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Published online before print August 23, 2006, 10.1148/radiol.2411050487
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(Radiology 2006;241:235-242.)
© RSNA, 2006

Technical Developments

Muscle Metabolites: Functional MR Spectroscopy during Exercise Imposed by Tetanic Electrical Nerve Stimulation1

Arto C. Nirkko, MD, Kai M. Rösler, MD and Johannes Slotboom, PhD

1 From the Departments of Neurology (A.C.N., K.M.R.) and Neuroradiology (J.S.), University Hospital, Inselspital, CH-3010 Bern, Switzerland. Received March 23, 2005; revision requested May 25; revision received October 25; accepted November 23; final version accepted December 15. Supported by the Departments of Neurology and Neuroradiology of the University Hospital of Bern, Switzerland, and by the Swiss National Science Foundation (SNF grant 3200B0-107499). Address correspondence to A.C.N. (e-mail: anirkko{at}insel.ch).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Permission from the ethics committee and informed consent were obtained. The purpose of this study was to prospectively evaluate a method developed for the noninvasive assessment of muscle metabolites during exercise. Hydrogen 1 magnetic resonance (MR) spectroscopy peaks were measured during tetanic isometric muscle contraction imposed by supramaximal repetitive nerve stimulation. The kinetics of creatine-phosphocreatine and acetylcarnitine signal changes (P < .001) could be assessed continuously before, during, and after exercise. The control peak (trimethylammonium compounds), which served as an internal reference, did not change. This technique—that is, functional MR spectroscopy—opens the possibility for noninvasive diagnostic muscle metabolite testing in a clinical setting.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Muscle weakness, exercise intolerance with excessive fatigue, and prolonged recovery after exercise are chief complaints for many muscle disorders. These symptoms are often caused by primary or secondary disturbances of the pathways involved in muscular energy metabolism. Clinical and electrophysiologic diagnostic tests for metabolic myopathies are of limited sensitivity (1). Exercise testing in patients suspected of having metabolic myopathies relies on the measurement of metabolites in blood samples (2–6) and does not enable assessment of intracellular metabolites. Standardization is difficult, and even when work levels are adjusted in relation to the maximal force of the patients, the diagnostic sensitivity (78%) and specificity (60%) are low because of broad normal limits (7).

Phosphorous 31 (31P) magnetic resonance (MR) spectroscopy can be used to quantify the final intracellular energy substrates adenosine triphosphate and phosphocreatine in vivo (8–11) and has been advocated for the work up of muscle diseases (12–14). In resting muscles, an increased intramuscular concentration of inorganic phosphates was found in patients with mitochondrial diseases (13), muscular dystrophy (15), myositis (16), and denervated muscles (17). During exercise of healthy muscle, phosphocreatine levels decrease and inorganic phosphate levels increase, while adenosine triphosphate levels remain constant (13). Apart from these findings at 31P MR spectroscopy, exercise-induced changes related to phosphocreatine and acetylcarnitine (AcCt) have also been observed with hydrogen 1 (1H) MR spectroscopy in healthy volunteers (18,19).

MR spectroscopy is difficult to perform during exercise and has not yet been established as a diagnostic tool in the clinical setting for various reasons. The main problems include standardization of workload and experimental requirements that are too cumbersome for clinical use (Table). Thus, the purpose of our study was to prospectively evaluate a method developed for the noninvasive assessment of muscle metabolites during exercise.


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  		Problems and Solutions for Clinical Exercise-dependent MR Spectroscopy

 

   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Subjects
A total of nine experiments (four in the left thenar muscles, four in the left anterior tibial muscle, and one in the left anterior tibial muscle that was repeated with a longer stimulation) were performed in five healthy men (age range, 39–54 years) who had no current illness and no history of neuromuscular disease. All participants gave informed consent, and experiments were performed with the approval of the local ethics committee.

Setup
To achieve a sufficient magnetic field homogeneity for examinations in the hand, the subjects wore a latex glove and placed their hand into a cylindrical plastic container that was filled with water. The hand was immobilized with tape in a fist position. The container was sealed by wrapping the opening of the glove around the rim of the container (Fig 1a, 1b). The container was fixed at the center of the magnet bore with padding and tape. The legs, which are sufficiently cylindrical for adequate field homogeneity (Fig 1c), were taped into the position that is assumed during maximal peroneal nerve stimulation (dorsal foot extension and eversion) to achieve immobilization and isometric conditions.


Figure 1
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  		Figure 1a: Setup for MR spectroscopy. (a) Hand is fixed in cylindrical water-filled container, and stimulating electrodes are placed over the ulnar nerve at the wrist. Images obtained by using transverse fast imaging with steady-state precession (4.6/2.3 [repetition time msec/echo time msec]) demonstrate (b) the hand in the container, showing placement of the spectroscopic volume (side length, 15 mm) in the ulnar-innervated thenar muscles, and (c) the lower leg, showing placement of the spectroscopic volume (side length, 20 mm) in the anterior tibial muscle. Boxes in b and c represent the outline of the sample volume.

 

Figure 1
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  		Figure 1b: Setup for MR spectroscopy. (a) Hand is fixed in cylindrical water-filled container, and stimulating electrodes are placed over the ulnar nerve at the wrist. Images obtained by using transverse fast imaging with steady-state precession (4.6/2.3 [repetition time msec/echo time msec]) demonstrate (b) the hand in the container, showing placement of the spectroscopic volume (side length, 15 mm) in the ulnar-innervated thenar muscles, and (c) the lower leg, showing placement of the spectroscopic volume (side length, 20 mm) in the anterior tibial muscle. Boxes in b and c represent the outline of the sample volume.

 

Figure 1
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  		Figure 1c: Setup for MR spectroscopy. (a) Hand is fixed in cylindrical water-filled container, and stimulating electrodes are placed over the ulnar nerve at the wrist. Images obtained by using transverse fast imaging with steady-state precession (4.6/2.3 [repetition time msec/echo time msec]) demonstrate (b) the hand in the container, showing placement of the spectroscopic volume (side length, 15 mm) in the ulnar-innervated thenar muscles, and (c) the lower leg, showing placement of the spectroscopic volume (side length, 20 mm) in the anterior tibial muscle. Boxes in b and c represent the outline of the sample volume.

 
Electrical Stimulation
A standard electrophysiologic apparatus (Viking III; Nicolet Biomedical Systems, Madison, Wis) located outside the imaging room was used for electrical nerve stimulation. Two silver chloride electrodes were connected to the stimulator by means of a bipolar shielded cable to avoid burns caused by radiofrequency coupling. The cable shield was connected to the shielding of the imaging room to reduce radiofrequency interference. The cable was wrapped to ensure a minimal distance of 50–100 mm on all sides, avoiding close proximity with the body and the gradient coils within the imaging bore to prevent burns caused by capacitive coupling.

The electrodes, which were spaced 25 mm apart, were placed either over the ulnar nerve at the wrist (Fig 1a), where a stimulus intensity of 25 mA was used, or over the peroneal nerve at the capitulum fibulae, where a stimulus intensity of 40 mA was used. Stimulus intensity was determined after ensuring that supramaximal conditions were achieved at least 10 mA below each intensity level, with no further increase in response twitches despite increasing current.

A sustained tetanic muscle contraction was achieved by using repetitive supramaximal stimulation. Pulse duration was 0.2 msec, pulse rate was 50 Hz, and pulse train duration was 120 seconds (total of 6000 stimuli).

1H MR Spectroscopy
MR spectroscopic recording was performed with a standard clinical 1.5-T MR imager (Magnetom Sonata, upgraded Vision; Siemens Medical Systems, Erlangen, Germany) by using the standard circular polarized knee coil. MR spectroscopic excitation was performed with a standard point-resolved spatially localized sequence (1500/135; radiofrequency pulse angles of 90°, 180°, and 180°), with eight averages for one data set every 12 seconds, which was repeated over a 360-second period (120 seconds before stimulation, 120 seconds during stimulation, and 120 seconds during recovery) yielding a total of 30 data sets or more; one additional experiment with a longer stimulation time (300 seconds) was performed to check whether steady state was reached after 120 seconds.

Localization was performed with MR imaging. For experiments in the hand, the sample volume measured 15 x 15 x 15 mm and was obtained in the adductor muscle group of the thenar muscles, which are innervated by the ulnar nerve (including parts of the first dorsal interosseus), to avoid the more radially located abductor parts that are innervated by the median nerve (Fig 1). Spacing of at least 1–2 mm to the nearest bone was attempted to allow for minimal dislodgement during stimulation. For experiments in the leg, the sample volume measured 20 x 20 x 30 mm and was obtained around the expected "motor point" in the anterior tibial muscle at its maximal circumference (Fig 1c).

Evaluation
Custom software, which was purpose-written in C and Java by two authors (A.C.N., J.S.), was used for evaluation. A reference spectrum without water suppression was used for eddy current correction (23). After phase correction (J.S., 7 years of experience with musculoskeletal MR spectroscopy), raw spectra were displayed (Fig 2), and the spectral peaks were quantified by fitting the time-dependent responses of the creatine (Cr2 doublet and Cr3 peaks), taurine, trimethylammonium (TMA) compound, AcCt, intramyocellular and extramyocellular lipid, and lactate peaks with appropriate model functions, as described elsewhere (24–26) (Figs 3, 4). Spectra were averaged within the three periods, which lasted 96 seconds each (before, during, and after stimulation, excluding a transient 24 seconds at the beginning of each phase).


Figure 2
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  		Figure 2: Time-averaged spectra (96 seconds) from hand (left) and leg (right) muscles of one subject, A, before, B, during, and C, after stimulation. In the hand, SNR was not sufficient to detect Cr2 doublet and AcCt peaks. In the leg, there was a decrease in Cr3 (arrows) and Cr2 doublet peaks and an increase in AcCt peak (arrowhead). The amplitude of the TMA peak, which served as an internal quality reference, remained constant. EMCL/IMCL = intramyocellular and extramyocellular lipid peak.

 

Figure 3
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  		Figure 3a: Cascade of time-resolved spectra (12-second steps) in anterior tibial muscle of one subject before, during, and after electrical stimulation of peroneal nerve. (a) Fitted spectra. (b) Residuals. Beginning with imposed exercise (120 seconds), a decrease in Cr3 and Cr2 doublet peaks was observed, which was followed by rapid recovery after the end of exercise (240 seconds). In parallel, a steady increase in AcCt peak that exceeded baseline levels is seen. An exercise-induced modulation of spectroscopic visibility at the taurine peak is also observed. EMCL/IMCL = intramyocellular and extramyocellular lipid peak.

 

Figure 3
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  		Figure 3b: Cascade of time-resolved spectra (12-second steps) in anterior tibial muscle of one subject before, during, and after electrical stimulation of peroneal nerve. (a) Fitted spectra. (b) Residuals. Beginning with imposed exercise (120 seconds), a decrease in Cr3 and Cr2 doublet peaks was observed, which was followed by rapid recovery after the end of exercise (240 seconds). In parallel, a steady increase in AcCt peak that exceeded baseline levels is seen. An exercise-induced modulation of spectroscopic visibility at the taurine peak is also observed. EMCL/IMCL = intramyocellular and extramyocellular lipid peak.

 

Figure 4
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  		Figure 4: Time course of quantified metabolite peaks for, A, Cr3 and, B, AcCt in two subjects. The depletion kinetics of Cr3 and the decrease and recovery of AcCt could be recorded throughout stimulation. Note that the increase in AcCt is already beginning during stimulation and that AcCt quickly reaches levels above baseline after stimulation.

 
Because of signal-to-noise ratio (SNR) limitations, only the Cr3 and TMA reference peaks could be assessed in the thenar muscles. For the anterior tibial muscle, the larger volume with better SNR additionally allowed fitting at each time point (12 seconds); the resulting metabolite time course allowed exponential fitting of onset and recovery kinetics and was displayed by using a moving average, including both neighbor samples.

Statistical Analysis
The mean and range of the quantified peaks were measured in arbitrary units and were expressed as a percentage relative to the average of each subject's baseline value. Cr3 and TMA peaks during stimulation were compared with baseline values by using the paired Student t test (applying standard algorithms). A P value of less than .05 was used for rejecting the validity of the null hypothesis, which states that the difference between stimulation and baseline values is zero. For P values between .05 and .001, exact values were specified. Statistical analysis was performed by using the authors' custom software (A.C.N., J.S.)


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Magnetic Field Homogeneity
With our protocol, a field homogeneity that was sufficient for spectroscopy, with a water linewidth of better than 10 Hz, was achieved in all experiments in the thenar hand muscles and anterior tibial leg muscle. We succeeded in obtaining a functional MR spectroscopic response to muscle contraction in each subject.

Hand Muscles
The results of functional MR spectroscopy in the thenar muscles showed a marked decrease in all three creatine-phosphocreatine peaks (Cr2 doublet and Cr3) (18) during the 2 minutes of imposed exercise in all four experiments (Fig 2), with Cr3 averaging –40% (range, –35% to –43%; P < .001) and partially recovering to –6% (range, –1% to –13%) in the 2-minute period after stimulation. The adjacent reference peak (for TMA) of the nonmetabolites that had a comparable width and amplitude remained constant within SNR fluctuations before, during, and after stimulation (range, –8% to 5%; P > .05), thereby confirming a constant quality of the spectra during the experiment.

Leg Muscles
Imposed exercise in the anterior tibial muscle resulted in a decrease in the Cr2 doublet and Cr3 peaks in each of the four experiments. The larger spectroscopic volume in the leg muscle yielded an SNR that was sufficient for quantification of the peaks at a 12-second time resolution. The time course of the acquired spectra shows constant baseline values before imposed exercise, a rapid decrease in the Cr2 doublet and Cr3 peaks during exercise (up to –70% at the minimum; average, –51%; range, –46% to –56%; P < .001) (Fig 3), and a recovery after exercise. An initial decrease in the AcCt peak (up to –55% at the minimum; Fig 4) was also seen, followed by a fast recovery that started before the cessation of exercise (average, –12% during exercise; range, –4% to –20%; P = .048) and overshot baseline values by up to 80% after exercise (average, 64%; range, 46%–80%; P < .001). The taurine peak increased briefly during the beginning of stimulation. Again, the TMA reference peak remained constant during the whole experiment (range, –9% to 9%; P > .05; Fig 3). The longer stimulation period of 5 minutes confirmed that both the AcCt increase and the beginning of Cr2 and Cr3 recovery occurred already during stimulation (data not shown).

Other Metabolites, Nonmetabolites, and Quality Parameters
No lactate could be observed in any of the experiments. A small change in the intramyocellular and extramyocellular lipid peaks could not always be avoided because of the expected small contraction-induced mechanical displacement of muscle fibers and intramuscular connective tissue (Fig 2). Because these broad peaks (short T2*) derive from smaller unevenly distributed extramyocellular lipid volumes and are generally rather large compared with metabolite peaks, even small shifts were easily detectable in the extramyocellular lipid signal. Such small shifts are not quantitatively important regarding the displacement of myocellular metabolites, which are evenly distributed over the whole muscle. Furthermore, such extramyocellular lipid changes do not impair quantification of the narrow muscle metabolite peaks (long T2*), as evidenced by the constant TMA peak which served both as a marker of the total amount of muscle tissue in the spectroscopic volume and as a control for constant quality of field homogeneity and spectra.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
We describe a simple and standardized method of functional assessment of muscle metabolism with MR spectroscopy during muscle exercise, which we term functional MR spectroscopy. Our method improves on some of the difficulties that are encountered when using MR spectroscopy during exercise in a clinical setting. Our method uses 1H MR spectroscopy instead of 31P MR spectroscopy so that a standard clinical imager is sufficient.

Methods
We imposed a maximal tetanic muscle contraction (sustained for 2 minutes) by using supramaximal electrical stimulation, which always produced the individual maximum (100%) muscle workload without the need for force feedback and continuous readjustment (22). This excluded the additional central nervous effects that contribute to muscle fatigue in healthy volunteers (27), which result from physiologic factors, such as spinal inhibition, fatigue, motivation, and concurrent or combined central nervous system disease in patients. Motion artifacts were avoided (isometric conditions), and measurements could be performed during the ongoing muscle contraction. Therefore, it was possible to determine metabolite kinetics not only during recovery but also during the evolving muscle fatigue (metabolite depletion). Electrical stimulation currents, which could disrupt the MR spectroscopy signal quality when flowing through the spectroscopic volume, were avoided; this required no particular technical precautions (22) because the exercise was imposed through stimulation of the proximal nerve instead of through stimulation of the muscle itself.

Some muscle and nerve diseases affect distal or proximal muscles selectively. To allow measurement in hand muscles, we placed the hand into a water-filled container, which resulted in a composite object (hand and container) of regular shape that enabled sufficient field homogeneity. A low SNR in small volumes (hand muscles) was compensated for by (a) a stronger maximal contraction with imposed exercise, which had a correspondingly larger effect on metabolites, and (b) a longer duration of measurement during exercise that approached steady state (as opposed to the short window of time after exercise during which metabolite changes were already beginning to recover).

In each of our healthy volunteers, we succeeded in measuring exercise-induced changes of muscle metabolites within 2 minutes of imposed exercise. Cross-subject averaging was not necessary; therefore, the method is well suited for clinical use. In patients with muscular atrophies, a cube with a 15-mm side length may not always be attainable in the small muscles of the hand. In such cases, a smaller volume could be compensated for by increasing the duration of the imposed exercise or by averaging multiple 2-minute cycles. In our volunteers, no anesthesia was necessary during stimulation. In patients, a proximal nerve conduction block with a local anesthetic could be considered.

Metabolites during Imposed Maximal Muscle Exercise
With this functional MR spectroscopic technique, we could determine not only the recovery of metabolites after exercise but also the kinetics and degree of depletion of the Cr2 doublet, Cr3, AcCt, and taurine peaks during the ongoing uninterrupted exercise. The time course of the Cr2 and Cr3 peaks is compatible with the findings of phosphocreatine kinetics observed with 31P MR spectroscopy (22). A rapid decrease during exercise was followed by a recovery beginning immediately after the end of the contraction or even before. With a stimulation of longer than 2 minutes, the recovery clearly started already during the ongoing contraction. A partial recovery during an ongoing electrically induced contraction has been seen by using 31P spectroscopy in an animal model (28). This has been attributed to an impaired propagation of muscle action potentials because, at a frequency of 100 Hz, alterations of the direct compound muscle potential (M wave) response were observed (28). The same explanation may also partly apply to our stimulation at 50 Hz when stimulating for longer than 2 minutes and may contribute to physiologic muscle fatigue.

An additional contributing factor seems to be that phosphocreatine recovery could also be driven by a beginning involvement of the acetylcoenzyme A and AcCt pathways (discussed below). Possible reasons why only phosphocreatine and not total creatine is visible with 1H MR spectroscopy include differentially limited rotational freedom and/or intracellular compartmentation (18,29). Independent of the causal explanation, our results—along with previous observations (18,19,22)—suggest that these Cr2 and Cr3 kinetics are robust and therefore are clinically applicable.

Alterations in AcCt levels were previously not measured during exercise, but an increase in the AcCt peak has been observed afterward (19). Our present results extend these observations and show that, at the beginning of exercise, AcCt decreases. This initial decrease is then followed by an increase in AcCt, which occurs during the ongoing exercise. Finally, after the exercise (corresponding with previous findings), an overshoot well above baseline levels was reproduced. Our data suggest that an early involvement of acetyl-group buffering, probably beginning with mitochondrial acetylcoenzyme A and AcCt exchanges and followed by the beginning of ß-oxidation of long-chain fatty acids (30), already occurs during the first few minutes of (in this case) an intense maximal muscle exercise. The continuing increase of AcCt levels during recovery might be related to the compensation of an accumulated oxygen deficit.

We never observed an increase in lactate during this short exercise period in healthy volunteers. The evaluation of lactate from peripheral blood samples does not correspond well with intramuscular changes. Measurements obtained by using interstitial microdialysis were shown to be more sensitive (31), but this is an invasive approach. Lactate accumulation, as can occur in diseased muscle, can be noninvasively assessed with MR spectroscopy, despite localization within the broad lipid peaks (21). The lipid spectral contents (intramyocellular vs extramyocellular lipids) (32–34) are also not expected to change within the short duration of the exercise.

It is unlikely that our results were caused by degraded field homogeneity from small movements or other technical artifacts. In such cases, the adjacent peak (TMA groups) would change in parallel. Such exercise-independent nonmetabolite peaks are an internal reference that is essential to ensuring a constant quality of the spectra before, during, and after stimulation. These peaks did not change in parallel with the metabolites in our experiments. Another pitfall, a change of dipolar coupling resulting from a change in muscle fiber orientation (29,35), could only affect creatine but not AcCt resonances and was excluded because the contractions were isometric.

Study Limitations
Applicability in patients and tolerance regarding electrical stimulation within the MR imager have not yet been assessed. This study design evaluated isometric contractions only. A simulation of longer duration may be necessary to assess both anaerobic and aerobic metabolism. Optimal parameters for investigating disease must still be established.

Clinical Potential
Assessment of muscle metabolism is often required for the diagnosis of myopathies (36). Conventional diagnostic methods include clinical, electrophysiologic, and functional testing of blood metabolites, as well as muscle biopsy and genetic testing. A noninvasive functional assessment of intracellular metabolites can be provided only with functional MR spectroscopy. Therefore, a clinically feasible functional MR spectroscopic method would be a welcome complement for the work up of muscle diseases. The short exercise duration of 2 minutes reduces the dependence of the results on blood supply, even in the case of coexisting ischemic disease. It may be that 1H functional MR spectroscopy could also provide a guide to therapy.

Our setup opens the possibility for functional metabolic diagnostic testing with 1H functional MR spectroscopy by using widely available imagers in a clinical setting; with electrical nerve stimulation, workload is standardized, maximal, and independent of central effort and allows the examination to be performed during exercise. In further studies, formal normal ranges of the metabolite parameters (amplitude of changes, depletion kinetics, and recovery kinetics) will have to be established, and abnormal values will have to be related to specific myopathies and coexisting diseases. It may also be possible to observe the effects of treatment, specifically the substitution of creatine or carnitine. Finally, applications in sports medicine, such as the assessment of specific training programs, are envisaged.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
We thank the technical staff of the Neuroradiology Department for their help in performing the data acquisition.


   FOOTNOTES
 

Abbreviations: AcCt = acetylcarnitine • SNR = signal-to-noise ratio • TMA = trimethylammonium

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, all authors; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, all authors; experimental studies, A.C.N., J.S.; statistical analysis, A.C.N., J.S.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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