. II. An NMR study of partially or totally fluorinated alkanes and alkenes. J Magn Reson (1969) 42(2):227–241. CrossRefGoogle Scholar
  32. 32.
    Thomas SR, Millard RW, Pratt RG, Shiferaw Y, Samaratunga RC (1994) Quantitative pO2 imaging in vivo with perfluorocarbon F-19 NMR: tracking oxygen from the airway through the blood to organ tissues. Artif Cells Blood Substit Immobil Biotechnol 22(4):1029–1042CrossRefPubMedGoogle Scholar
  33. 33.
    Mason RP, Shukla H, Antich PP (1993) In vivo oxygen tension and temperature: simultaneous determination using 19F NMR spectroscopy of perfluorocarbon. Magn Reson Med 29:296–302CrossRefPubMedGoogle Scholar
  34. 34.
    Mason RP (1994) Non-invasive physiology: 19F NMR of perfluorocarbons. Artif Cells Blood Substit Immobil Biotechnol 22(4):1141–1153CrossRefPubMedGoogle Scholar
  35. 35.
    Sotak CH, Hees PS, Huang HN, Hung MH, Krespan CG, Raynolds S (1993) A new perfluorocarbon for use in fluorine-19 magnetic resonance imaging and spectroscopy. Magn Reson Med 29(2):188–195CrossRefPubMedGoogle Scholar
  36. 36.
    Jordan BF, Cron GO, Gallez B (2009) Rapid monitoring of oxygenation by 19F magnetic resonance imaging: Simultaneous comparison with fluorescence quenching. Magn Reson Med 61(3):634–638. CrossRefPubMedGoogle Scholar
  37. 37.
    Liu S, Shah SJ, Wilmes LJ, Feiner J, Kodibagkar VD, Wendland MF, Mason RP, Hylton N, Hopf HW, Rollins MD (2011) Quantitative tissue oxygen measurement in multiple organs using 19F MRI in a rat model. Magn Reson Med 66(6):1722–1730. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Zhao D, Jiang L, Mason RP (2004) Measuring changes in tumor oxygenation. Methods Enzymol 386:378–418CrossRefPubMedGoogle Scholar
  39. 39.
    Kodibagkar VD, Cui W, Merritt ME, Mason RP (2006) Novel 1H NMR approach to quantitative tissue oximetry using hexamethyldisiloxane. Magn Reson Med 55(4):743–748CrossRefPubMedGoogle Scholar
  40. 40.
    Kodibagkar VD, Wang X, Pacheco-Torres J, Gulaka P, Mason RP (2008) Proton imaging of siloxanes to map tissue oxygenation levels (PISTOL): a tool for quantitative tissue oximetry. NMR Biomed 21(8):899–907CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Gulaka PK, Rastogi U, McKay MA, Wang X, Mason RP, Kodibagkar VD (2011) Hexamethyldisiloxane-based nanoprobes for (1) H MRI oximetry. NMR Biomed 24(10):1226–1234. CrossRefPubMedGoogle Scholar
  42. 42.
    Greve JM (2011) The BOLD effect. Methods Mol Biol 771:153–169. CrossRefPubMedGoogle Scholar
  43. 43.
    Nield LE, Qi X, Yoo SJ, Valsangiacomo ER, Hornberger LK, Wright GA (2002) MRI-based blood oxygen saturation measurements in infants and children with congenital heart disease. Pediatr Radiol 32(7):518–522. CrossRefPubMedGoogle Scholar
  44. 44.
    Ndubuizu O, La Manna JC (2007) Brain tissue oxygen concentration measurements. Antioxid Redox Signal 9(8):1207–1219CrossRefPubMedGoogle Scholar
  45. 45.
    Dunn JF (2011) MR oximetry. Methods Mol Biol 771:227–240. CrossRefPubMedGoogle Scholar
  46. 46.
    Howe FA, Robinson SP, McIntyre DJ, Stubbs M, Griffiths JR (2001) Issues in flow and oxygenation dependent contrast (FLOOD) imaging of tumours. NMR Biomed 14(7–8):497–506CrossRefPubMedGoogle Scholar
  47. 47.
    Baudelet C, Gallez B (2005) Current issues in the utility of blood oxygen level dependent MRI for the assessment of modulations in tumor oxygenation. Curr Med Imaging Rev 1(3):229–243. CrossRefGoogle Scholar
  48. 48.
    Al-Hallaq HA, River JN, Zamora M, Oikawa H, Karczmar GS (1998) Correlation of magnetic resonance and oxygen microelectrode measurements of carbogen-induced changes in tumor oxygenation. Int J Radiat Oncol Biol Phys 41(1):151–159CrossRefPubMedGoogle Scholar
  49. 49.
    Zhao D, Jiang L, Hahn EW, Mason RP (2009) Comparison of1H blood oxygen level-dependent (BOLD) and19F MRI to investigate tumor oxygenation. Magn Reson Med 62(2):357–364CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hallac RR, Zhou H, Pidikiti R, Song K, Stojadinovic S, Zhao D, Solberg T, Peschke P, Mason RP (2014) Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response. Magn Reson Med 71(5):1863–1873. CrossRefPubMedGoogle Scholar
  51. 51.
    Matsumoto K, Bernardo M, Subramanian S, Choyke P, Mitchell JB, Krishna MC, Lizak MJ (2006) MR assessment of changes of tumor in response to hyperbaric oxygen treatment. Magn Reson Med 56(2):240–246. CrossRefPubMedGoogle Scholar
  52. 52.
    Beeman SC, Shui YB, Perez-Torres CJ, Engelbach JA, Ackerman JJ, Garbow JR (2016) O2-sensitive MRI distinguishes brain tumor versus radiation necrosis in murine models. Magn Reson Med 75(6):2442–2447. CrossRefPubMedGoogle Scholar
  53. 53.
    O'Connor JP, Naish JH, Jackson A, Waterton JC, Watson Y, Cheung S, Buckley DL, McGrath DM, Buonaccorsi GA, Mills SJ, Roberts C, Jayson GC, Parker GJ (2009) Comparison of normal tissue R1 and R*2 modulation by oxygen and carbogen. Magn Reson Med 61(1):75–83CrossRefPubMedGoogle Scholar
  54. 54.
    Berkowitz BA, McDonald C, Ito Y, Tofts PS, Latif Z, Gross J (2001) Measuring the human retinal oxygenation response to a hyperoxic challenge using MRI: eliminating blinking artifacts and demonstrating proof of concept. Magn Reson Med 46(2):412–416CrossRefPubMedGoogle Scholar
  55. 55.
    O’Connor JP, Boult JK, Jamin Y, Babur M, Finegan KG, Williams KJ, Little RA, Jackson A, Parker GJ, Reynolds AR, Waterton JC, Robinson SP (2016) Oxygen-enhanced MRI accurately identifies, quantifies, and maps tumor hypoxia in preclinical cancer models. Cancer Res 76(4):787–795. CrossRefPubMedGoogle Scholar
  56. 56.
    Tennant DA, Duran RV, Gottlieb E (2010) Targeting metabolic transformation for cancer therapy. Nat Rev Cancer 10(4):267–277. CrossRefPubMedGoogle Scholar
  57. 57.
    European Convention for the Protection of vertebrate animals used for experimental and other scientific purposes (2006) Appendix A. Guidelines for accommodation and care of animals (Article 5 of the Convention)Google Scholar
  58. 58.
    Sicard KM, Duong TQ (2005) Effects of hypoxia, hyperoxia, and hypercapnia on baseline and stimulus-evoked BOLD, CBF, and CMRO2 in spontaneously breathing animals. NeuroImage 25(3):850–858. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Masamoto K, Kanno I (2012) Anesthesia and the quantitative evaluation of neurovascular coupling. J Cereb Blood Flow Metab 32(7):1233–1247. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Duong TQ (2007) Cerebral blood flow and BOLD fMRI responses to hypoxia in awake and anesthetized rats. Brain Res 1135(1):186–194. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Hendrich KS, Kochanek PM, Melick JA, Schiding JK, Statler KD, Williams DS, Marion DW, Ho C (2001) Cerebral perfusion during anesthesia with fentanyl, isoflurane, or pentobarbital in normal rats studied by arterial spin-labeled MRI. Magn Reson Med 46(1):202–206CrossRefPubMedGoogle Scholar
  62. 62.
    Schroeter A, Schlegel F, Seuwen A, Grandjean J, Rudin M (2014) Specificity of stimulus-evoked fMRI responses in the mouse: the influence of systemic physiological changes associated with innocuous stimulation under four different anesthetics. NeuroImage 94:372–384. CrossRefPubMedGoogle Scholar
  63. 63.
    Sonnay S, Just N, Duarte JM, Gruetter R (2015) Imaging of prolonged BOLD response in the somatosensory cortex of the rat. NMR Biomed 28(3):414–421. CrossRefPubMedGoogle Scholar
  64. 64.
    Liu ZM, Schmidt KF, Sicard KM, Duong TQ (2004) Imaging oxygen consumption in forepaw somatosensory stimulation in rats under isoflurane anesthesia. Magn Reson Med 52(2):277–285. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lei H, Grinberg O, Nwaigwe CI, Hou HG, Williams H, Swartz HM, Dunn JF (2001) The effects of ketamine-xylazine anesthesia on cerebral blood flow and oxygenation observed using nuclear magnetic resonance perfusion imaging and electron paramagnetic resonance oximetry. Brain Res 913(2):174–179CrossRefPubMedGoogle Scholar
  66. 66.
    Mikkelsen ML, Ambrus R, Miles JE, Poulsen HH, Moltke FB, Eriksen T (2016) Effect of propofol and remifentanil on cerebral perfusion and oxygenation in pigs: a systematic review. Acta Vet Scand 58(1):42. CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Paasonen J, Salo RA, Shatillo A, Forsberg MM, Narvainen J, Huttunen JK, Grohn O (2016) Comparison of seven different anesthesia protocols for nicotine pharmacologic magnetic resonance imaging in rat. Eur Neuropsychopharmacol 26(3):518–531. CrossRefPubMedGoogle Scholar
  68. 68.
    Zhao D, Pacheco-Torres J, Hallac RR, White D, Peschke P, Cerdan S, Mason RP (2015) Dynamic oxygen challenge evaluated by NMR T1 and T2*—insights into tumor oxygenation. NMR Biomed 28(8):937–947. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Zhang N, Yacoub E, Zhu XH, Ugurbil K, Chen W (2009) Linearity of blood-oxygenation-level dependent signal at microvasculature. NeuroImage 48(2):313–318. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Dunn JF, Swartz HM (1997) Blood oxygenation. Heterogeneity of hypoxic tissues monitored using bold MR imaging. Adv Exp Med Biol 428:645–650CrossRefPubMedGoogle Scholar
  71. 71.
    Silvennoinen MJ, Clingman CS, Golay X, Kauppinen RA, van Zijl PC (2003) Comparison of the dependence of blood R2 and R2* on oxygen saturation at 1.5 and 4.7 Tesla. Magn Reson Med 49(1):47–60. CrossRefPubMedGoogle Scholar
  72. 72.
    Zhou H, Hallac RR, Lopez R, Denney R, MacDonough MT, Li L, Liu L, Graves EE, Trawick ML, Pinney KG, Mason RP (2015) Evaluation of tumor ischemia in response to an indole-based vascular disrupting agent using BLI and (19)F MRI. Am J Nucl Med Mol Imaging 5(2):143–153PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  • Heling Zhou
    • 1
  • Nuria Arias-Ramos
    • 2
  • Pilar López-Larrubia
    • 3
  • Ralph P. Mason
    • 1
  • Sebastián Cerdán
    • 3
  • Jesús Pacheco-Torres
    • 4
    Email author
  1. 1.Prognostic Imaging Research Laboratory, Department of RadiologyUT Southwestern Medical CenterDallasUSA
  2. 2.Departament de Bioquímica i Biologia Molecular, Unitat de Bioquímica de Biociències, Edifici CsUniversitat Autònoma de BarcelonaCerdanyola del VallèsSpain
  3. 3.Instituto de Investigaciones Biomédicas ‘Alberto Sols’ C.S.I.C./U.A.M.MadridSpain
  4. 4.Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas, Universidad Miguel HernándezSan Juan de AlicanteSpain

Personalised recommendations