principles of epr oxygen imaging in vivo oxygen imaging workshop university of chicago june 25 2012 n.
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  1. Principles of EPR oxygen imagingIn Vivo Oxygen Imaging Workshop University of Chicago June 25, 2012 Boris Epel

  2. Outline • Principles of EPR • EPR spin probes • EPR imaging principles • Image registration and tumor localization • Image visualization and statistics

  3. What is spin • fundamental property of electron, like electrical charge or mass. • the rotation of a particle around some axis • Characterized by a spin quantum number, S • electron have spin ½ • In EPR, it is unpaired spins that are of importance.

  4. e- Angular and Magnetic Moments • Electron is a moving charge –it gives rise to a magnetic moment, µ • Electron can be described as a magnetic dipole– bar magnet N S

  5. Design of EPR experiment Radio frequency,  Electron magnetic moment isn’t free to adopt an arbitrary orientation. There is a discrete set of orientations possible. N N N EPR is the resonant absorption of radio frequency radiation by paramagnetic systems in the presence of an applied constant magnetic field S S S Constant field B0 Magnet will return back in some time: longitudinal relaxation

  6. EPR spin probes Endogenous paramagnetic species found in mammalian bodies have very short live times, broad lines, or very low concentrations. At present, exogenous spin probes are the only practical reporters, and appropriate spin probes are the key to successful imaging. At present,iv injections are used for the delivery of spin probe. The development of other means of spin probe delivery (arterial and direct injection) is under way.

  7. EPR oxymetry probes Soluble probes A Nitroxides B Trityl radicals • Concentration (μM) of dissolved oxygen in the bulk volume • Resolution 1 mmHg Particulate (Solid) probes C Lithium phthalocyanine and its derivatives

  8. What EPR can measure Oxygen, pO2 Redox status Acidosis, pH Thiols (GSH) Cell viability Viscosity Tissue perfusion Molecular motion Oxygen, pO2

  9. Operational frequency Biological samples contain large proportion of water. They are aqueous and highly dielectric. Conventional EPR spectrometers operate at X-band ~9 GHz frequencies, which result in (i) ‘non-resonant’ absorption of energy (sample heating) and (ii) poor penetration of samples. Hence the frequency of the instrumentation needs to be reduced. What is the optimum frequency? - depends on sample size

  10. EPR vs MRI

  11. In Vivo EPR Oxygen Imaging Trityl iv line Bladder flushing line Resonator Mouse cradle Fiducials Gas anesthe-sia mask Tumor in the cast Cutaneous thermocouple

  12. Spectroscopy vs Parametric Imaging Inhomogeneous distribution Low O2 Slow relax. High O2 Fast relax.

  13. Image Dimensionality Two dimensional One dimensional Three-dimensional

  14. Imaging Principles • Application of the linear magnetic field gradient   B

  15. Magnetic Field Gradient Homogeneous field, B0 Linear gradient, 450 Linear gradient, 00        ‘projection’ Please do not leave metal objects close to the imager

  16. Imaging Principles • Application of the linear magnetic field gradient • Obtaining multiple projections by use of different gradients orientations   B

  17. Imaging Principles • Application of the linear magnetic field gradient • Obtaining multiple projections by use of different gradients orientations • Image reconstruction (filtered backprojection)   B

  18. Imager magnet

  19. Electron Spin Echo Oxygen Imaging T1or T2 [s] Amplitude [a.u.] Deoxygenated OXO63 spin probe pO2 =  (R – R(0 torr, 0 mM) - C) R= 1/2T1 or 2[mG] pO2 [torr] Spin-probe concentration [mM]

  20. Image resolution spatial 1.2 mm temporal 10 min (2.5 min rapid protocol) pO2 1 torr

  21. Pulse EPR: imaging sequences Electron Spin Echo (ESE) – T2 imaging t t Inversion recovery (IRESE) – T1 imaging T t t

  22. Concentration Dependence in Vivo T1 shows only weak dependence on spin probe concentration T1 – based EPR imaging is the perfect method for precise oxygen imaging

  23. Imaging Procedures Prepare an animal Determine area of interest Install animal in the resonator cradle Optional ROI Acquire MRI image Install resonator into imager Register EPRI and MRI Inject spin probe Acquire CT/PET image Register CT/PET and EPR Image an animal Acquire pO2 statistics Observe pO2 image

  24. ESE and MR Image Registration 3D view of MRI and amplitude ESEI image registration. Fiducialsare used to establish the coordinate transformation from MRI into ESE coordinate system Mouse leg in the resonator. Polysiloxane half-cast with inserted fiducials EPRI – 3mM deuterated FINLAND fiducials(~ 0.5 mm resolution) MRI – water fiducials Haney C. et al., Concepts in Magnetic Resonance B (2008), 33, 138-144. 24

  25. ESE and MRI Image Registration Fiducials MRI EPROI pO2

  26. Multimodality Rat Imaging A C Multi-B ESE B pO2 C 18F-FDG PET D T2-weighted MRI

  27. EPR oxygen image visualization Region of interest in this case area of the tumor from a registered MRI image ‘Three orthogonal slices’ view Cursor statistics Colormap and view adjustment Cursor ROI and general statistics

  28. Summary In vivo EPR spectroscopy and imaging methods enable noninvasive measurement and mapping of tissue pO2. Image resolution spatial 1.2 mm temporal 10 min (2.5 min rapid protocol) pO2 1 torr

  29. Direct injection of spin probe into artery • 51 mm diameter loop-gap resonator • 4 cm VX2 carcinoma • Spin probe was continuously injected directly into the artery feeding the leg. This allowed us to use only 1/4 of the calculated injection dose  B. Epel et al. Medical Physics 37 (2010) 2553-2559.

  30. Imaging of Cycling Hypoxia EPR Single Point Imaging Image duration 3 minutes. Matsumoto, S., H. Yasui, et al. (2010). "Imaging Cycling Tumor Hypoxia." Cancer Research 70(24): 10019-10023. Yasui, H., S. Matsumoto, et al. (2010). "Low-Field Magnetic Resonance Imaging to Visualize Chronic and Cycling Hypoxia in Tumor-Bearing Mice." Cancer Research 70(16): 6427-6436. 19F MRI Image duration 3 minutes. Magat, J., B. F. Jordan, et al. (2010). "Noninvasive mapping of spontaneous fluctuations in tumor oxygenation using F-19 MRI." Medical Physics 37(10): 5434-5441.

  31. Rapid ESE Oxygen Imaging – 1 min Resolution 1 Spontaneous fluctuations of pO2 in tissues pO2 [torr] 2 60 3 1 2 0 3 T2 – based pO2 imaging

  32. Carbogen Challenge Experiment (2.5 min Images) The breathing gas is switched periodically between air and carbogen (95% O2 and 5% CO2) 95 % O2 21 % T1 +T2 pO2 imaging 1 60 50 pO2 pO2 [torr] 40 30 20 1 10 2 2 20 1 cm 10 pO2 [torr] 0 0 0 12.5 12.5 25 25 37.5 37.5 50 50 62.5 62.5 75 75 minutes minutes