REVIEW ARTICLE

Techniques and Applications of Skeletal Muscle Diffusion Tensor Imaging: A Review Jos Oudeman, MD,1 Aart J. Nederveen, PhD,1 Gustav J. Strijkers, PhD,2 Mario Maas, MD, PhD,1 Peter R. Luijten, PhD,3 and Martijn Froeling, PhD1,3* Diffusion tensor imaging (DTI) is increasingly applied to study skeletal muscle physiology, anatomy, and pathology. The reason for this growing interest is that DTI offers unique, noninvasive, and potentially diagnostically relevant imaging readouts of skeletal muscle structure that are difficult or impossible to obtain otherwise. DTI has been shown to be feasible within most skeletal muscles. DTI parameters are highly sensitive to patient-specific properties such as age, body mass index (BMI), and gender, but also to more transient factors such as exercise, rest, pressure, temperature, and relative joint position. However, when designing a DTI study one should not only be aware of sensitivity to the abovementioned factors but also the fact that the DTI parameters are dependent on several acquisition parameters such as echo time, b-value, and diffusion mixing time. The purpose of this review is to provide an overview of DTI studies covering the technical, demographic, and clinical aspects of DTI in skeletal muscles. First we will focus on the critical aspects of the acquisition protocol. Second, we will cover the reported normal variance in skeletal muscle diffusion parameters, and finally we provide an overview of clinical studies and reported parameter changes due to several (patho-)physiological conditions. J. MAGN. RESON. IMAGING 2016;43:773–788.

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hanges in muscle tissue structure due to (patho-)physiological conditions such as inflammation, trauma, atrophy, or hypertrophy can be assessed on T1- and T2weighted imaging. However, early (patho-)physiological changes often start at the cellular or fascicular level, which is beyond the detection capabilities of regular T1- and T2weighted magnetic resonance imaging (MRI). This also means that it is difficult to assess early treatment and training effects with MRI. For detecting or monitoring early changes on a cellular to fascicular level, which are not yet clinically evident or visible on regular T1 and T2 imaging, one has to rely on histology requiring invasive biopsies. The invasive character of a biopsy precludes routine use and regular follow-up in healthy volunteers. A sensitive noninvasive imaging readout of early (patho-)physiological changes in skeletal muscle is therefore in great demand. Diffusion tensor imaging (DTI) may provide such an imaging readout as it is very sensitive to changes in tissue

microstructure and simultaneously allows for quantification and visualization of the macroscopic muscle architecture.1 For this reason DTI has increasingly been applied to study skeletal muscle physiology, anatomy, and pathology (Fig. 1). Furthermore, DTI in combination with MR spectroscopy of muscle metabolism and other imaging techniques, eg, T2 mapping or perfusion imaging, might provide more specific information about muscle pathology.2 For example, in the area of muscle injuries there is a great demand for sensitive markers to improve prognosis, as the recurrence rate is high.3,4 DTI may provide such a marker, as has been shown to be sensitive for muscle alterations after strenuous exercise, which could not be detected by T2-weighted imaging.5 Another area of potential use for DTI is in longitudinal studies of muscular dystrophies. Clinical tests are lacking suitability and objectivity to measure subtle changes in muscle status, which is needed to evaluate and monitor progression or efficacy of treatments.6

View this article online at wileyonlinelibrary.com. DOI: 10.1002/jmri.25016 Received Oct 4, 2014, Accepted for publication Jul 6, 2015. *Address reprint requests to: M.F., Department of Radiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail: [email protected] From the 1Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands; 2Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands; and 3Department of Radiology, University Medical Center, Utrecht, Utrecht, The Netherlands

C 2015 Wiley Periodicals, Inc. V 773

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Theory and Acquisition

FIGURE 1: Graph illustrating the increasing number of skeletal muscle DTI articles published over the years 1999 to 2014 (see Appendix for details on the search criteria). Separate lines subsequently denote all articles, review articles in which DTI is one of the main topics, fundamental articles mainly covering acquisition or postprocessing techniques, experimental articles covering reference values, and clinical articles covering the use of DTI in relation with clinical questions.

Moreover, DTI postprocessing software is becoming widely available as commercial packages and as freeware,7 making its application more accessible to a wider user group. As we will show in this review, DTI is a powerful tool for monitoring and quantifying changes in muscle status and structure due to muscle injury, disease, or physiological processes.8–14 Moreover, DTI is able to detect subtle subject specific variations such as age, body mass index (BMI), and gender15–18 or more transient factors such as exercise, rest, pressure, temperature, and relative joint position.19–24 Apart from detecting changes in tissue microstructure, DTI can also be applied for in vivo quantification and 3D visualization of muscle fiber architecture.14 DTI exploits the property that the diffusivity of water is greatest in the direction parallel to the dominant muscle fiber direction. Thereby, DTI permits the quantification of directional anisotropy of muscle fibers25–27 and muscle architectural parameters.28,29 However, the sensitive character of the DTI parameters to the acquisition and subject-specific conditions complicate the interpretation and design of skeletal muscle DTI studies.30–35 Nevertheless, with a carefully designed experiment, DTI has the unique capability of providing insights into the (patho)physiological processes in muscle tissue. The purpose of this review is therefore to provide an overview of the current status of DTI in skeletal muscle, with a focus on the critical technical aspects of the DTI acquisition protocol. Furthermore, we will review the reported normal variances in skeletal muscle diffusion parameters. Finally, we will discuss several clinical skeletal muscle DTI studies with respect to observed changes in DTI parameters as a consequence of several (patho-)physiological conditions in vitro and in vivo. We have included work covering DTI from 1999 to November 2014, published in the English language (Appendix). 774

Diffusion-Weighted Imaging Diffusion is the random displacement of molecules under the influence of temperature and/or concentration gradients. The amount of diffusion is quantified by the diffusion coefficient. In biological tissue diffusion can be hindered by a wide range of factors, eg, specific binding and physical barriers like cellular membranes. Diffusion is then rather described by the apparent diffusion coefficient (ADC) to discriminate it from unhindered diffusion. Diffusion of water can be measured using diffusion-weighted imaging (DWI). DWI typically employs a single-shot diffusionweighted spin echo (SE) echo planar imaging (EPI) pulse sequence (Fig. 2a). However, stimulated echo (STE) pulse sequences are also often used of skeletal muscle DWI.36–41 With STE the 1808 refocusing pulse is replaced by two 908 radiofrequency (RF) pulses. Although this results in a 50% signal loss, it allows for stronger diffusion weighting by increasing the mixing time (TM), which lengthens the time between the diffusion gradients (D), without increasing the echo time and therefore can have higher signal-to-noise ratio (SNR) in certain conditions (37 41) (Fig. 2b). Another commonly used method is the twice refocused spin echo sequence (Fig. 2c), which can reduce the effect of eddy currents.42 However, this method increases the echo time and is therefore less preferred for skeletal muscle applications. For all these methods diffusion sensitizing is accomplished by using diffusion gradients that cause signal attenuation. The resulting signal intensity relates to the ADC [mm2/s] by: Sb 5S0 e 2b ADC

(1)

where Sb is the diffusion-weighted signal and S0 the nonweighted signal (Fig. 3b,c), b is the b-value, which is the

FIGURE 2: Schematic representation of a diffusion-weighted spin-echo sequence. a: Stejskal-Tanner pulsed field gradients, with: G the gradient strength, d the gradient duration, f the rise time of the gradients, and D the delay between the leading edges of the two pulsed field gradients. b: Stimulated echo sequence with TM the mixing time in which the magnetization is subject to T1 relaxation instead of T2 relaxation. c: Twice refocused spin echo sequence.

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FIGURE 3: The top row shows two axial slices through both upper legs: (a) T2-weighted images, (b) nonweighted (b 5 0 s/mm2) images, and (c) diffusion-weighted (b 5 400 s/mm2) images. The bottom row shows the calculated MD (d) and FA (e) maps for the same axial slices.

amount of diffusion weighting and depends on the gradient strength G and gradient timing.43 DTI DWI can be extended by measuring the ADC in at least six independent directions to quantify the directional anisotropy of the diffusion. Instead of a scalar ADC parameter, the diffusivity is then described by a 3 3 3 tensor D (Eq. 2)—hence the name diffusion tensor imaging (DTI)— which can be reconstructed using several methods, eg, Linear Least Squares (LLS), Weighted Linear Least Squares (WLLS), or Nonlinear Least Squares (NLS).15,16 2 3 Dxx Dxy Dxz 6 7 7 (2) D56 4 Dxy Dyy Dyz 5 Dxz Dyz Dzz The tensor can be diagonalized by performing an eigenvector and eigenvalue analysis. The three eigenvectors ~ e1, ~ e 2 and ~ e 3 are orthonormal (principal diffusion directions) and their corresponding eigenvalues k1, k2, and k3 (principal effective diffusivity) are positive and k1  k2  k3. The principal eigenvector yields the direction with the highApril 2016

est diffusion, which has been shown to correspond to the local muscle fiber orientation.12 Principal diffusion directions of neighboring voxels are combined for 3D muscle fiber tractography17–19 (Fig. 4). The diffusion tensor provides information about the directional properties of diffusion and provides the basis for fiber tractography. However, it is rather hard to interpret quantitative changes in the diffusivity and diffusion anisotropy directly from the diffusion tensor itself. Therefore, several rotation and scaling invariant scalar indices were introduced, which can be quantitatively compared between measurements and subjects. The mean diffusivity (MD), given in Eq. (3), is an index that describes the directional average of the diffusion in the tissue (Fig. 3d). MD5

TrðDÞ ðk1 1k2 1k3 Þ  5 5k 3 3

(3)

To quantify the diffusion anisotropy, the fractional anisotropy (FA) scalar index (Eq. (4)) was introduced.25,44,45 FA is dimensionless and equals 0 for an isotropic medium (Fig. 3c). For a cylindrically symmetric anisotropic medium the FA value approaches 1. 775

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FIGURE 4: Principle of fiber tractography, based on Mori et al.63 Anisotropic diffusion in an environment with strongly aligned fibers (a) is represented by an ellipsoid (b). From the ellipsoid the fiber direction is determined for each voxel, represented by the open arrows (c). Fiber tractography starts in the voxel indicated with (*) in panel C. Actual fibers are represented by the curved black lines. The connected voxels are shaded gray. Tractography can be performed as shown by the by the train of red arrows (C). This approach can also be used in three dimensions, where common stopping criteria for tractography are based on the FA and the angular change of the fibers. Example of diffusion ellipsoids in an axial slice and fiber tractography of the gastrocnemius (bottom) and tibialis anterior (top) in a human calf (d).

rffiffiffi 3 FA5 2

qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ðk1 2kÞ2 1ðk2 2kÞ2 1ðk3 2kÞ2 pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi k1 2 1k2 2 1k3 2

(4)

The values of the diffusion tensor components and the derived scalar parameters can be strongly biased by a low SNR.32,33 Therefore, the SNR should always be reported. The SNR in skeletal muscles depends on various hardware and acquisition parameters, such as the echo time (TE),32,33 the diffusion b-value,34,35,46 and diffusion mixing time.47,48 Moreover, the SNR of the diffusion-weighted spin-echo EPI measurement depends strongly on the T2 relaxation time (TR), because of the relatively long TE.32,33 For low SNR generally k1 and FA are overestimated and k3 is underestimated. However, the amount of the error can change depending on the method used for tensor calculation, the height of the tissue diffusion parameters, as well as the bvalue.32,33 To ensure sufficient SNR typical voxel volumes range between 20 and 30 mm3, notwithstanding the resolution differs greatly between studies, eg, 3 3 3 3 3, 2.5 3 2.5 3 5, or 1.6 3 1.6 3 8 mm3. Based on simulations it is recommended to use a short TE to maximize SNR and to use a b-value between 400 and 500 s/mm2 32,33 and to use 776

at least 10 gradient directions.33 Depending on the number of slices measured, typical acquisition times range between 5 and 10 minutes. Other optimal acquisition parameters will differ for different applications (eg, small or large muscles) and available hardware (eg, strong gradients and specialized coils). Next to choosing the proper acquisition parameters, it is important to minimize the effect of artifacts commonly associated with DTI, eg, susceptibility-induced deformations, eddy current distortions, motion artifacts, and chemical shift. Susceptibility-induced deformations can be reduced by proper shimming and increasing the EPI bandwidth in the phase-encoding directions. Remaining deformations can be further decreased by correcting the distortions using a B0-map49 or nonrigid registration.50 To minimize the effect of subject motion, affine registration with the appropriate bmatrix correction is recommended.51 Furthermore, proper fat suppression52 is needed to reduce the effect of chemical shift artifacts. Removal of (olefinic) fat signal from DW-EPI acquisitions can also be accomplished by alternative acquisition methods such as echo time-shifted acquisition.53 However, even with appropriate fat suppression DTI analysis will be affected in voxels containing a high percentage fat.52 Next to DWI and DTI, many other models of diffusion exist, ie, intravoxel incoherent motion (IVIM),27 diffusion kurtosis imaging (DKI),54 diffusion spectrum imaging (DSI),55 Q-ball imaging (QBI),56 constrained spherical deconvolution (CSD),57 composite hindered and restricted model of diffusion (CHARMED),58 and neurite orientation dispersion and density imaging (NODDI).59 Most of these models have been developed to describe diffusion in brain tissue. However, almost none have been optimized or used for skeletal muscle imaging and only a few models specific for skeletal muscle have been developed.48,60 Tractography DTI enables visualization of muscle architecture with the use of fiber tractography algorithms. The principal diffusion directions (the first eigenvector ~ e 1 ) of neighboring voxels are combined for 3D muscle fiber tractography.61–63 Fiber tractography is generally started from a manually or automatically selected region of interest and continues until a cutoff value is reached. Commonly used cutoff values are a minimal and maximal FA and the angular change of the fiber tract per integration step (Fig. 4). For accurate fiber tractography an SNR of at least 30 is advised.32,33 With adequate SNR, tractography cutoff values can be as high as 458 in angular difference and an FA cutoff of 0.1 will be enough for accurately reconstructing the architecture.64 However stricter cutoff values are more frequently used for practical reasons, which makes comparisons between different studies complicated.18,49,65 Next to SNR, adequate resolution is vital to avoid partial volume Volume 43, No. 4

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effects. Partial volume effects can result in falsely elongated, crossing, or unrealistically short fibers.66–68 Fiber tractography allows for the quantification of architectural parameters such as pennation angle,69 curvature,70 fiber length, and physiological cross-sectional area (PCSA).71 The quantification of muscle architectural parameters in human DTI studies started with the calculation of the azimuth and elevation angles relative to the imaging plane in 2002 by Sinha et al.,34 but was also done in more recent studies.23,24 In 2007 Lansdown et al.69 described a technique to determine muscle fiber pennation angle relative to the muscle aponeurosis and showed that there was a significant difference in pennation angle of the deep and superficial compartments of the tibialis anterior muscle.

Feasibility Studies and Reported Variances in Healthy Skeletal Muscle Feasibility Most early work focused on the feasibility of DTI for quantification of diffusion in skeletal muscle and on muscle fiber tractography of the muscles of the calf.26,34,61,72–74 Since then most other limbs, such as forearms,49,75 upper legs,65,76,77 and also more complicated structures such as the tongue,68,72 muscles of the feet,78 ocular muscles,79 and the small pelvic musculature80–82 have been successfully studied with DTI. Quantification of the diffusion tensor derived scalar parameters (the tensor eigenvalues, MD and FA) has been shown to be reproducible.23,76,77,83,84 Their coefficient of variation (CV), defined as the standard deviation divided by the mean, and the coefficient of repeatability (CR), defined as 1.96 times the standard deviation of the paired difference, varies depending on the field strength23,84 and muscle group of interest.23,84,85 Reported values of CV are between 2 and 8% for the tensor eigenvalues and MD and between 6 and 12% for the FA. Reported values of CR are between 0.1 and 0.3 for the tensor eigenvalues and MD and between 0.02 and 0.1 for the FA. However, the CV between studies is found to be much higher when the literature concerning the healthy tibialis anterior muscle of the human calf in neutral position is analyzed (13% for the MD and 23% for the FA) (Fig. 5). Reasons for this spread can be found in differences in acquisition protocols, as described above, but can also originate from differences in demographics (eg, gender or age) or transients differences (eg, exercise or limb position), which are described in the next section. To interpret results, it is important to understand what physiological structures and mechanisms lead to changes in the DTI-derived parameters. More specifically, how do the eigenvalues, MD, and FA relate with muscle properties? There is a general consensus that the principal eigenvector aligns with the local muscle fiber orientation.26 However, the relation of the second and third eigenvector with the April 2016

FIGURE 5: Reported values of MD and FA in the tibialis anterior muscle of the calf with the ankle in the neutral position. The dashed-dotted line indicates the mean and the thin dashed lines two times standard deviation. Error bars are given when reported in the literature, some values have been calculated from given tensors.

muscle microstructure is less clear and has been the subject of several studies. Galban et al.16,73 proposed that k2 is related to the cross-section geometry of the endomysium and that k3 reflects the variations in the average muscle fiber radius. Karampinos et al.86 hypothesized that the difference in k2 and k3 reflect the cross-sectional shape of the myofibrils. This model is supported by the long-range organization of the second eigenvector, which can even be tracked.87 Studies of DTI parameter changes due to physiological or pathological conditions and which performed histology as well seem to support the latter model. The mean cell diameter was found to be positively correlated with k2 and k3. However, most of the time cell swelling was accompanied by an increase of extracellular fluid.2,88–93 Next to diffusion, blood flow in the capillaries will also cause signal attenuation in diffusion-weighted MRI images,27,60,94–97 an effect called pseudodiffusion. Since pseudodiffusion is not truly diffusion, but perfusion, it leads to higher signal attenuation than from diffusion alone (Fig. 777

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FIGURE 6: The effect of IVIM on the ADC estimation. a,b: Log of the signal as a function of b-value. Without IVIM contribution the signal attenuation would be a line for which the slope is the ADC (A: blue line). When there is a substantial contribution of perfusion to the signal attenuation the signal curve shifts down (A: blue dashed line). If the ADC is estimated from signal with substantial contribution of perfusion this can lead to an overestimation of the ADC (B: green and red lines for b 5 400 and 200 s/mm2, respectively). The amount of overestimation of the ADC will depend on the chosen b-value (B: green and red lines).

6a). Although the signal contribution of the perfusion component is absent at high b-values, the signal contribution from the perfusion is present in the reference b 5 0 s/mm2 images. As a result, perfusion will always influence the ADC estimation because its signal is present in the reference images (Fig. 6b). Therefore, a multiexponential fit of the tensor is more accurate since the effect of the pseudodiffusion can influence the MD estimation differently for different b-values. When investigating muscle exercise or damage one has to keep in mind that the muscle perfusion and blood volume will increase and that the change in the measured diffusion can be largely due to pseudodiffusion, as shown by Sigmund et al.98 Sensitivity to Demographic Factors Measurements of tensor parameters showed to be sensitive to patient demographics such as gender and age.15–18 Galban et al.16 found a significantly higher diffusivity in muscles of female subjects as compared to males; however, no clear explanation could be given. Moreover, these findings seem to be more pronounced in the flexor muscles, but cannot be reproduced by others.17,94,99 With respect to age, an overall decrease in diffusivity and increase in FA values in calf muscles has been found with increasing age, which is hypothesized to be caused by age-induced atrophy.88 However, reported changes differ per muscle(-group) (flexors/ extensors or lower/upper extremities), sometimes are absent, or contradictory between studies.15,17,88,94,100 BMI is found to correlate negatively with diffusivity in muscles of the lower back and thigh,6,76,99 which could be a direct result of the increased intramuscular fat fraction.52 Next, Scheel et al.92 showed that higher FA values are positively correlated with the proportion of type 1 to type 2 muscle fibers in the soleus muscle. The authors hypothesized that the difference in FA can be explained by the difference in fiber diameter for type 1 and 2 muscle fibers.92,93 Although muscle strength is correlated with muscle fiber type composition,92 Okamoto et al.101 found no overall difference in FA 778

between muscles of athletes and nonathletes, but instead found a higher MD in athletes. They also found that training of thigh muscles to increase muscle strength resulted in an overall increase of MD and decrease of FA.102 However, Nakai et al.103 reported a contradictory effect with an increase of FA in muscles which were subject to extra stress during walking exercises for over a month. An FA increase was absent in muscles that were not stressed. Transient Factors and Joint Position The effects of transient conditions such as exercise, rest, temperature, and relative joint position on diffusivity of water in skeletal muscles has been covered in several articles. For exercise, Okamoto et al.104 found a decrease in FA values in the exercise loaded gastrocnemius and soleus muscles. This decrease could be observed up to 48 hours after the exercise. The last result was reproduced by Yanagisawa et al.,105 who evaluated diffusivity changes over multiple days after eccentric contraction exercises and found that the FA of the medial gastrocnemius was decreased up to 2 to 5 days after the exercise. Furthermore, k2, k3, MD, and T2 relaxation times were elevated up to even 3 days after the exercise. This might explain the higher MD in athletes compared to nonathletes in an earlier mentioned study by Okamoto et al.,101 in which the athletes were scanned only 48 hours after their last training. In contrast to exercise, laying supine for a period of 30 minutes significantly decreased diffusivity.106 Moreover, applying pressure or cooling muscles also decreased diffusivity significantly.107–109 Galban et al.73 showed the ability of DTI to differentiate between functionally different muscles in the same region of the body on the basis of their diffusive properties and hypothesized DTI parameters reflected muscle architecture. Thereafter, it was hypothesized that changes in joint position, which lead to muscle shortening or lengthening, would lead to changes in muscle architecture and therefore in DTI parameters as well. For the ankle this was addressed in several studies,19–21,23,24,110–112 of which six reported Volume 43, No. 4

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"(103)

"(19–21, 24, " (21) #(19,

Muscle elongation Muscle shortening

#(21)

20, 23, 24, 110, 112)

110, 112)

"(20, "(19,

5

5

(21)

#(19,

110, 111) 20, 23, 24, 102, 110, 111)

24)

(108)

109)

(106)

#(94,

#

105, 109, 124)

#

19, 94, 99)

(15, 88, 94, 100)

5(17,

Increased/decreased cell diameter in shortened/elongated muscles. Changed composition in extra and intracellular fluids. Postexercise effects.

Reduced cell size and reduced extracellular fluid.

Decreased diffusivity.

#T2 time, # extracellular space and # pseudo-diffusion.

Various explanations: " T2 time, " blood volume, " pseudo-diffusion," SNR; " Temperature, changed intra- extracellular volume and cell swelling.

Type 2 muscle fibers give strength and have larger cell diameter.

Smaller diameter of type 1 fibers.

Increased intra muscular fat-fraction (52).

Reduced fiber diameter due to age-induced atrophy. Changes in type 1 and 2 fiber composition.

Mostly unclear.

Suggested explanations

" indicates the value is increased; # indicates the value is decreased; 5 indicates no change was seen. References are given in subscript next to the effect. Studies that reported significance (at least P< 0.05) are underlined.

"

Applying pressure on the muscles

(108)

5(106)

Laying supine

Cooling of the muscles

#

Post-Exercise

(92)

(93)

"(48,

"

#(92)

Higher muscle force (48, 104, 105)

#

"

85)

(17, 99)

#(99)

5

Relative increased levels of Type 1 fibers

"(99)

Increased BMI

5

(17, 99)

(93)

"

Ageing

(15, 88, 94, 100)

"(16,

#(16) 5(15,

Female vs. Male

17, 85, 99)

MD

FA

Demographic and transient changes

TABLE 1. Effects of Physiological and Transient Changes

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or T2-relaxation time change due to muscle work may have influenced the measurements even more. Muscle Microstructure and Architecture DTI and fiber tractography for quantification of architectural parameters such as PCSA, fiber length, and pennation angle has been shown to be reproducible.18,23,84 It has been used to study the effect of joint movement on muscle architecture.24 Several studies quantified PCSA, fiber length, and pennation angles of the calf at different ankle positions.23,24,64,84 Sinha et al.24 showed that in different compartments of the soleus the fiber length and fiber angles change between the neutral and 308 plantar flexed ankle positions. They showed an angle change of the first eigenvector between 128 and 508 with a 308 plantar flexion of the ankle. More recently, Damon et al.70 proposed a method for accurate estimation of fiber curvature, which is an important parameter that is needed to predict strain patterns during muscle contraction.113 In a study by Englund et al.,22 it was shown that during contraction the direction of fiber shortening as measured with DTI differed from the principal direction of muscle shortening as measured using tagging MRI, which indicates the presence of shear strain in the muscle tissue.

Application to Muscle Diseases, Injuries, and Other Conditions FIGURE 7: Results for MD and FA with the ankle in neutral position and during plantar and dorsiflexion. The asterisk shows reported significant differences.

values for the tibialis anterior muscle and five dealt with the medial gastrocnemius muscle. Changes in DTI parameters were linked to increased cell diameter in shortened muscles, changes in extra and intracellular fluids, and postexercise effects (Table 1). Unfortunately, the methods among studies differ to a large extent, which complicates making comparisons. There were differences in the method of flexion (active or passive), the angle of flexion (between 108 dorsiflexion to 408 plantar flexion), measurement setup, and acquisition parameters (field strength 1.5 and 3T, gradient directions: 6 to 12, b-value: 450 to 1000 s/mm2, and TE: 36 to 104 msec). Although most studies report an increase of FA and decrease of MD with elongation of the muscle and the opposite effect for muscle shortening, effect sizes differ between studies and significance was not always reached, and one study even reported the opposite effect (Table 1). This variation in measurement parameters and methods is reflected in the difference of DTI parameters for measurements of the tibialis anterior muscle of the calf at rest, plantar flexion, and dorsal flexion (Fig. 7). Furthermore, earlier described effects like temperature change, differences in SNR, muscle exhaustions, 780

Changes due to (patho-)physiological processes often start at the cellular or fascicular level, which is beyond the detection capabilities of regular T1- and T2-weighted MR-imaging.3 In the literature DTI is considered a sensitive tool for assessing these (patho-)physiological processes, processes that are reflected in changes in tissue diffusivity. Next, DTI enables assessment of disease severity, progression, or remission, In general, there has been interest to investigate the use of DTI as a biomarker for various diseases8–10,12–14,28 (Table 2). In this section we will first cover the preclinical (in vitro) studies followed by the human (in vivo) studies. Ischemia and Denervation The first who used DTI to investigate its use as a potential imaging biomarker for muscle damage and regeneration was Heemskerk et al.89,90 They studied muscle damage and regeneration during and after ischemia in mouse hind limb. During ischemia, MD in the muscles tended to decrease. After the reperfusion the MD, FA, and T2 response was different if the muscle had been stimulated during the ischemia. In the nonstimulated situation, the MD and T2 initially increased and then normalized, whereas in the case of stimulation the FA decreased and the MD and T2 increased even further.90 Similar results were found in the study of femoral artery ligation. However, after 10 days in that setting diffusion values were lower than the initial Volume 43, No. 4

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"(120)

Overuse in dystrophic muscles

91)

"(88)

117, 118)

"(125)

#(125)

"(2, 88, 91) 5 (120)

"(116)

"(125)

#(88)

117, 118)

90, 114)

"(120)

(120)

#(116,

"(90)

"(89,

T2 Acute

"(120)

"(2, 88, 91) " (123, 124) 5

116)

5(89)

MD Follow-up/ chronic

"(125)

"(88)

"(116)

5(89)

T2 Follow-up/ chronic

Acute: Cell swelling and increased extracellular fluid due to inflammatory response Chronic: Loss of muscle organization, reduced diffusivity due to fat-infiltration (52)

Chronic: Reduced fiber diameters due to atrophy

Acute: Cell swelling and increased extracellular fluid due to inflammatory response

Acute: Cell swelling and increased extracellular fluid due to inflammatory response Chronic: Reduced fiber diameters due to atrophy

Cell swelling and increased extracellular fluid due to inflammatory response

Suggested explanations

" indicates the value is increased; #indicates the value is decreased; 5 indicates no change was seen. References are given in subscript next to the effect. Studies that reported significance (at least P< 0.05) are underlined.

Inflammation in polymyositis and dermatomyositis

#(2, 88, 5(120)

Chemical induced Overuse

Trauma

"(116,

"(115,

116)

#(115,

Denervation of muscles

90, 114)

"(90)

"(89,

#(90)

"(89)

MD Acute

Stimulated

90, 114)

FA Follow-up/ chronic

#(89,

FA Acute

Ischemia Nonstimulated

Clinical conditions compared to healthy controls

TABLE 2. Effects of Muscle Damage and Disease

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values, whereas T2 was still increased. Regional differences were found between T2-values and diffusion parameters, which corresponded to the different phases of tissue de- and regeneration as confirmed by histology. Increased ADC corresponded well with the presence of round cells, whereas high T2 values corresponded best with areas in which an influx of inflammatory cells was present. These different phases could not be identified based on T2 alone, indicating that DTI provides supplementary valuable information on muscle injury and regeneration. Similar results were shown in a study by Zhang et al.114 in ischemic muscles of rabbits, which showed an increase of MD and T2 next to a decrease of FA values after ischemia. During histology the muscle fibers were shown to be swollen, which was accompanied by an increase of extracellular fluid. For denervation of the muscles in rabbits the same pattern of increased diffusivity with a decrease of FA was seen in the acute phase.115 In studies of rats and mice that underwent neurotomy and were followed up for 2 to 12 weeks, first a rapid increase of the MD was seen followed by a late increase of T2; however, the MD normalized, the T2 remained high,116 and finally the FA increased significantly, which was correlated with a significant decrease of muscle fiber diameter.117,118 In both studies the increased FA was due to a decrease of the second and third eigenvalue. Hara et al.119 studied impaired muscle function in rats by performing tenotomy of the Achilles tendon. This resulted histologically in atrophied muscles and a decline of all eigenvalues and a significant rise of FA after 4 weeks of follow up. Trauma and Exercise-Induced Muscle Damage The same pattern of increased T2 values due to edema together with a significant increase of the MD and decrease of FA was observed in sterile muscle trauma.88,91 Moreover, Esposito et al.88 found that the combination of T2 and FA correlated with histological signs of inflammation and repair. Bryant et al.2 studied sterile muscle trauma using several MRI modalities combined with histology and could only partially reproduce the above-mentioned results. An increase of all eigenvalues was measured, of which the increase of k3 was greatest, leading to a significant increase of MD. The latter correlated well with other imaging sequences (T1 and T2 mapping, and magnetization transfer imaging) and with a histologically identified increase of extracellular water. However, no significant decrease in FA was observed.2 In studies in which exercise-induced muscle damage was simulated by applying lengthening contractions on mice, McMillan et al.120 showed that the MD and FA increased significantly. McMillan et al.120 also stated that DTI is a reliable method for assessment of muscle damage, as T1 and T2weighted MR signals in the acute phase are dominated by 782

edema. Gineste et al.121 used multiple MRI modalities (Dixon, DTI, 31-phosporous MR-spectroscopy) to investigate the ACTA1(Asp286Gly) mouse model of nemaline myopathy to provide in vivo, noninvasive evidence of impaired in vivo muscle function, and altered muscle structure. They found an increase of k2 and k3 together with increased T2 relaxation times in affected muscles and considered these as relevant imaging biomarkers for monitoring the severity and/or the progression of the disease and for assessing the efficacy of potential therapeutic interventions. In Vivo Applications Holl et al.115 found an increased MD after denervation in muscles of rats, which could be reproduced in the leg musculature of patients with lumbosacral radiculopathy, providing evidence for acute denervation. Furthermore, Froeling122 showed that in a patient with muscle atrophy due to denervation caused by focal/monomelic spinal muscular atrophy (SMA) the affected muscles could be identified by elevated FA values (Fig. 8c,d). These results are in agreement with the study by Yamabe et al.,116 who found a significantly elevated FA in denervated muscles of rats in the chronic phase. Studies on muscle damage due to eccentric contractions or muscle tears support the in vitro results and reported an increased MD together with decreased FA in comparison to healthy controls.123,124 Using tractography the architecture was found to be disorganized.123 For assessing the use of DTI as a potential readout of overuse injuries Froeling et al.5 performed a longitudinal study in marathon runners in which they found an elevated MD in the biceps femoris up to 3 weeks after the marathon. Interestingly the biceps femoris is prone to injury in long-distance running (Fig. 9). Moreover, there was no change visible in conventional T2-weighted imaging. Ponrartana et al.6 used DTI to study the effectiveness of DTI to provide suitable objective endpoints for measuring disease progression in Duchenne muscular dystrophy. Clinical testing has in general a poor intrarater variability and therefore these tests are inadequate to measure subtle changes for assessing disease progression or monitor therapeutic responses in therapeutic intervention studies. The study showed good correlations of DTI parameters with muscle strength and muscle fat infiltrations, suggesting DTI can be a valuable noninvasive marker for disease severity. In inflamed muscles due to diseases such as polymyositis and dermatomyositis an increase in MD and T2 was reported in active inflammation.125 However, in chronically affected and fat-infiltrated muscles the MD was lower.125 Furthermore, the authors stated that DTI parameters were more sensitive to the further deterioration of the muscles than T1 and T2. Next, pseudodiffusion was elevated in inflamed muscles compared with healthy muscles, an effect Volume 43, No. 4

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FIGURE 8: Different examples of fiber tractography, the tracts are color coded for the fractional anisotropy (FA). a: Fiber tractography of the lumbar erector spinea muscles.132 b: Whole volume tractography of the upper legs.5 c: Whole volume fiber tractography of the forearm.49 d,e: Fiber tractography of healthy forearm muscles, next to those of atrophic forearm muscles due to focal/ monomelic spinal muscular atrophy, increased FA values can be seen in the affected extensor digitorum muscle, which was also identified by electromyography.122

that was also seen in chronically inflamed muscles due to whiplash.125,126 Sigmund et al.48 used diffusion-weighted data at multiple diffusion mixing times together with a random permeable barrier model (RPBM) to describe the effects of exercise on permeability and diameter of muscle cells in patients with chronic exertional compartment syndrome (CECS) and healthy controls. They found an increase of diffusivity in both groups. However, in the healthy controls this was mainly due to an increase of the muscle fiber diameter, whereas in patients the apparent membrane permeability increased, likely due to an increase of extracellular edema. Besides the potential value for diag-

nosing CECS, models like the RPBM can add specificity to DTI and potentially enlarge its diagnostic value. Structural Change Fiber tractography can provide insights at the structural level of muscle pathophysiology (Fig. 8a–c). Kan et al.127 used fiber tractography and derived architectural parameters to create biomechanical models of the quadriceps mechanism in healthy subjects and those with chronic lateral patellar dislocation. Such models can be useful for monitoring physical therapy or a rehabilitation process. Within the tongue, fiber tractography was used to study muscle deformations

FIGURE 9: Fiber tractography of the biceps femoris and semitendinosus muscle at three different timepoints (a: 1 week before; b: 72 hours after; and c: 3 weeks after running a marathon). The fiber tracts are color coded for the mean diffusivity (MD). Based on Froeling et al.5

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caused by oral appliances used for obstructive sleep apnea (OSA)128 and to study altered anatomy after glossectomy.129 Fiber tractography was used to obtain boundary conditions for accurate finite element models to study motion of the tongue during swallowing and speech and can be of significant value for improving rehabilitation programs or presurgical planning.29,129,130

Discussion DTI of skeletal muscles has become a widely available research tool over the last decade, which resulted in an increasing number of studies using this technique. DTI has been shown to be feasible within most skeletal muscles and its reproducibility has been established for the calf, thigh, and forearm muscles. Importantly, when designing a DTI study one should be aware of the fact that the DTI parameters are directly dependent on the measurement setup and acquisition parameters. Next, DTI parameters have been shown to be sensitive to both demographics and transient conditions (Tables 1, 2). Therefore, reference values for FA and MD cannot yet be given. Moreover, DTI has been shown to be very sensitive for (patho-)physiological muscle changes due to ischemia, denervation, trauma, exercise, dermatomyositis, and polymyositis. Altogether, the acute phase of all conditions coincides with an increased diffusivity, which was greatest for k1 and k3 and decreased FA values. These findings corresponded well with increased cell diameters and extracellular fluid fraction found with histology. All of which are the general signs of both inflammatory response and cell deand regeneration. Although T2 relaxation follows the same pattern for the acute phase, DTI can provide useful supplementary information in the follow-up. In some studies there was a normalization of diffusion parameters during followup, whereas T2 had the tendency to stay increased. DTI is also stated to be more specific for muscle damage in the acute phase, when T2 values are mainly influenced by edema. For atrophied muscles, diffusion parameters decrease while T2 remains increased. Therefore, we believe DTI is a valuable tool especially when used with other modalities. Furthermore, specific models such as the RPMB and IVIM will possibly further increase the value of DTI in the clinical setting. These models will help to provide insights into the level of change in diffusivity due to, eg, edema, pseudodiffusion, or cell swelling. For example, DTI can play a role in muscle injuries, as recurrence rates are high3 and T1- and T2-weighted imaging does not provide a good prognosis.131 We see potential value in (neuro-)muscular disorders, as DTI provides a sensitive readout of muscle status and can provide a patient-friendly and objective measure of disease progression, treatment effects, and prognosis. DTI fiber tractography allows for an accurate reconstruction of the 3D muscle architecture from which muscle 784

architectural measures such as the PCSA, fiber length, and pennation angle can be derived. These parameters can be used in biomechanical modeling and have already been used to describe the biomechanics of the quadriceps in patients with chronic lateral patellar dislocation. In conclusion, DTI is a sensitive and reproducible tool for assessing muscle (patho-)physiology. However, when designing new studies the sensitivity of DTI parameters to the acquisition, demographics, and transient conditions presented in this review should be carefully reflected. Presently, DTI seems especially suited as a research tool for group comparisons and longitudinal and prospective studies. Before DTI can be implemented in the clinical routine more studies are needed that focus on the standardization of protocols, determining reference values for a wide range of demographic factors, and assess sensitivity and specificity of DTI parameters for various diseases.

Appendix Literature Search Strategy To identify the literature covering DTI in skeletal muscles and covering the technical advances, normal variations, and its applications we conducted a literature search in November 2014. The following databases were searched: PubMed (103 included and 105 excluded), Embase (no additional inclusions), and Cochrane (no additional inclusions). We excluded articles older than 15 years and not written in English. The search terms for the PubMed electronic database were as follows: (“Muscle, Striated”[Mesh] OR “Muscle, Skeletal” [Mesh]OR (striated muscle[All Fields] OR striated muscled[All Fields] OR striated muscles[All Fields] OR (skeletal muscle[All Fields] OR skeletal muscles [All Fields] OR skeletal muscles[All Fields] OR skeletal muscles[All Fields]) AND (DTI[All Fields] OR DT-MRI[All Fields] OR (“diffusion tensor imaging” [MeSH Terms] OR (“diffusion”[All Fields] AND “tensor”[All Fields] OR “diffusion tensor imaging”[All Fields]) The search was adapted as necessary for the other databases. References were managed with the aid of reference managing software (Mendelay Desktop 1).

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