Sodium MRI in the Clinic: What You Can Learn from a 10 Min Scan
Armin Nagel1

1Institute of Radiology, University Hospital Erlangen, Erlangen, Germany

Synopsis

Sodium Ions (Na+) play an important role in many cellular physiological processes. In healthy tissue, the extracellular concentration of Na+ is approximately ten-fold higher than the intra­cellular concentration. A breakdown of this concentration gradient or an increase of the intracellular sodium content can be used as an early marker in many disease processes. In this presentation the focus will be on brain-related applications of sodium MRI. In addition, the required hardware, as well as image acquisition and post-processing techniques that are suitable for sodium MRI will be discussed.

Target Audience

MR scientists and clinicians interested in gathering the operational knowledge required to use sodium (23Na) MRI for studying basic and pathological brain metabolism.

Highlights

  • Sodium ions (Na+) play an important role in cellular ion homeostasis and cell viability.
  • In healthy tissue, the extracellular Na+ concentration (Na+ec = 145 mmol/L) is about ten-fold higher than the intracellular concentration (Na+ic = 10 – 15 mmol/L).
  • Sodium (23Na) has the most favorable properties for in vivo MRI after 1H.
  • 23Na MRI requires dedicated hardware and efficient UTE acquisition techniques. In addition, iterative image reconstruction and advanced post-processing techniques can be beneficial.

Introduction

Sodium ions (Na+) play an important role in many cellular physiological processes. In healthy tissue, the extracellular concentration of Na+ is approximately ten-fold higher than the intracellular concentration ([Na+]ic = 10 – 15 mmol/L, [Na+]ec = 145 mmol/L). The enzyme Na+-K+-ATPase helps to maintain this gradient by pumping Na+ out and potassium (K+) into the cell with a ratio of 3:2. A breakdown of this concentration gradient or an increase of the intracellular sodium content can be used as an early marker in many disease processes. There is a large variety of biomedical research applications where sodium MRI has been applied (1). This topic is covered by several review articles (e.g. (2-6)). In this presentation, the focus will be on brain-related applications. In addition, the required hardware, as well as image acquisition and post-processing techniques that are suitable for sodium MRI will be discussed.

Applications of Sodium MRI in the Brain

Sodium MRI has been used to study brain tumors (3,7-11), ischemic stroke (12,13), Alzheimer’s diseases (14), Huntington’s disease (15), traumatic brain injury (16) and multiple sclerosis (17). Sodium ion channels and sodium accumulation are expected to play a role in the pathogenesis of multiple sclerosis (18,19). Thus, several recent studies focused on sodium MRI in multiple sclerosis (17). In brain tumors, sodium concentrations are typically increased. This increase can be caused by edema (i.e. increased extracellular volume fraction) or by an increase of the intracellular concentration (e.g. due to cell depolarization). Sodium inversion recovery imaging might help to separate between these two underlying reasons (8). In ischemic stroke, sodium MRI might be used to identify regions with preservation of the ionic homeostasis (20). Tissue sodium concentrations above approximately 70 mmol/L indicate irreversible tissue damage (13). However, long acquisition times and the experimental character of sodium MRI (e.g. the requirement for a change of the RF coil) have so far prevented application of sodium MRI in larger clinical studies that involve stroke patients. Sodium MRI can also be used to study the cell volume fraction during normal ageing (21). It was shown that the in vivo tissue cell volume fraction remains constant with advancing age in all brain regions in normal individuals.

Challenges of Sodium MRI

As indicated above, there is a large variety of interesting clinical research applications for sodium MRI. However, imaging of sodium (23Na) is challenging due to several reasons:

  1. The in vivo concentration of 23Na is more than 1000-fold lower than the in vivo concentration of 1H.
  2. The MR sensitivity of the 23Na nucleus is only 9.3% of the MR sensitivity of 1H.
  3. The spin-3/2 nucleus 23Na exhibits an electrical quadrupole moment that leads to short transverse relaxation times.
  4. The Larmor frequency of 23Na is approximately a factor of four lower than the Larmor frequency of 1H. This requires additional hardware and radiofrequency coils.

Technical Developments for Sodium MRI

There are several technical developments that help to overcome the above mentioned limitations. The first sodium MR images of an animal and the human brain were already acquired in the 1980s (22,23). In the past decade, there was an increase of interest in sodium MRI due to the increasing availability of high-field (B0 = 3 T) and ultra-high field MRI systems (B0 ≥ 7 T). Ultra-high field MRI largely extends the capabilities of sodium MRI (24), since the increased signal-to-noise ratio (SNR) enables increased spatial resolutions. In addition, high-performance radiofrequency coils (25), efficient ultra-short echo time (UTE) pulse sequences (26), iterative image reconstruction techniques (27-29), and new post-processing techniques (30) have further improved image quality and quantitative accuracy of sodium MRI.

Hardware:

Since all nuclei exhibit different Larmor frequencies, imaging of 23Na (and also other non-proton nuclei) requires dedicated hardware, such as a broad-band amplifier and appropriate transmit and receive radiofrequency (RF) coils. Double-tuned RF coils are often used. Normally, they are tuned to the desired non-proton frequency and to the 1H frequency. The latter enables co-registered acquisition of morphological images and non-proton data. Additionally, B0-shimming can be performed on the 1H frequency. However, the double-resonance complicates coil design and leads to a tradeoff compared to signal-tuned coils (31). Since the RF coils are usually optimized for the low SNR non-proton nucleus (e.g. 23Na), SNR, and diagnostic quality of the conventional 1H MRI data is usually reduced compared to conventional, single resonant 1H RF coils. Wiggins et al. provided an up-to-date review article about high-performance radiofrequency coils for 23Na MRI (25). Array coils can be used to improve SNR in sodium MRI (32-34). However, a conventional sum-of-squares reconstruction of the multi-channel data can result in a noise floor that degrades image quality. Thus, the application of multichannel array coils requires advanced image reconstruction techniques such as sensitivity encoding (SENSE) (35,36) or adaptive combination (33,37).

Image acquisition techniques:

Due to the short transverse relaxation times, ultra-short echo time (UTE) techniques are recommended to acquire the images. The shortest TEs can be achieved by acquiring the data from the center of k-space in a radial or spiral manner. Conventional 3D radial MRI has been widely used for sodium MRI (38). However, improvements in terms of SNR efficiency and reduced susceptibility to artifacts can be achieved by modifying the sampling density along a radial projection (39) or by spiral readout trajectories such as twisted-projection imaging (40), 3D cones (41), or the FLORET technique (42). Techniques to correct for B0- and B1-inhomogeneities can be applied to further improve the quantitative accuracy (43-45). In general, sodium MRI provides a volume- and relaxation-weighted signal of the intra- and extracellular compartment. To derive the total tissue sodium concentration, relaxation-weighting needs to be minimized (i.e. TE < 0.5 ms; TR > 150 ms). However, relaxation-weighting can also be used to provide at least a partial separation between different sodium compartments. For instance an inversion recovery preparation can be employed to suppress signal from the cerebrospinal fluid (46) and, for example, has been applied to study brain tumors (8,47). Another non-invasive approach to separate different sodium pools is based on multiple-quantum filtering techniques (48,49).

Image reconstruction and post-processing techniques:

Iterative image reconstruction techniques can markedly improve image quality in sodium MRI (27,28,50). In addition, prior knowledge about tissue boundaries can be incorporated into the image reconstruction process to reduce partial volume effects (29,51). In particular in sodium MRI of the brain, partial volume effects can lead to a bias in measured sodium concentrations of brain gray and white matter. Methods that enable correction of partial volume effects such as the geometric transfer matrix approach can reduce this bias (30).

Conclusions

Sodium MRI largely benefits from the advent of ultra-high field MRI systems (B0 ≥ 7 T) and the development of new image acquisition and reconstruction techniques. In brain, sodium MRI has been applied - among others - to study the progression of multiple sclerosis, to investigate brain tumors and ischemic stroke. Sodium MRI is a valuable research tool which can help to visualize pathological processes that involve the ion homeostasis. Thus, sodium MRI has the potential to evolve from a clinical research tool to a diagnostic tool in the near future.

Acknowledgements

References

  1. Madelin G, Regatte RR. Biomedical applications of sodium MRI in vivo. J Magn Reson Imaging 2013;38(3):511-529.
  2. Regatte RR. Advances in sodium MRI: biomedical applications from head to foot. NMR Biomed 2016;29(2):94-95.
  3. Schepkin VD. Sodium MRI of glioma in animal models at ultrahigh magnetic fields. NMR Biomed 2016;29(2):175-186.
  4. Shah NJ, Worthoff WA, Langen KJ. Imaging of sodium in the brain: a brief review. NMR Biomed 2016;29(2):162-174.
  5. Boada FE, Laverde G, Jungreis C, Nemoto E, Tanase C, Hancu I. Loss of cell ion homeostasis and cell viability in the brain: what sodium MRI can tell us. Curr Top Dev Biol 2005;70:77-101.
  6. Ouwerkerk R. Sodium MRI. Methods Mol Biol 2011;711:175-201.
  7. Biller A, Badde S, Nagel A, Neumann JO, Wick W, Hertenstein A, Bendszus M, Sahm F, Benkhedah N, Kleesiek J. Improved Brain Tumor Classification by Sodium MR Imaging: Prediction of IDH Mutation Status and Tumor Progression. AJNR Am J Neuroradiol 2016;37(1):66-73.
  8. Nagel AM, Bock M, Hartmann C, Gerigk L, Neumann JO, Weber MA, Bendszus M, Radbruch A, Wick W, Schlemmer HP, Semmler W, Biller A. The potential of relaxation-weighted sodium magnetic resonance imaging as demonstrated on brain tumors. Invest Radiol 2011;46(9):539-547.
  9. Thulborn KR, Lu A, Atkinson IC, Damen F, Villano JL. Quantitative sodium MR imaging and sodium bioscales for the management of brain tumors. Neuroimaging Clin N Am 2009;19(4):615-624.
  10. Ouwerkerk R, Bleich KB, Gillen JS, Pomper MG, Bottomley PA. Tissue sodium concentration in human brain tumors as measured with 23Na MR imaging. Radiology 2003;227(2):529-537.
  11. Laymon CM, Oborski MJ, Lee VK, Davis DK, Wiener EC, Lieberman FS, Boada FE, Mountz JM. Combined imaging biomarkers for therapy evaluation in glioblastoma multiforme: correlating sodium MRI and F-18 FLT PET on a voxel-wise basis. Magn Reson Imaging 2012;30(9):1268-1278.
  12. Thulborn KR, Gindin TS, Davis D, Erb P. Comprehensive MR imaging protocol for stroke management: tissue sodium concentration as a measure of tissue viability in nonhuman primate studies and in clinical studies. Radiology 1999;213(1):156-166.
  13. Thulborn KR, Davis D, Snyder J, Yonas H, Kassam A. Sodium MR imaging of acute and subacute stroke for assessment of tissue viability. Neuroimaging Clin N Am 2005;15(3):639-653, xi-xii.
  14. Mellon EA, Pilkinton DT, Clark CM, Elliott MA, Witschey WR, 2nd, Borthakur A, Reddy R. Sodium MR imaging detection of mild Alzheimer disease: preliminary study. AJNR Am J Neuroradiol 2009;30(5):978-984.
  15. Reetz K, Romanzetti S, Dogan I, Sass C, Werner CJ, Schiefer J, Schulz JB, Shah NJ. Increased brain tissue sodium concentration in Huntington's Disease - a sodium imaging study at 4 T. Neuroimage 2012;63(1):517-524.
  16. Madelin G, Silver JM, Bushnik T, Kirov II. In: Proc Intl Soc Mag Reson Med 24 (2016):1210.
  17. Petracca M, Fleysher L, Oesingmann N, Inglese M. Sodium MRI of multiple sclerosis. NMR Biomed 2016;29(2):153-161.
  18. Waxman SG. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nat Rev Neurosci 2006;7(12):932-941.
  19. Smith KJ. Sodium channels and multiple sclerosis: roles in symptom production, damage and therapy. Brain Pathol 2007;17(2):230-242.
  20. Tsang A, Stobbe RW, Asdaghi N, Hussain MS, Bhagat YA, Beaulieu C, Emery D, Butcher KS. Relationship between sodium intensity and perfusion deficits in acute ischemic stroke. J Magn Reson Imaging 2011;33(1):41-47.
  21. Thulborn K, Lui E, Guntin J, Jamil S, Sun Z, Claiborne TC, Atkinson IC. Quantitative sodium MRI of the human brain at 9.4 T provides assessment of tissue sodium concentration and cell volume fraction during normal aging. NMR Biomed 2016;29(2):137-143.
  22. Hilal SK, Maudsley AA, Ra JB, Simon HE, Roschmann P, Wittekoek S, Cho ZH, Mun SK. In vivo NMR imaging of sodium-23 in the human head. J Comput Assist Tomogr 1985;9(1):1-7.
  23. Hilal SK, Maudsley AA, Simon HE, Perman WH, Bonn J, Mawad ME, Silver AJ, Ganti SR, Sane P, Chien IC. In vivo NMR imaging of tissue sodium in the intact cat before and after acute cerebral stroke. AJNR Am J Neuroradiol 1983;4(3):245-249.
  24. Kraff O, Fischer A, Nagel AM, Monninghoff C, Ladd ME. MRI at 7 Tesla and Above: Demonstrated and Potential Capabilities. J Magn Reson Imaging 2015;41(1):13-33.
  25. Wiggins GC, Brown R, Lakshmanan K. High-performance radiofrequency coils for 23Na MRI: brain and musculoskeletal applications. NMR Biomed 2016;29(2):96-106.
  26. Konstandin S, Nagel AM. Measurement techniques for magnetic resonance imaging of fast relaxing nuclei. Magn Reson Mater Phy 2014;27(1):5-19.
  27. Madelin G, Chang G, Otazo R, Jerschow A, Regatte RR. Compressed sensing sodium MRI of cartilage at 7T: preliminary study. J Magn Reson 2012;214(1):360-365.
  28. Behl NG, Gnahm C, Bachert P, Ladd ME, Nagel AM. Three-dimensional dictionary-learning reconstruction of 23Na MRI data. Magn Reson Med 2016;75(4):1605-1616.
  29. Gnahm C, Bock M, Bachert P, Semmler W, Behl NG, Nagel AM. Iterative 3D projection reconstruction of 23Na data with an 1H MRI constraint. Magn Reson Med 2014;71(5):1720-1732.
  30. Niesporek SC, Hoffmann SH, Berger MC, Benkhedah N, Kujawa A, Bachert P, Nagel AM. Partial volume correction for in vivo 23Na-MRI data of the human brain. Neuroimage 2015;112:353-363.
  31. Mispelter J, Lupu M, Briguet A. Nmr Probeheads for Biophysical And Biomedical Experiments: Theoretical Principles And Practical Guidelines. London: Imperial College Press; 2006.
  32. Qian Y, Zhao T, Wiggins GC, Wald LL, Zheng H, Weimer J, Boada FE. Sodium imaging of human brain at 7 T with 15-channel array coil. Magn Reson Med 2012;68(6):1807-1814.
  33. Benkhedah N, Hoffmann SH, Biller A, Nagel AM. Evaluation of adaptive combination of 30-channel head receive coil array data in 23Na MR imaging. Magn Reson Med 2016;75(2):527-536.
  34. Shajan G, Mirkes C, Buckenmaier K, Hoffmann J, Pohmann R, Scheffler K. Three-layered radio frequency coil arrangement for sodium MRI of the human brain at 9.4 Tesla. Magn Reson Med 2016;75(2):906-916.
  35. Pruessmann KP, Weiger M, Scheidegger MB, Boesiger P. SENSE: sensitivity encoding for fast MRI. Magn Reson Med 1999;42(5):952-962.
  36. Qian Y, Stenger VA, Boada FE. Parallel imaging with 3D TPI trajectory: SNR and acceleration benefits. Magn Reson Imaging 2009;27(5):656-663.
  37. Walsh DO, Gmitro AF, Marcellin MW. Adaptive reconstruction of phased array MR imagery. Magn Reson Med 2000;43(5):682-690. (6):1565-1573.
  38. Jerecic R, Bock M, Nielles-Vallespin S, Wacker C, Bauer W, Schad LR. ECG-gated 23Na-MRI of the human heart using a 3D-radial projection technique with ultra-short echo times. MAGMA 2004;16(6):297-302.
  39. Nagel AM, Laun FB, Weber MA, Matthies C, Semmler W, Schad LR. Sodium MRI using a density-adapted 3D radial acquisition technique. Magn Reson Med 2009;62(6):1565-1573.
  40. Boada FE, Gillen JS, Shen GX, Chang SY, Thulborn KR. Fast three dimensional sodium imaging. Magn Reson Med 1997;37(5):706-715.
  41. Gurney PT, Hargreaves BA, Nishimura DG. Design and analysis of a practical 3D cones trajectory. Magn Reson Med 2006;55(3):575-582.
  42. Pipe JG, Zwart NR, Aboussouan EA, Robison RK, Devaraj A, Johnson KO. A new design and rationale for 3D orthogonally oversampled k-space trajectories. Magn Reson Med 2011;66(5):1303-1311.
  43. Lu A, Atkinson IC, Claiborne TC, Damen FC, Thulborn KR. Quantitative sodium imaging with a flexible twisted projection pulse sequence. Magn Reson Med 2010;63(6):1583-1593.
  44. Allen SP, Morrell GR, Peterson B, Park D, Gold GE, Kaggie JD, Bangerter NK. Phase-sensitive sodium B1 mapping. Magn Reson Med 2011;65(4):1125-1130.
  45. Lommen J, Konstandin S, Kramer P, Schad LR. Enhancing the quantification of tissue sodium content by MRI: time-efficient sodium B mapping at clinical field strengths. NMR in Biomed 2016;29(2):129-136.
  46. Stobbe R, Beaulieu C. In vivo sodium magnetic resonance imaging of the human brain using soft inversion recovery fluid attenuation. Magn Reson Med 2005;54(5):1305-1310.
  47. Kline RP, Wu EX, Petrylak DP, Szabolcs M, Alderson PO, Weisfeldt ML, Cannon P, Katz J. Rapid in vivo monitoring of chemotherapeutic response using weighted sodium magnetic resonance imaging. Clin Cancer Res 2000;6(6):2146-2156.
  48. Pekar J, Renshaw PF, Leigh JS. Selective detection of intracellular sodium by coherence-transfer NMR. J Magn Reson (1969) 1987;72(1):159-161.
  49. Jaccard G, Wimperis S, Bodenhausen G. Multiplequantum NMR spectroscopy of S=3/2 spins in isotropic phase: A new probe for multiexponential relaxation. J Chem Phys 1986;85:6282.
  50. Weingartner S, Wetterling F, Konstandin S, Fatar M, Neumaier-Probst E, Schad LR. Scan time reduction in Na-magnetic resonance imaging using the chemical shift imaging sequence: Evaluation of an iterative reconstruction method. Z Med Phys 2015;25(3):275-286.
  51. Gnahm C, Nagel AM. Anatomically weighted second-order total variation reconstruction of 23Na MRI using prior information from 1H MRI. Neuroimage 2015;105:452-461.
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