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Principles of EPR oxygen imaging In Vivo Oxygen Imaging Workshop University of Chicago June 25, 2012. Boris Epel. Outline. Principles of EPR EPR spin probes EPR imaging principles Image registration and tumor localization Image visualization and statistics. What is spin. - PowerPoint PPT Presentation
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Principles of EPR oxygen imagingIn Vivo Oxygen Imaging Workshop University of Chicago June 25, 2012
Boris Epel
Outline
• Principles of EPR• EPR spin probes• EPR imaging principles• Image registration and tumor localization• Image visualization and statistics
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.
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
μ
SNe-
Design of EPR experiment
S
N S
N
S
N
Constant field B0
Radio frequency,
Magnet will return back in some time:longitudinal relaxation
EPR is the resonant absorption of radio frequency radiation by paramagnetic systems in the presence of an applied constant magnetic field
Electron magnetic moment isn’t free to adopt an arbitrary orientation. There is a discrete set of orientations possible.
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.
EPR oxymetry probes
Soluble probes
A NitroxidesB Trityl radicals • Concentration (μM) of dissolved oxygen in the
bulk volume• Resolution 1 mmHgParticulate (Solid) probes
C Lithium phthalocyanine and its derivatives
What EPR can measure
Oxygen, pO2
Redox statusAcidosis, pHThiols (GSH)Cell viabilityViscosityTissue perfusionMolecular motion
Oxygen, pO2
Operational frequency
What is the optimum frequency? - depends on sample size
Frequency ~250 MHz ~750 MHz 1-2 GHz
Penetration > 10 cm 6-8 cm 1-1.5 cm
Object Mouse, rat, rabbit
Mouse, full body
Mouse part
Biological samples contain large proportion of water. They are aqueous andhighly 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.
EPR vs MRI
MRI EPR
Magnetic field at 250 MHz 5.9 T 9 mT
Radiofrequency pulse width μsec – msec 10 – 100 nsec
Relaxation rates msec – sec nsec - μsec
Endogenous probes Water protons -
Exogenous probes - Nitroxides, trityl
Concentration >60 M < 1 mM
Stability Stable Minutes
Line width Hz – kHz 100 kHz - MHz
In Vivo EPR Oxygen Imaging
Trityl iv line
Mousecradle
Resonator
Fiducials
Bladder flushing line
Cutaneous thermocouple
Gas anesthe-sia mask
Tumor in the cast
Spectroscopy vs Parametric Imaging
Inhomogeneous distribution
High O2
Low O2
Slow relax.
Fast relax.
One dimensional Two dimensional Three-dimensional
Image Dimensionality
Imaging Principles
• Application of the linear magnetic field gradient
B
Magnetic Field Gradient
Please do not leave metal objects close to the imager
Homogeneous field, B0 Linear gradient, 00 Linear gradient, 450
‘projection’
Imaging Principles
• Application of the linear magnetic field gradient
• Obtaining multiple projections by use of different gradients orientations
B
-0.50
0.5-0.5
0
0.5
0.2
0.4
0.6
0.8
GX
(G/cm)
GY
(G/cm)
GZ (
G/c
m)
Imaging Principles
• Application of the linear magnetic field gradient
• Obtaining multiple projections by use of different gradients orientations
• Image reconstruction (filtered backprojection)
B
-0.50
0.5-0.5
0
0.5
0.2
0.4
0.6
0.8
GX
(G/cm)
GY
(G/cm)
GZ (
G/c
m)
Imager magnet
Electron Spin Echo Oxygen Imaging
T1 or T2 [s]
pO2 [torr]
Spin-probeconcentration [mM]
Amplitude [a.u.]
Deoxygenated OXO63 spin probe
pO2 = (R – R (0 torr, 0 mM) - C)
R = 1/2T1 or 2 [mG]
Image resolution
spatial 1.2 mmtemporal 10 min (2.5 min rapid protocol)pO2 1 torr
Pulse EPR: imaging sequences
Electron Spin Echo (ESE) – T2 imaging
t t
t tT
Inversion recovery (IRESE) – T1 imaging
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
Imaging Procedures
Prepare an animal
Install animal in the resonator cradle
Install resonator into imager
Inject spin probe
Image an animal
Observe pO2 imageAcquire pO2 statistics
Determine area of interest
Acquire MRI image
Register EPRI and MRI
Acquire CT/PET image
Register CT/PET and EPR
Optional
ROI
ESE and MR Image Registration
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.
Mouse leg in the resonator. Polysiloxane half-cast with inserted fiducials
3D view of MRI and amplitude ESEI image registration. Fiducials are used to establish the coordinate transformation from MRI into ESE coordinate system
24
ESE and MRI Image RegistrationFiducials
MRI
EPROI pO2
Multimodality Rat Imaging
A
B
C
D
Multi-B ESE
18F-FDG PET
T2-weighted MRI
C
pO2
EPR oxygen image visualization
Region of interestin this case area of the tumor from a registered MRI image
‘Three orthogonal slices’ view
ROI and general statistics
Colormap and view adjustment
Cursor statistics
Cursor
Summary
In vivo EPR spectroscopy and imaging methodsenable noninvasive measurement and mapping of tissue pO2.
Image resolutionspatial 1.2 mmtemporal 10 min (2.5 min rapid protocol)pO2 1 torr
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.
Imaging of Cycling Hypoxia
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.
EPR Single Point ImagingImage 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.
19F MRIImage duration 3 minutes.
Rapid ESE Oxygen Imaging – 1 min Resolution
0 5 10 15 20 2530
35
40
45
50
55
60
N image
0 5 10 15 20 2510
15
20
25
30
35
40
N image
0 5 10 15 20 250
5
10
15
20
25
N image
13
2
1
2
3
pO2 [torr]
T2 – based pO2 imaging
Spontaneous fluctuations of pO2 in tissues
60
0
Carbogen Challenge Experiment (2.5 min Images)
The breathing gas is switched periodically between air and carbogen (95% O2 and 5% CO2)
1 cm
10
20
30
40
50
60
0 12.5 25 37.5 50 62.5 75
minutes
21 %
95 %
0
10
20
0 12.5 25 37.5 50 62.5 75
minutes
pO2 [
torr
]pO
2 [to
rr]
O2
12
1
2
pO2
T1 +T2 pO2 imaging