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Spatial Localization and Multinuclear MR Spectroscopy Techniques
Navin Bansal, Ph.D. Associate Professor and Director of MR Research
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Proton MR Image MR images contain anatomical information based on the distribution of protons and the relative proton relaxation rates in various tissues MR images are based on proton signals from water and fat
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MR Spectrum MR spectroscopy determines the presence of certain chemical compounds Stress, functional disorders, or diseases can cause the metabolite concentration to vary Metabolite concentrations are low, generating ~10,000 times less signal intensity than the water signal
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Chemical Shift 1H MR spectra
The electron cloud around each nuclei shields the external magnetic field Because of differences in electron shielding, identical nuclei resonate at different frequencies The resonance frequency in the presence of shielding is expressed as: = (1- )Bo Where is the gyromagnetic ratio and Bo is the external magnetic field strength 1H MR spectra -CH3 -OH , ppm 2 1
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= (water - fat) 106/Bo, in ppm units
Chemical Shift The frequency shift increases with field strength. For example, shift difference between water and fat (water - fat) at 1.5 T is 255 Hz at 3.0 T is 510 Hz = (water - fat) 106/Bo, in ppm units water-fat is 3.5 ppm independent of field strength By convention Signals of weakly shielded nuclei with higher frequency are on the left Signals of more heavily shielded nuclei with lower frequency are on the right Chemical shift of water is set to 4.7 ppm at body temperature
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MR Spectrum: Peak Characteristics
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1H MR Spectrum from Brain
Water Signal Metabolite Signals
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Spatial Localization Surface Coil Localization
Simple surface coil acquisition Depth Resolved Surface Coil Spectroscopy, DRESS Single Volume Localization Image Selected In Vivo Spectroscopy, ISIS Point Resolved Spectroscopy, PRESS Stimulated Echo Acquisition Mode, STEAM Multiple Volume Acquisition Chemical Shift Imaging, CSI
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Surface Coil Acquisition
A simple loop of wire and associated circuit tuned to the desired frequency are placed directly over the tissue of interest to obtain spectra A surface coil Advantages Easy to build and does not require specialized pulse sequence Superb SNR and filling factor Disadvantages Must be close to region of interest Changing ROI is difficult Inhomogeneous RF field RF Pulse-acquire sequence
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Spin Echo Imaging Sequence
90° 180° 90° RF G z G y G x TE TR
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Depth Resolved Surface Coil
Spectroscopy, DRESS A disk-shaped slice is excited parallel to the surface coil with a frequency selective RF pulse in the presence of a gradient. Advantages Relatively simple Suppresses signal from superficial tissue Multi-slice acquisition, SLIT-DRESS Disadvantages T2 loss Partial Localization RF G slice
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Single Volume Localization
RF Gx Gy Gz Localized spectra is obtained from a single volume of interest (VOI) Localization is achieved by sequential selection of three orthogonal slices The size and location of VOI can be easily controlled Anatomic 1H images are used for localizing the VOI
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Single Volume Localization
Image selected in vivo spectroscopy, ISIS Point resolved spectroscopy, PRESS Stimulated echo acquisition mode, STEAM
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Image Selected In Vivo Spectroscopy ISIS
One Dimensional Slice inversion No inversion Subtraction 180o 90o RF G slice Two acquisitions with and without inversion of a selected slice are obtained and subtracted
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3D ISIS T1 G x y z 180° 1 90° 3 2 4 5 7 6 RF 8 + - A set of eight pulse sequences with one, two, or three slice selective inversion pulses are used The signal is localized to a VOI by adding signals from sequences 1, 5, 6, and 7 and subtracting signals from 2, 3, 4, and 8.
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Image Selected In Vivo Spectroscopy, ISIS
Advantages No T2 loss – 31P MRS Less sensitive to gradient imperfections Can be used with a surface coil Disadvantages Dynamic range Subtraction error due to motion
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Point Resolved Spectroscopy, PRESS
180° 180° 90° RF G x G y G z TE1/2 (TE1+TE2)/2 TE2/2 A slice-selective 90o pulse is followed by two slice-selective 180o refocusing pulses Achieves localization within a single acquisition Suitable for signals with long T2 – 1H MRS
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Stimulated Echo Acquisition Mode, STEAM
90° TM RF G x y z Three slice-selective 90o pulses form a stimulated echo from a single voxel. Achieves localization within a single acquisition Only half of the available signal is obtained Can achieve shorter TE than PRESS
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Effects of MR Parameters on
PRESS spectra Repetition Time, TR Number of Signal Averages Echo Time, TE Voxel Size
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Effect of Repetition Time (TR)
TR = 1500 ms TR = 5000 ms NAA Cr/PCr Cho
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Effect of Signal Averaging
8 Averages 64 Averages 256 Averages
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Effect of Voxel Size 1 cc 2 cc 4 cc 8 cc
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Effect of Echo Time, TE TE = 144 ms TE = 288 ms
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Short TE 1H Brain Spectrum
Healthy volunteer Additional Peaks Glx ppm ppm mI ppm Glucose ppm ppm And more
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The Lactate Doublet Tumor spectra: showing no NAA, Cho, mI, lactate Lipids and lactate Inverted lactate Upright lactate
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Single Voxel Spectroscopy: Overview
Simplicity Flexibility in voxel size and position Accurate definition of VOI Excellent shim and spectral resolution Many voxels within the same dataset
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Chemical Shift Imaging
Multiple localized spectra are obtained simultaneously from a set of voxels spanning the region of interest Uses same phase-encoding principles as imaging No gradient is applied during data collection, so spectral information is preserved RF G slice y z 90°
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CSI Spectral Map Display of all spectra
Underlying reference image shows voxel position Individual spectra can be displayed enlarged Spectral map can be archived together with the reference image and the CSI grid
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CSI Data Analysis Image showing voxel position Spectrum from a voxel
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Spectral Map and Metabolite Images
NAA NAA/Cho
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CSI: Overview Advantages Acquisition of multiple voxels
Metabolite images, spectral maps, peak information maps, and results table Many voxels within the same dataset Disadvantages Large volume – more difficult to shim Voxel bleeding Large datasets
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Multinuclear MR Spectroscopy
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Important Nuclei for Biomedical MR
Nucleus Spin , MHz/T Natural Abundance Relative Sensitivity 1H 1/2 42.576 99.985 100 2H 1 6.536 0.015 0.96 3He 32.433 .00013 44 13C 10.705 1.108 1.6 17O 3/2 5.772 0.037 2.9 19F 40.055 83.4 23Na 11.262 9.3 31P 17.236 6.6 39K 1.987 93.08 .05
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Important Nuclei for Biomedical MR
1H – Neurotransmitters, amino acids, membrane constituents 2H – Perfusion, drug metabolism, tissue and cartilage structure. 13C – Glycogen, metabolic rates, substrate preference, drug metabolism, etc. 19F – Drug metabolism, pH, Ca2+ and other metal ion concentration, pO2, temperature, etc 23Na – Transmembrane Na+ gradient, tissue and cartilage structure. 31P – Cellular energetics, membrane constituents, pHi, [Mg2+], kinetics of creatine kinase and ATP hydrolysis.
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1H MR Spectroscopy
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1H MR Spectra of the Brain
Short TE NAA Cr Cho Glx Ins Glx Lipids Cr 1.0 4.5 2.5 3.0 2.0 1.5 3.5 0.5 ppm
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Important 1H Signals N-Acetyl aspartate (NAA)
NAA is a neuronal marker and indicates density and viability of neurons. It is decreased in glioma, ischemia and degenerative diseases. CH3-C-NH-CH-CH2-COOH O CH2-COOH 2.02, CH3 2.52, CH2 2.70, CH2 4.40, CH Creatine (Cr), phosphocreatine (PCr) Cr is a marker of aerobic energy metabolism Cr signal is constant even with pathologic changes and may be used as a control value However, isolated cases of Cr deficiency may occur in children NH2-C-N-CH2-COOH CH3 NH 3.04, CH3 3.93, CH2
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Important 1H Signals Choline (Cho), choline compounds
Cho compounds are involved in phospholipid metabolism of cell membrane. Increase Cho mark tumor tissue or multiple sclerosis plaques 3.24, CH3 3.56, CH2 4.07, CH2 CH3-N-CH2-CH2-OH CH3 Glutamate (Glu), glutamine (Gln) Glu is a neurotransmitter, Gln a regulator of Glu metabolism It is hardly possible to detect their signals sepratly. The signals are jointly designated “Glx”. HOOC-CH2-CH2-CH-COOH NH2 NH2-CH2-CH2-CH-COOH 2.1, CH2 2.4, CH2 3.7, CH
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Important 1H Signals Lactate (Lac)
Lactate is the final product of glycolysis It can be detected in ischemic/hypoxic tissue and tumors indicating lack of oxygen CH3-CH-COOH OH 1.33, CH3 4.12, CH Taurine (Tau) Cells examination indicates taurine synthesis in astrocytes 3.27, NCH2 3.44, SCH2 NH2-CH2-CH2-S-OH Myo-inositol (Ins) Ins marks glia cells in brain It is decreased in hepatic encephalopathy and elevated in Alzheimer’s disease. PO4- 3.56, CH
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31P MR Spectroscopy
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31P MR Spectra of Normal Tissue
4 3 2 6 1 Muscle Heart Liver Kidney Brain -ATP -ATP -ATP PCr PDE Pi PME 4 2 6 3 1 7 5 3 6 2 7 4 1 6 5 3 2 4 1 7 6 5 4 3 2 1 10 -10 -20 ppm
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Important 31P Signals Adenosine triphosphate (ATP)
ATP is the energy currency in living systems - and -ATP have contributions from ADP, NAD and NADH -ATP is uncontaminated and used for quantification -ATP -7.8 -ATP -2.7 -ATP Phosphocreatine (PCr) PCr is used for storing energy and converting ADP to ATP It is absent in liver, kideny and red cells It is used as an internal reference for chemical shift 0 PCr
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Important 31P Signals Inorganic Phosphate (Pi) Phosphomonoester (PME)
Pi is generated from hydrolysis of ATP and increased in compromised tissue Its chemical shift is sensitive to pH 3.7 to 5.7 Pi Phosphomonoester (PME) PME signal contains contribution from membrane constituents and glucose-6-phosphate and glycerol-3 phosphate. It is elevated in tumors 5.6 to 8.1 PME Phosphodiester (PDE) PME signal contains contribution from membrane constituents 0.6 to 3.7 PDE
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Measurement of pH by 31P MRS
Shift, ppm 30 20 10 -10 -20 PCr ATP Pi PME H2PO4- HPO42- + H+ pKa = 6.75 é - ù ê obs H PO - pH = a pk + ú log 2 4 ê - ú ë û HPO 2 - obs 4
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Effect of Exercise on 31P MRS
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Detection of myocardial infarctions by
31P-MR spectroscopy Beer et al., J Magn Reson Imaging. 2004;20:
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A Lesson from 31P MRS Tumor Microenvironment Tumors are expected
Poor Vascularization and Perfusion Tumors are expected to be acidic Hypoxia Anaerobic Glycolysis Aerobic Glycolysis Increased Acid Production
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ü ý þ pH of Tumors and Normal Tissue Electrode Measurements Normal
5.6 6.0 6.4 6.8 7.2 7.6 A: pH POT ü ý þ Skeletal Muscle Normal Brain Tissue Skin Glioblastomas Astrocytomas Meningiomas Brain Metastases Malignant Melanomas Sarcomas Mammary Ca. Adenocarcenomas Squamous Cell Ca.
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pH of Tumors and Normal Tissue
MRS Measurements pH 5.6 6.0 6.4 6.8 7.2 7.6 B: pH NMR Skeletal Muscle ü ý þ Brain Normal Skin Tissue Heart Sarcomas Squamous Cell Ca. Mammary Ca. Brain Tumors Non-Hodgkin Lymp. Misc Tumors Bansal, et al.
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Spectroscopy and Imaging
23Na MR Spectroscopy and Imaging
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Biological Importance of Sodium
Sodium and other ions are inhomogeneously distributed across the cell membrane. A transmembrane sodium gradient reflects a dynamic equilibrium between Na+-K+ ATPase versus passive or mediated flux. The sodium gradient may be altered in certain diseased states. Normal cells maintain an intracellular concentration of approximately 5-35 mM against an extracellular concentration of approximately mM. This sodium concentration gradent is maintained by Na+-K+ ATPase and is essential to drive many physiologic function such as transport of other ions and substrats, maintenance of normal cell volume, muscle contractile function and transmission of nervous impulse, etc. In many diseased states such as hypertension, manic depressive disease, oncogensis and sepsis, alteration in intracellular concentration may occur due to abnormalities in ion transport and exchange process across the cell membrane. Therefore, noninvasive observation of intracellular Na+ may be useful in understanding the mechanism of diseased state and may also have important diagnostic utility. Bansal, et al.
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Biomedical 23Na NMR 23Na is the second most sensitive nucleus for biomedical NMR. Intra- and extracellular sodium resonate at the same frequency. Two approaches to distinguish between different sodium pools: Paramagnetic Shift Reagents Multiple Quantum Filters 23Na is the second most sensitive NMR nuclei in tissue and has been the focus of numerous recent imaging studies in humans. However, standard NMR techniques alone are unable to separate intra- and extracellular Na+ because, Na+ exists in only one chemical form is tissue and the 23Na signals from intra- and extracellular compartments are coincident. Our current research involves developing and evaluating two techniques for discriminating between intra- and extracellular sodium. The first technique is based on the use of paramagnetic shift reagents. The second technique, multiple quantum filters, does not require any exogenous reagent and can be applied to humans. Bansal, et al.
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23Na Shift Reagents SRs are membrane impermeable negatively charged chelates of a lanthanide metal ion. They interact with extracellular Na+, causing its signal to be shifted away from intracellular Na+. Na+e Na+e Na+e Na+i Na+i Na+e Na+e Na+e SR Na+e SR SR
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Action of a Typical Shift Reagent
With SR Nae Nai 10 ppm Without SR Nai + Nae 10 ppm Bansal, et al.
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23Na Shift Reagents O N Dy P Tm Dy(PPP)27- DyTTHA3- TmDOTP5-
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In Vivo 23Na Spectra after TmDOTP5- Infusion
Muscle Heart Liver Brain Kidney Ext Int x 5 Urine 9L Glioma 40 30 20 10 -10 ppm Bansal, et al.
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Nai in Perfused RIF-1 Tumor Cells
Significance: ** p < 0.01 (with vs without EIPA) 200 37 oC 45 oC 37 oC Hyperthermia produced a 60-70% increase in Nai+. The increase in Nai+ is mainly due to an increase Na+/H+ antiporter activity ** 180 ** w/o EIPA ** 160 with EIPA Relative Nai Signal Intensity 140 120 EIPA 100 80 -10 -20 -10 10 20 30 40 50 60 70 80 Time, min Bansal, et al.
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Multiple-Quantum Filters
MQFs depend only on the relaxation properties of 23Na. Thus, they do not produce any known physiological perturbation to the biological system and cab be applied to humans. Disadvantages Low signal-to-noise ratio Some Nae+ contribution Bansal, et al.
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MQ Filtered 23Na NMR “Transiently bound” Na+ can pass through a MQ filter. |-3/2> SQ outer |-1/2> SQ inner TQ DQ |1/2> SQ outer DQ |3/2> “Free” Na+ “Transiently Bound” Na+ Concentration of macromolecules within the cytoplasm is relatively high while the extracellular milieu is largely aqueous.
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SQ and TQ Filtered 23Na Spectra of a Phantom
Aqueous Agarose 40 mM TmDOTP5- 10% Agarose SQ TQ Agarose ppm 50 -50 ppm 50 -50 Bansal, et al.
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Composition of Tissue Compartments
200 180 160 140 120 100 80 60 40 20 m Eq/L H2O H2CO3 HCO3- Cl - Nonelectrolytes H2CO3 Nonelectrolytes H2CO3 HCO3- HCO3- HPO4-2 K+ Na+ Cl - Na+ SO4-2 Cl - Na+ HPO4-2 Protein SO4-2 HPO4-2 Organic acids SO4-2 Mg+2 K+ Organic acids Ca+2 Protein Ca+2 K+ Mg+2 Mg+2 Protein Blood plasma Interstitial fluid Intracellular fluid
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3D MQF 23Na Imaging Pulse Sequence
RF Readout Phase Encoding 1 Phase Encoding 2 PD (100 ms) DELTA () (3 µs) TAU () (3 ms) TE (4 ms)
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3D SQ and TQF 23Na MRI of a Live Rat
Caronal Sections SQ TQF
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SQ and TQF 23Na MRI of Rat In vivo
Effect of CCl4 Treatment Control CCl4 Treated bladder kidney heart lung saline agarose SQ Liver TQF
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