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(Radiology. 2000;216:559-568.)
© RSNA, 2000

Musculoskeletal Imaging

Human Skeletal Muscle: Sodium MR Imaging and Quantification-Potential Applications in Exercise and Disease1

Chris D. Constantinides, MSE, Joseph S. Gillen, BS, Fernando E. Boada, PhD, Martin G. Pomper, MD, PhD and Paul A. Bottomley, PhD

1 From the Departments of Biomedical Engineering (C.D.C.) and Radiology (J.S.G., M.G.P., P.A.B.), Johns Hopkins University School of Medicine, 720 Rutland Ave, Traylor Bldg, 6th Floor, Rm 606, Baltimore, MD 21205; and the Department of Radiology, University of Pittsburgh Medical Center, Pa (F.E.B.). From the 1999 RSNA scientific assembly. Received May 25, 1999; revision requested July 22; final revision received October 12; accepted October 21. C.D.C. and J.S.G supported in part and P.A.B. supported by National Institutes of Health grant RO1 HL61695. C.D.C. and F.E.B. funded partially through the Whitaker Foundation. Address correspondence to C.D.C. (e-mail: constant@bme.jhu.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
PURPOSE: To use sodium 23 magnetic resonance (MR) imaging to quantify noninvasively total sodium in human muscle and to apply the technique in exercise and musculoskeletal disease.

MATERIALS AND METHODS: Total [Na] sodium was determined from the ratio of the relaxation-corrected 23Na signal intensities measured from short echo-time (0.4 msec) 23Na images to those from an external saline solution reference. The method was validated with the blinded use of saline solutions of varying sodium concentrations. [Na] was measured in the calf muscles in 10 healthy volunteers. 23Na MR imaging also was performed in two healthy subjects after exercise, two patients with myotonic dystrophy, and two patients with osteoarthritis.

RESULTS: 23Na MR imaging yielded a total [Na] value of 28.4 mmol/kg of wet weight ± 3.6 (SD) in normal muscle, consistent with prior biopsy data. Spatial resolution was 0.22 mL, with signal-to-noise ratio of 10–15. Mean signal intensity elevations were 16% and 22% after exercise and 47% and 70% in dystrophic muscles compared with those at normal resting levels. In osteoarthritis, mean signal intensity reductions were 36% and 15% compared with those in unaffected knee joints.

CONCLUSION: 23Na MR imaging can be used to quantify total [Na] in human muscle. The technique may facilitate understanding of the role of the sodium-potassium pump and perfusion in normal and diseased muscle.

Index terms: Arthritis, degenerative, 452.77 • Cartilage, MR, 452.121412, 452.12145 • Magnetic resonance (MR), sodium studies, 45.121412, 45.12145 • Magnetic resonance (MR), spectroscopy, three-dimensional, 45.12145 • Muscles, diseases, 45.831 • Muscles, MR, 45.121412, 45.12145


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
Sodium plays a vital role in cellular function and integrity. It is overall eight to 10 times more concentrated in the extracellular than in the intracellular space. The sodium concentration gradient across the cellular membrane and the transmembrane sodium fluxes are regulated by the sodium-potassium pump, which plays an important role in cellular processes, including synaptic transmission, osmotic balance, solute transport, and calcium exchange in muscular contraction. Alterations in total sodium content and in transmembrane sodium flux rates occur in numerous normal and disease conditions, including exercising muscle (1), cellular proliferation during oncogenesis (2,3), ischemic heart disease (4,5), and skeletal myopathies (6,7).

Myotonic dystrophy is, for example, an inherited dominant multisystem disease with high penetrance and prevalence (8), and it has been linked to alterations in sodium channel conductance regulation (6,9,10). Such alterations have been shown to cause elevated muscle fiber concentrations that correlate with disease severity (7). In cartilage, too, sodium ions bind to macromolecular cartilaginous glycosaminoglycan complexes in the extracellular matrix, the content of which is an important index of the severity of osteoarthritic disease (11–14).

Serum sodium measurements are used routinely in the clinic to detect electrolyte imbalances and to assess response to therapy. Although serum measurements are minimally invasive, they indicate changes only as they affect the entire blood pool and are therefore relatively insensitive to local changes in tissue sodium within an organ. The standard method of providing localized measurements of tissue sodium levels is the needle biopsy. Muscle tissue biopsy, however, is invasive and painful. It generally is limited to sampling only relatively superficial locations, and it often is subject to errors associated with contamination from sodium in blood and fat, variability in the extracellular fluid content, and fiber type (15).

Sodium 23 magnetic resonance (MR) provides a unique tool for noninvasive in vivo study of total tissue sodium. 23Na MR spectroscopic and MR imaging studies have been performed for more than 3 decades for detection, imaging, and quantification of total tissue sodium in biologic tissue (16–20). A concern, however, of some investigators (16,21,22) was that only 30%–40% of total tissue sodium content was visible from the evoked MR imaging or MR spectroscopic signal intensity from muscle, kidney, and brain. Such observations were attributed to nuclear quadripolar interactions that resulted from the spin quantum number of 3/2 of the sodium nucleus (23) and its interactions with tissue macromolecules. Consistent with such observations is the fact that, in biologic tissue, sodium exhibits a biexponential transverse relaxation, with fast (T2f) and slow (T2s) spin-spin relaxation times (24). The slow component potentially can represent up to 60% of the total sodium signal intensity, depending on the tissue type (24,25). For skeletal muscle, T2f values of approximately 1 msec result in the loss of a major portion of this short component with the use of long echo times (echo time >= 3T2f), which leads to reduced signal-to-noise ratios and potential errors in the determination of tissue sodium content by means of 23Na MR imaging.

We demonstrate a method for measuring sodium in skeletal muscle by using a three-dimensional twisted-projection imaging sequence with a short echo time. We report three-dimensional, high-spatial-resolution (0.22-mL) 23Na images of skeletal muscle obtained with the use of a clinical 1.5-T MR imaging system and present a method for noninvasive quantification of total sodium from such images. We demonstrate applications of 23Na imaging to selective muscle recruitment in exercise, knee cartilage degeneration in osteoarthritis, and atrophy in myotonic dystrophy, in which anatomic proton, or hydrogen 1, MR imaging abnormalities were previously reported (26–28). Our intent is that the addition of quantitative 23Na MR imaging to conventional 1H MR imaging performed with the use of clinical 1.5-T imagers will provide new opportunities for probing the role of sodium in muscle disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
Muscle MR Imaging Protocol
All MR imaging studies were performed with a commercially available 1.5-T MR imaging system (Signa, Horizon, or Echo Speed on a 5.6 Epic platform; GE Medical Systems, Milwaukee, Wis) equipped with spectroscopic broadband capabilities and a gradient accelerator module. Gradient amplifiers were capable of generating waveforms with a maximum amplitude of 2.2 mT/m and a maximum slew rate of 120 mT/m/msec, with a slew rate duty cycle limit of 20%.

Muscle 23Na MR imaging was performed in the lower legs of a group of 10 healthy volunteers (eight men, two women; age range, 22–34 years). Written informed consent was obtained from all volunteers prior to the studies, as required by the Johns Hopkins institutional review board that approved our study. The volunteers were positioned with the calf in the center of a 16-pole sodium birdcage coil (Qloaded/Qunloaded = 3.15) singly tuned to 16.9 MHz and interfaced with a quadrature 90° phase-splitter circuit.

Subjects were positioned in the magnet, and multisection gradient-echo transverse proton, or 1H, MR imaging was performed with the body or extremity coil at the level of interest. The imager's automatic shimming routine was used to optimize the magnetic field homogeneity on the basis of the 1H signal. The lower legs were then positioned at the same location in the 23Na coil, and a nonselective 23Na-free induction decay spectroscopic sequence was used to center the spectrometer frequency to the sodium resonance and optimize the transmit and receive gains for a nominal 90° flip angle.

For 23Na MR imaging, a three-dimensional twisted-projection imaging sequence with short echo-time capability (echo time, 0.37 msec) was used with receiver bandwidths up to 31.25 kHz, 1,240 projections, and gradient strengths up to 1.6 mT/m. To maximize detection of the short T2 component, a nonselective 90° radio-frequency pulse of 0.4 msec was used with a delay time of 172 µsec to allow for transmit-receive switching delays and hardware recovery times. The image k-space traversals of the twisted-projection imaging sequence were along the surface of concentric cones contained inside a sphere (29). The desired gradient waveforms were computed from these k-space traversals and used to drive the free-induction decay.

Since muscle sodium has a short longitudinal relaxation time (T1 {approx} 20–35 msec) (30,31) and an extremely short, fast transverse relaxation time (T2f) (32), quantitative muscle images were acquired at fully relaxed longitudinal magnetization conditions (repetition time > 2T1). We used a repetition time of only 120 msec and the minimum possible echo time of 0.37 msec. The number of signals acquired per projection was 14 for 24–34 minutes of total imaging time.

The quantitative human leg protocol also was applied to imaging of the knee in two volunteers and in two patients (two men, 65 and 60 years old) with osteoarthritis, as well as in two patients (two women, 30 and 35 years old) with myotonic dystrophy.

Phantom Studies
Prior to human studies, the protocol was tested in six cylindric phantoms with diameters of 15 cm and sodium saline solution concentrations that ranged in the physiologic range of 15–150 mM. Phantom imaging also was performed to assess the radio-frequency magnetic field homogeneity of the birdcage coil with the same acquisition protocol used in vivo. To establish the concentration sensitivity limit of our in vivo imaging protocol, we imaged a phantom that consisted of nine 50-mL, 4-cm-diameter vials filled with saline solution that had concentrations of 15–125 mM. To determine the true spatial resolution limit of the imaging sequence used in vivo, we constructed a resolution phantom. The resolution phantom consisted of a Plexiglas cylinder containing five rows of plastic rods of different diameters (3–17 mm) that were filled with normal saline solution (154 mM) and doped with copper sulfate (2.9 g/L). Profiles were obtained along the rows of the image, and the resolution was computed by means of convolution of the profile with a Gaussian kernel, detection of minima, and calculation of the distances at full width at half maximum.

Muscle Exercise Protocol
23Na MR imaging was performed before and during the first 16 minutes of recovery from dynamic exercise in two healthy male volunteers (22 and 30 years old). Dynamic ankle plantar flexion was performed against a flexible rubber tube (Dow Corning, Midland, Mich) to a peak target force of 120 N at 1 Hz for 5 minutes. The semiflexible tube was used to provide a graded force of continually varying resistance with workloads of 40%–50% of the maximum voluntary contraction, which thereby isolated the posterior compartment muscles (gastrocnemius, soleus) of the lower leg. Although every effort was made to avoid lift off of the heel of the lower leg during exercise, which would result in recruitment of the anterior compartment thigh muscles, inability to avoid lift off of the lower leg was a potential limitation of the proposed exercise protocol; this may be important in other protocols in which variations in exercise are studied. Multiple transverse 1H spin-echo and three-dimensional 23Na MR images were obtained before and after exercise. For 1H MR imaging, the following parameters were used: 800/25 (repetition time msec/echo time msec) and one signal acquired per projection in 6 minutes of total imaging time. For 23Na MR imaging, the following parameters were used: 55/0.37, 14 signals acquired, and 1,240 projections with 16 minutes of total imaging time.

Spin-Lattice (T1) and Spin-Spin (T2) Relaxation Measurements
Sodium T1 and T2 relaxation measurements were obtained in aqueous solutions of saline (concentration range, 15–150 mM), sodium chloride (150 mM, 1 M) solutions, blood, packed red blood cells, and skeletal muscle. Unlocalized saturation recovery and Carr-Purcell-Meiboom-Gill spin-echo MR spectroscopic sequences were used for relaxation measurements in solutions and physiologic fluids (55/9).

Blood relaxation measurements were obtained not only to extract T1 and T2 values, which are important factors affecting contrast on 23Na MR images, but also to test the capability of our technique to measure multiexponential relaxation in vitro. Arterial blood (50–100 mL aliquots) was obtained from normal dogs (n = 5). The blood was collected in tubes containing 10 mL of heparin per 80–100 mL of whole blood. The heparin solution that was added contained 0.15 mM in sodium concentration, and this had no effect on the relaxation rates or blood concentration, within experimental error. Relaxation measurements also were obtained from packed red blood cells (five 500-mL bags). The standard anticoagulant solution added to the blood in blood banks (Adenine-Saline AS-1; Hemasure, Marlborough, Mass) contained 16.9 mEq of sodium and did not have a measurable effect on either the T1 or T2 values of 23Na, which is in agreement with results of previous studies (33,34).

The twisted-projection imaging sequence was used to measure the fast and the slow T2 components and the T1 component of muscle in the leg. Sequential images obtained at different repetition times (55–120 msec for imaging times of 9–24 minutes per image) and echo times (0.37–20 msec for imaging times of 9 minutes per image) were acquired with 1,240 projections for measurement of T1, T2f, and T2s.

Processing of Spectroscopic Chemical-Shift Data
MR spectra were processed with software developed previously for T1 and T2 measurements (35). Unlocalized spectra were reconstructed by using the one-dimensional Fourier transform and a 3–20-Hz line-broadening exponential filter. No baseline correction was applied. Selected peaks were fitted in the frequency domain by using Lorentzian functions, and areas were computed by means of integration of the processed fitted spectra. Peak areas subsequently were fitted to monoexponential or biexponential curves for the extraction of all the relaxation parameters (T1, T2f, and T2s), and their relative amplitudes, by using a nonlinear mean least squares fitting procedure based on the Marquardt-Levenberg algorithm (Multifit, version 2.0; Day Computing, Cambridge, UK).

Processing of 23Na Image Data
Raw data were collected and images reconstructed off-line on a workstation (Silicon Graphics, Mountview, Calif) by using a regridding and three-dimensional Fourier transform algorithm described elsewhere (29). Software routines (Matlab; Mathworks, Natick, Mass) were developed to select interactively and display images from the volumetric stack of the 64 reconstructed images with a 64 x 64 array. These routines also allowed us to interpolate to the desired matrix resolution by using bicubic interpolation schemes; to adjust the image window and level threshold, color code, and zoom interactively; and to place square and circular regions of interest for signal intensity, noise, and concentration measurements.

For T1 and T2 measurements from skeletal muscle images, mean signal intensities of the calf muscle were measured by means of placing multiple regions of interest in the desired regions on sequential images obtained at different echo times and repetition times. The mean intensities were fitted to single or double exponential curves by using the same software used for the spectroscopic fitting described earlier.

Quantification
The absolute concentration of total sodium in muscle was achieved by placing three cylindric saline solution reference markers of known concentrations (15, 20, and 25 mM) within the volume being investigated. Concentration estimates were obtained directly from the images by placing regions of interest in each of the three reference markers and calculating the mean signal intensity for each. These mean values (SNaref) were then used to define a linear regression curve of signal intensity versus concentration from which mean signal intensity measurements from skeletal muscle regions (SNatis) were extrapolated (36). The concentration of the total sodium in tissue ([Na]tis) was calculated from the equation:

where FNa and FNaref are saturation factors and ENa and ENaref are T2 correction factors for the tissue and standard references, respectively, assuming homogeneous radio-frequency magnetic field excitation and detection (37). [Na]ref is the sodium concentration of the externally placed cylindric saline solution phantom.

For sodium quantification in phantoms and muscle, the saturation factor ratio FNa:FNaref was unity because the imaging was performed under fully relaxed longitudinal magnetization conditions (repetition time > 2T1). For phantom studies, the ratio of the correction factors ENa:ENaref was also set to unity (T2ref > echo time). However, in skeletal muscle, the signal loss from the fast transverse relaxation component (T2f) is not negligible, even with the echo time of 0.37 msec used throughout the study. Sodium tissue concentration estimates were thus corrected by using the measured ENa:ENaref factors, mathematically expressed in the Appendix. This correction necessitated knowledge of the reference solution T2ref value, and most importantly, knowledge of the tissue T2f and of the relative amplitudes of the fast and the slow sodium components.

The ENa:ENaref correction ratio was measured individually on sequential 23Na MR images of the legs of human volunteers. These images were acquired at echo times of 0.37–12 msec, 1,240 projections, and eight signals acquired per projection for a total imaging time of 9 minutes. Mean signal intensities (SNatis) were calculated from regions of the gastrocnemius and soleus muscles for each echo time, and the results were fitted to a biexponential relaxation decay curve for extraction of the relative signal intensity proportions (If, Is) and transverse relaxation times (T2f, T2s) of the fast and the slow sodium components, respectively. The use of direct measurements of the ENa:ENaref correction ratio provides a way of correcting for T2, and/or T2*, relaxation effects that avoids systematic bias, but not random, errors (38).

Statistical Analyses
Paired Student t tests were performed to evaluate the statistical significance of measured sodium content differences in (a) resting and exercised muscle groups in healthy volunteers, (b) the unaffected and osteoarthritic knee joints studied, and (c) the unaffected and atrophic muscles of the patients with myotonic dystrophy. Two-way analysis of variance also was performed to assess intra- and intersubject heterogeneity of muscle sodium content in the healthy volunteers. A P value less than .05 was considered to indicate a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
Phantom Validation Studies
Measured spin-lattice (T1) and spin-spin (T2f, T2s) relaxation times for sodium in saline solutions (n = 5, 15–150 mM) and aqueous sodium chloride (n = 5, 150 mM; n = 5, 1 M) solutions, blood (n = 5), packed red blood cells (n = 5), and skeletal muscle are shown in Table 1 and compared with relaxation measurements reported in the literature (7,13,14, 22,30,32–34,39–41). The measured T1 and T2 values are consistent with the range of previously reported values. For saline solutions, no concentration dependence on T1 or T2 values was found in the 15–150-mM range.


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  		TABLE 1. Sodium Spin-Lattice and Spin-Spin Relaxation Values in Saline Solutions, Sodium Chloride Solutions, Blood, Red Blood Cells, Cartilage, and Skeletal Muscle
 
To test the assumption that the radio-frequency magnetic field was homogeneous (Eq [1]), we imaged cylindric phantoms of saline solutions with a concentration of 154 mM and a diameter of 15 cm. Profiles were obtained from the phantom images in a stack of 20 contiguous sections, and the mean profile plus or minus SD was computed (Fig 1a). The coefficient of variation of the measured signal intensity (SD/mean) was within 3.1% of the mean, which confirms the highly homogeneous field of the birdcage coil in its central 12 x 12-cm2 region and the validity of Eq (1). Shown in Figure 1b is the reference calibration curve (signal intensity vs concentration) of cylindric reference saline solutions with a diameter of 14 cm and concentrations of 15–150 mM. The calibration curve was fitted to a linear regression line (y = 1.08x + 1.36; r = 0.99).



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  		Figure 1a. (a) Graph shows the profile (mean ± SD) from 20 contiguous 23Na phantom images of 150-mM sodium concentration, which confirms the radio-frequency magnetic field homogeneity within the central region of the birdcage coil. (b) Graph shows linear mean least squares phantom reference curve for concentrations in the range of 15-150 mM. Phantom images were acquired with the same experimental protocol used in vivo.

 


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  		Figure 1b. (a) Graph shows the profile (mean ± SD) from 20 contiguous 23Na phantom images of 150-mM sodium concentration, which confirms the radio-frequency magnetic field homogeneity within the central region of the birdcage coil. (b) Graph shows linear mean least squares phantom reference curve for concentrations in the range of 15-150 mM. Phantom images were acquired with the same experimental protocol used in vivo.

 
23Na imaging also was performed to establish the concentration sensitivity limit for the reference standard solutions, which was subsequently used for quantification, with a concentration range of 15–125 mM, by using the same acquisition protocol used in vivo (Fig 2, top row). Concentrations as low as 15 mM can be imaged (Fig 2, top row), with signal-to-noise ratio per unit volume per unit time values of 0.005–0.04 mL-1min-1. Imaging of the resolution phantom (Fig 2, middle row) and processing of the profiles acquired from adjacent rows yielded an isotropic resolution of 6 x 6 x 6 mm3 with signal-to-noise ratios in the range of 20–24.



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  		Figure 2. Top row: Coronal sensitivity phantom MR images (120/0.37; 14 signals acquired per projection in 34 minutes) of vials with different saline solution concentrations, from 125 mM down to 15 mM. Middle row: Coronal MR images (55/0.37; two signals acquired; total imaging time, 4 minutes) show a resolution phantom containing 154 mM saline solution. Bottom row: Coronal quantitative 23Na MR images (120/0.37) from a phantom arrangement of two 500-mL bottles containing a 100-mM (reference) and a 150-mM (unknown) saline solution. All data (reconstructed from 1,240 projections and 0.22-mL voxels) are composed of 64 contiguous images displayed on an 8 x 8 grid window.

 
The sodium quantification procedure was applied to a series of six cylindric 500-mL bottles (Fig 2, bottom row) containing saline solution concentrations in the range of 15–150 mM that were prepared and assayed blindly with respect to the concentration. The results, summarized in Table 2, yielded concentration estimates of high accuracy (0–2.6 mM) and precision (0.3–1.6 mM) that compared well with the correct values within experimental error.


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  		TABLE 2. Total Sodium Concentrations Measured in Test Phantoms
 
Sodium Quantification in Muscle
Typical high-spatial-resolution sequential images (0.22-mL voxels, signal-to-noise ratios of 10–15) from the leg of a healthy volunteer are shown in Figure 3. Images show relatively uniform levels of sodium in skeletal muscle; bright signal intensity regions in the anterior, posterior tibial, and peroneal arteries and veins; and lower sodium levels in the tibia, fibula, and subcutaneous fat, which have low sodium content (42) and short relaxation times.



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  		Figure 3. Transverse quantitative 23Na MR images (120/0.37, 1,240 projections, 14 signals acquired per projection, 0.22-mL voxels in 34 minutes) of the human calf muscle show relatively uniform skeletal muscle sodium; blood vessels appear as areas of high signal intensity and bones appear as areas of low signal intensity.

 
Measurement of the fast relaxation parameter yielded values of T2f = 0.46 msec ± 0.21 (SD; n = 10 data sets) and T2s = 12.27 msec ± 1.94 (n = 10 data sets). These results yielded correction factors of ENa/ENaref, with a mean value of 1.41, which subsequently were used for total tissue sodium concentration measurements. Spin-lattice (T1) muscle relaxation estimates were 32.3 msec ± 0.5. Total sodium signal intensities (SNatis, SNaref) were measured in 20–30 voxels in each two-dimensional leg image in five to six images that were in the volumetric stack and located within homogeneous-appearing muscle regions, away from the periphery, bone, or blood vessel areas. Relaxation-corrected sodium signal intensity values yielded estimates of 28.4 mmol/kg of wet weight ± 3.6 by using noninvasive 23Na MR imaging (n = 10). These estimates are in excellent agreement with the mean biopsy estimate of 29.5 mmol/kg of wet weight ± 2.4 from previously published results (Table 3). No significant differences between men (n = 8) and women (n = 2) were observed (P > .09 in 30 voxels per section in six contiguous sections).


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  		TABLE 3. Total Sodium Concentration in Human Skeletal Muscle at Biopsy and Noninvasive 23Na MR Imaging
 
Analysis of variance was used to explore muscle image heterogeneity, whereby the SDs of the mean values of the MR signal intensities in all voxels lying within the two-dimensional muscle images were calculated for comparisons within and between groups. Care was taken to avoid vessels that appeared bright owing to their high sodium content and low relaxation times. SDs were 0.8–4.3 within the two-dimensional images and 0.3–1.7 in the volumetric leg image stacks in all 10 volunteers together. Analysis of variance yielded significant evidence (P < .05) for intrasubject sodium signal intensity variation in the same calf muscles in most of the volunteers.

Exercise Studies
Figure 4 shows a schematic of the experimental setup used for the exercise protocol in the calf muscles of the two volunteers. Figure 5 shows 1H (Figs 5a, 5b) and 23Na (Figs 5c, 5d) MR images obtained in a normal leg at rest and after exercise.



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  		Figure 4. Schematic shows experimental setup used for the exercise protocol in the human calf muscle.

 


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  		Figure 5a. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5b. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5c. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5d. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5e. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5f. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5g. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5h. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5i. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 


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  		Figure 5j. (a, b) Transverse spin-echo T1-weighted MR images (800/25) of the calf muscles of a healthy volunteer (a) at baseline and (b) after a dynamic plantar flexion exercise protocol. (c, d) Corresponding transverse 23Na images (55/0.37, 0.22-mL voxels, 14 signals acquired, total imaging time < 16 minutes) obtained (c) before and (d) after exercise. Arrows in d show the regions of exercised, stressed gastrocnemius and soleus muscle fibers. (e-h) Transverse 1H MR images (800/20; two signals acquired per projection) of (e) a normal and (f) an osteoarthritic knee joint (arrow in f and h), and (g, h) corresponding transverse 23Na images (55/0.37; 14 signals acquired per projection). (i) Transverse T1-weighted 1H MR image (800/20; two signals acquired per projection) and (j) typical transverse 23Na image (120/0.37; 14 signals acquired per projection) of a patient with myotonic dystrophy; arrow in j indicates atrophic muscle. The calf muscle is compressed in j compared with that in i because of the positioning of the leg within a foam support.

 
After exercise, mean 23Na MR imaging signal elevations of 16% and 22% in the soleus and gastrocnemius muscle fibers in the two volunteers were measured and compared with those in resting muscle (Figs 5c, 5d). These elevations correspond to total sodium concentrations of 33.3 and 38.9 mmol/kg of wet weight, respectively, compared with resting concentrations of 27.3 and 33.6 mmol/kg of wet weight, assuming that there are no relaxation time changes that affect the acquisitions at echo time of 0.4 msec. Also evident are increases in the sodium signal intensity in the anterior and posterior tibial and deep peroneal blood vessels (Fig 5d), which is consistent with vasodilation.

Patient Studies
Evidence for substantial alterations in the fast sodium transverse relaxation times exists for osteoarthritis (54) and myotonic dystrophy (7). Measurements of such changes were not obtained in the limited patient population examined. Nevertheless, the direct measurements of T2f are simple and convenient to implement in patient studies and subsequently can be omitted from the protocol once their dependence on disease is established. Sodium signal intensities, normalized to the intensities of the standard reference markers within the image plane, were measured in resting and exercising muscles, in degenerating cartilage in osteoarthritis, and in atrophic muscle in myotonic dystrophy.

In 23Na images of the knee joint, major sources of relatively strong sodium signal intensities included the blood vessels (eg, popliteal artery and vein), joint synovial fluid in the bursa, ligaments, and cartilaginous areas (Fig 5g). One patient with osteoarthritis had grade II chondromalacia, and the other had grade III; both had lateral meniscal cartilage degeneration. Unlike the 1H MR images (Fig 5f), the 23Na MR images showed enhanced signal intensity in the medial joint side, which is indicative of the increased sodium content of the bursa fluid and normal cartilage (Fig 5h) and reduced mean signal intensities of 15% and 36% in the lateral joint in the two patients examined.

In patients with myotonic dystrophy, muscle atrophy was prominent in the gastrocnemius (Fig 5i) and surrounding muscles. Significant elevations in normalized sodium signal intensities (to a 25-mM saline solution reference standard) were measured in both patients with myotonic dystrophy. In an unaffected muscle group in the first patient with myotonic dystrophy, the mean sodium signal intensity was 0.86 ± 0.07, whereas the affected side showed a 70% increase at 1.45 ± 0.15 (measured in 30 voxels in 10 contiguous sections) (Fig 5j). In the second patient with myotonic dystrophy, a less dramatic increase was observed (0.85 ± 0.01 to 1.25 ± 0.01), for a change of 47% (measured in 20 voxels per section in 10 contiguous sections). These elevations correspond to [Na] levels of 54.2 and 47.5 mmol/kg of wet weight in the two patients examined, compared with normal unaffected [Na] levels of 31.5 and 32.5 mmol/kg of wet weight in the same patients, assuming no relaxation time changes.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
APPENDIX
 REFERENCES
 
Results of this study demonstrate the feasibility of the imaging and noninvasive quantification of total sodium in human skeletal muscle. 23Na imaging in muscle is more challenging than brain studies (55), because the total sodium concentration is about 32% lower than the brain value of 43–45 mmol/kg of wet weight. This translates directly into a reduced signal-to-noise ratio that leads to decreased spatial resolution, prolonged image acquisition times, or both.

Our studies benefitted from short echo-time, twisted-projection imaging in which weighted k-space trajectories were used to sample k-space uniformly, which resulted in a decreased noise variance and an improved signal-to-noise ratio. The 23Na twisted-projection imaging method was implemented with a clinical imager. Implementation of the method with other systems similarly would require broadband MR spectroscopic, or MR imaging, capability with a coil and a preamplifier tuned for 23Na. In addition, the twisted-projection imaging pulse sequence is required, with its associated gradient waveforms, as well as software for off-line twisted-projection imaging reconstruction (29).

From a technical standpoint, gradient heating, as a result of the gradient trajectories used is not a concern because of the low peak gradients used (Gmax <= 1.6 mT/m). However, the need for sinusoidally varying gradient waveforms compared with conventional spoiled gradient-echo sequences may be limited by MR imaging system constraints on the gradient accelerator module's duty cycle and maximum slew rate values. In our implementation, these constraints limited us to a minimum repetition time of 55 msec for imaging with 1,240 projections, although further reductions in repetition time could be achieved by decreasing the number of projections. The use of the twisted-projection imaging sequence allows fast, high-spatial-resolution 23Na imaging (0.22-mL voxels), whereas in conventional three-dimensional gradient-echo refocused 23Na imaging studies, the best spatial resolution achieved to date is 0.44 mL (56). Further work is needed to explore the limits of the twisted-projection imaging sequence in signal-to-noise ratio and spatial resolution in musculoskeletal imaging.

The value of the total sodium concentration measured by means of noninvasive 23Na MR imaging in healthy muscle is in excellent agreement with prior invasive, destructive determinations after biopsy. As part of the quantification protocol, we measured in vivo sodium T1 and T2 relaxation components directly from images. Previous studies (22,30,33,34,39–41,57) of T1 and T2 values of extracellular fluid (edema, vitreous humor, cerebrospinal fluid) indicate almost identical relaxation times and absence of a short T2 component, which is consistent with the notion that in vivo extracellular sodium does not undergo considerable quadrupolar interactions and therefore behaves like saline solution. The saline solution and aqueous sodium chloride T1 and T2 values were approximately equal, composed of single exponential signal decays with time constants approximately equal to 54 msec. The T2 values of blood and red blood cells were biexponential, as expected.

As a method of quantification, 23Na MR imaging compares favorably with other commonly used techniques, such as flame emission spectrophotometry or atomic absorption spectrophotometry, in that it avoids time-consuming and destructive tissue sampling. Key advantages of the method over MR spectroscopic and biopsy techniques include avoidance of the complex data postprocessing required by MR spectroscopy; its noninvasive nature; and its ability to provide high-spatial-resolution, three-dimensional, direct representation of sodium distribution with imaging times less than 10 minutes. Nevertheless, absolute sodium quantification in skeletal muscle is limited by the fast T2f sodium component, which requires 23Na MR imaging with short echo time for deriving the appropriate corrections.

The volumetric nature of the technique allows investigation of inter- and intramuscular concentration variation. The source of variability between muscle groups in some of the volunteers is likely attributed to physiologic factors, including muscle fiber type, and perhaps protein composition, sodium content, diet, and exercise habits. Although indirect evidence exists for differences in total sodium in different skeletal muscle groups (50), such variability in total sodium levels has not been reported previously in skeletal muscle, to our knowledge, and it would be interesting to explore further the applicability of the technique toward the study of sodium content with age, fiber type, and sex. Whether the source of such differences is sodium-potassium adenosine triphosphatase content levels, perfusion, or muscle protein composition remains to be determined.

The potential clinical applications of this technique are promising. The ability of 23Na imaging to show changes in sodium levels in exercised muscles (58) has potentially practical applications to the study of ischemia, neuromuscular conditions, exercise physiology, and sports medicine. In 1H MR imaging, the primary source of exercise-induced signal intensity changes is attributed to changes in T2 of tissue water and water content (26,27,59,60). The most widely accepted explanation is an increase in the total water content, with recent evidence (26) attributing the changes primarily to the intracellular water alterations. Muscle perfusion also is believed to be at least a partial contributor to the mechanism of 1H exercise-induced T2 changes. Although T2-weighted 1H MR imaging times may be shorter than total 23Na MR imaging times (Fig 5d), 23Na MR imaging permits depiction of ionic changes; this is consistent with results of prior work (1) that suggest augmented Na+-K+ pump activity, which may be attributed to circulating catecholamines or possible regulatory effects of the intracellular sodium levels (61).

Whether sodium changes during exercise are accompanied by changes in water content or transport, and share a common mechanism, presently is not well understood and needs further study. The exact time frame for maximal changes in sodium signal intensity following exercise and recovery could be established with carefully designed exercise protocols in dynamic 23Na MR imaging studies. Such studies also may help to elucidate, for example, whether changes in exercise are due to a hyperemic response, changes in pump function activity, or both.

In osteoarthritis, 23Na imaging may provide a tool for noninvasive monitoring of proteoglycan and glycosaminoglycan levels that correlate with severity of disease. Although emerging 1H contrast material–based (28,62) and other fast imaging (63–65) techniques seem promising for cartilage assessment, the role of 23Na MR imaging in osteoarthritis needs further exploration. The thin layers of joint cartilage, typically of the order of 3–5 mm, in association with increased sodium signal intensity from bursa fluid and ligaments may require triple quantum techniques to suppress the bursa fluid and isolate the cartilaginous parts of the bone endplates.

Our 23Na imaging results in patients with myotonic dystrophy are consistent with the known imbalance in sodium homeostasis in dystrophic muscle fibers (6), as evidenced by the 60% mean sodium signal intensity elevations. The clinical diagnosis of myotonic dystrophy is based on electromyographic activity recordings and on molecular genetic screenings (66), and it often is confirmed by means of histopathologic and radiologic findings in the affected muscles. These findings include muscle atrophy and fatty and collagenous tissue infiltration. Although 1H MR imaging facilitates diagnosis in advanced disease stages, diagnosis may be difficult in the early stages (27,66) in which myotonia, muscle weakness, or both are minimal. 23Na imaging could be valuable in characterizing the early onset, pathogenesis, and monitoring of pharmacologic treatment of dystrophic muscle by providing noninvasive, direct, quantitative sodium concentration estimates in the degenerating muscle (7).

Crucial to the potential clinical use of 23Na imaging will be its ability to localize the sodium elevations to diseased myocytes or collagenous tissue. For sodium quantification in disease states of different severity, changes in protein content, owing to muscle atrophy and increased membrane leakiness, that lead to alterations in the long T2s and the short T2f sodium component (7) need to be identified. Specifically, if T2f increases in the disease states studied, our [Na] estimates in patients would be relatively unchanged because of the short echo time used. If, on the other hand, T2f were reduced in the diseased tissues, then our observations of altered [Na] in these patients would be conservative. Overall, it is hoped that quantitative 23Na MR imaging may help in the assessment of the degree and distribution of muscle wasting and disease progression and possibly address questions relevant to the underlying mechanisms of the selectivity of dystrophic muscle deterioration.

The combined measurement of sodium concentrations and imaging in vivo offers exciting possibilities for the study of physiologic and pathophysiologic processes in the musculoskeletal system, most of which remain to be exploited.


   APPENDIX
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 APPENDIX
REFERENCES
 
If I(t) denotes the total sodium time-varying signal intensity, with If and Is representing the proportions of the signal intensity contributions due to the fast and slow relaxation components, having amplitudes Af and As, respectively, then


with If + Is = 1. The tissue and reference signal intensities can thus be expressed as


where c is a scalar constant. The measured tissue sodium concentration is given by

Imaging at fully relaxed conditions implies that FNa/FNaref = 1. Use of Equations (A3) and (A4) in Equation (A5) leads to

Therefore, the transverse relaxation correction factor is


   ACKNOWLEDGMENTS
 
The authors thank Han Wen, PhD, for his help with the hardware development. We thank Divya Bolar, B Eng, for his contributions to software development and data analysis and Dara L. Kraitchman, VMD, PhD, for providing us with the blood samples. We thank Arhonda Gogos, PhD, for coding the saline solution phantoms for blinded image review and Daniel B. Drachman, MD, for recruiting the patients with myotonic dystrophy. We are grateful to Mary McAllister, MA, for editorial assistance.


   FOOTNOTES
 
Author contributions: Guarantors of integrity of entire study, C.D.C., P.A.B.; study concepts, all authors; study design, C.D.C., F.E.B., M.G.P.; definition of intellectual content, C.D.C., P.A.B.; literature research, C.D.C.; clinical studies, C.D.C., M.G.P.; experimental studies, C.D.C., J.S.G.; data acquisition and analysis, C.D.C.; statistical analysis, C.D.C., M.G.P.; manuscript preparation, C.D.C.; manuscript editing and review, all authors


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 

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