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Characterization of Skeletal Muscle Elasticity Using Magnetic Resonance Elastography
a report by
Q i n g s h a n C h e n , M S , 1 A r m a n d o M a n d u c a , P h D 2 and K a i - N a n A n , P h D 2
1. Biomechanics Laboratory, Division of Orthopaedic Research, Mayo Clinic;
2. Magnetic Resonance Imaging Research Laboratory, Department of Radiology, Mayo Clinic
Anatomy/Physiology/Pathology
Information on the elasticity of skeletal muscle (often called muscle
stiffness) in vivo has clinical applications in several fields, including
orthopaedics, sports medicine, physical medicine and rehabilitation,
endocrinology, and rheumatology. Muscle stiffness can be evaluated in
either the relaxed (passive) state or the contracted state; the mechanisms
involved in each state are different. Muscle resistance to passive
stretching comes primarily from two sources: titin and the extracellular
matrix (ECM).1–3 In contrast, when muscle is actively contracted, muscle
stiffness reflects the elasticity of the actin–myosin cross-bridges within
the muscle fibers.
The ECM of skeletal muscle occupies the intercellular space and is indirectly
connected to the contractile proteins of the muscle cell through the
subsarcolemmal cytoskeleton.4 In addition to providing mechanical support
for the tissue and passive resistance to stretching, the ECM has a number of
important roles.5–7 Two are particularly important: the transmission of force
from muscle fibers to the tendon and the transfer of mechanical signaling
to the muscle cells (mechanotransduction).
Qingshan Chen, MS, is an Assistant Professor of Biomedical
Engineering and a Research Engineer in the Orthopaedic
Biomechanics Laboratory at Mayo Clinic College of Medicine.
His research interests include magnetic resonance
elastography and soft-tissue modeling.
E: [email protected]
Armando Manduca, PhD, is a Professor of Biomedical
Engineering, an Associate Professor of Biophysics, an
Assistant Professor of Radiology, and a Consultant in
Physiology and Biomedical Engineering at Mayo Clinic College
of Medicine. His research interests are in image processing,
computer-aided diagnosis, and computational intelligence.
Kai-Nan An, PhD, is a Professor of Bioengineering at Mayo
Medical School. He holds a joint appointment as a
Consultant in the Division of Orthopedic Research,
Department of Orthopaedic Surgery, Mayo Clinic, and in the
Department of Physiology and Biomedical Engineering, Mayo
Clinic. Dr An is Director of the Biomechanics Laboratory and
the John and Posy Krehbiel Professor of Orthopaedics. His
research interests include biomechanics, biomaterials,
orthopaedics, and rehabilitation.
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Pathological skeletal muscle tissues often exhibit a noticeable difference
in stiffness compared with normal healthy tissue. This change in muscle
stiffness is thought to likely result from structural or compositional changes
in either the ECM or muscle fiber. Examples of these two situations are
idiopathic inflammatory myopathy (IIM) and Graves’ disease, respectively,
both of which are briefly described below.
IIM is a heterogeneous group of disorders characterized by symmetrical
proximal muscle weakness and elevated serum levels of enzymes derived
from skeletal muscle. Types of myositis include dermatomyositis, polymyositis,
and inclusion body myositis. All have in common lymphocytic infiltration
of muscles, edema within the muscle, altered muscle composition, and
impaired muscle function. Associated with these changes is a decrease in
muscle endurance and/or strength.8 The following vicious cycle in IIM is
hypothesized: first, the inflammation causes certain pathological degradation
of the ECM in the affected muscles; next, the degradation of ECM blocks the
mechanotransduction pathway; consequently, the lack of mechano-biological
signaling results in decreased cellular activity of the muscle cells and the
further reduced synthesis of the ECM by muscle cells.
Graves’ disease is a common cause of hyperthyroidism and leads to a variety
of clinical symptoms, including skeletal muscle weakness (i.e. hyperthyroid
myopathy) that may be quite profound but is reversible following correction
of hyperthyroidism. In hyperthyroidism, a decrease in the number of slowtwitch muscle fibers and an increase in the number of fast-twitch muscle
fibers are observed, thought to be related to the decrease in muscle stiffness.9
An additional area of interest that involves stiffness of skeletal muscle tissue
is the diagnosis of myofascial pain syndrome (MPS), a painful musculoskeletal
condition and a common cause of musculoskeletal pain.10–13 The main
findings about myofascial pain are localized taut bands of increased tone and
stiffness and even more circumscribed points of tenderness (i.e. trigger
points) that when compressed produce stereotypical patterns of referred
pain.12,14–17 Taut bands are currently thought to represent a discrete group of
muscle fibers that have contracted for unknown reasons.16 The identification
of taut bands and trigger points is important not only for diagnosis, but also
for potential treatment. Despite their importance, there is still no laboratory
test or imaging technique capable of objectively confirming either their
nature or location, while criticisms remain in terms of repeatability and
subjectivity issues of conventional manual palpation examination.14,16–21
Evaluation of Skeletal Muscle Tissue Stiffness
Conventionally, in vivo skeletal muscles are clinically assessed with functional
examinations, validated clinical scales, force measurements using handheld
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Characterization of Skeletal Muscle Elasticity Using Magnetic Resonance Elastography
and isokinetic dynamometers, and surface and fine-wire electromyography
(EMG).22–25 While these measurements provide information that clinicians can
use to track changes in muscle function in their patients, they do not provide
any quantitative information about muscle stiffness, which is an important
parameter in assessing muscle properties.
Figure 1: Magnetic Resonance Images of a Phantom Gel
Technically, Young’s modulus is the quantity delineating a material’s
elasticity. In conventional in vitro evaluation of skeletal muscle stiffness in
clinical settings, elasticity is often assumed, and the local slope of the nonlinear stress–strain curve at a given strain is considered the ‘modulus’ at
that strain level. A different approach, magnetic resonance elastography
(MRE), as described in greater detail in the following section, assesses
tissue stiffness in vivo by calculating the modulus from its effect on shear
wave propagation.
Magnetic Resonance Elastography
MRE is a non-invasive phase-contrast technique that directly visualizes and
quantitatively measures propagating shear waves in tissue-like materials
subject to harmonic mechanical excitation.26,27 MRE uses mechanical shear
vibration rather than static stress as a probe. The major advantage of this
method is that it does not require estimation of the stress distribution. A
phase-contrast MR imaging (MRI) technique is used to spatially map the
shear wave displacement fields. Specifically, a motion-sensitizing gradient
(square wave, sinusoidal wave, or triangular wave) switching in polarity at
the same frequency as the mechanical shear vibration is imposed on the
conventional MRI gradients of the MRI scanner. The cyclic motion of
the nuclei spins in the presence of the motion-sensitizing gradient causes
measurable accumulative spin-phase shifts in the received MR signal,
which can be used to calculate the pixel vibratory displacement. A wave
image is thus formed from the pixel vibratory displacement. Subsequently,
the elastic shear modulus can be calculated locally based on analysis of the
shear wave displacement pattern and its propagation, a process generally
termed ‘stiffness inversion.’ The shear modulus image is termed an
elastogram (see Figure 1).
Because of its ability to map material elastic modulus, MRE has been
proposed for quantitative characterization of muscle tissue stiffness
in vivo. Since its invention, MRE has been applied to skeletal muscles in the
biceps brachii, flexor digitorum profundus, thigh muscles, and upper
trapezius.28–36 Some studies have developed methods for collecting MRE
data in specific muscles and reported a database of muscle stiffness, and
other studies have used MRE for determination of changes in shear
stiffness in pathological muscles. Specifically, examples of MRE studies on
muscle stiffness in patients with IIM, Graves’ disease, and MPS are
described in this article.
Compared with conventional examinations, MRE imaging of skeletal
muscle offers the following advantages: visualization and quantitative
measurement of tissue stiffness; high sensitivity to small motions in the
order of microns; and the ability to obtain full 3D displacement
information throughout a 3D volume.
Instrumentation
In terms of hardware realization, the motion-sensitizing gradient can be
readily incorporated into gradient echo (GRE) pulse sequences, usually for
2D imaging, or, more recently, echo-planar imaging (EPI) pulse sequences,
US MUSCULOSKELETAL REVIEW
A: 2D magnetic resonance (MR) magnitude image of a phantom gel. The electromechanical
driver applies horizontal shear waves to the phantom via a surface plate applicator.
B: 2D MR elastography (MRE) wave image of the gel phantom, showing the shear wave
propagation in the gel phantom. Red indicates wave peak and blue indicates wave valley.
C: 2D MRE stiffness image (elastogram) of the gel phantom reconstructed by stiffness inversion
process, showing circular inclusions with higher stiffness than the surrounding phantom matrix.
Red indicates ‘stiffer’ region and blue indicates ‘softer’ region.
Figure 2: Examples of Positioning, Loading, and Force
Measurement Devices and Driver Used to Collect Muscle
Magnetic Resonance Elastography Data
A: Weights connected to a cable and pulley system applied plantarflexion and dorsiflexion
moments to the ankle joint.
B: Leg press and pneumatic drivers used to induce shear waves into the proximal leg muscles.
Source: Ringleb et al., 2007.37
which enable the fast imaging times desirable for 3D imaging.26 The choice
of mechanical vibration frequency for a particular application depends on
a trade-off: on the one hand, increasing frequency yields higher resolution,
since the propagating wavelength is small; on the other hand, increasing
frequency leads to higher attenuation, as tissue viscoelasticity increases at
higher frequencies. In practice, excitation frequencies in the range of
90–200Hz are used for skeletal muscle MRE imaging.37
The choice of drivers that create the mechanical excitation on skeletal
muscles in vivo include electromagnetic coil drivers, piezoelectric drivers,
pneumatic drivers, and focused ultrasound.26 An electromagnetic coil
driver applies alternating currents to an annular coil to generate motion. It
is easy to construct and relatively low-cost, and can be customized easily
for special in vivo applications such as muscle, breast, or brain MRE.
However, artifacts may be produced due to the magnetic interference of
the driver coil. A piezoelectric driver has the advantage of arbitrary
orientation with respect to the main magnetic field, but its fabrication is
elaborate and time-consuming, and it has a limited maximum
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Figure 3: Stiffness of Vastus Medialis Measured at Relaxed and
Contracted State Before and After Treatment of Hyperthyroidism
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Positioning and loading devices are often used to acquire MRE image data
on skeletal muscles in relaxed, passively loaded, and isometrically
contracted conditions. These devices usually run at 5–20% of maximal
voluntary contracture (MVC). For instance, to test the biceps under load, a
pulley system consisting of a hand grip at one end and weights at the
other end was used.38 The muscles in the lower limb were tested in the
relaxed configuration as well as in an actively contracted state using three
types of positioning and loading devices:
8
7
6
Stiffness of VM (KPa)
chosen, trigger pulses are always provided by the sequencing computer of
the MR scanner, and are fed to a function generator to generate a
coupled-motion waveform that is amplified and applied to the driver.
5
4
3
2
1
0
Before treatment
After treatment
Colored lines represent different patient subjects.
Figure 4: Typical Magnetic Resonance (MR) Elastography Stiffness
Image of the Upper Trapezius of a Patient with Myofascial Pain,
Superimposed on the MR Image of the Same Subject
• a positioning and loading device capable of adjusting the position of
the ankle joint where weights connected to a cable and pulley system
applied plantarflexion and dorsiflexion moments, thus investigating an
isotonic contraction;33
• a foot plate with a strain gauge incorporated to measure isometric
force with the ankle fixed in a neutral position;37 or
• a positioning and loading device with an MR-compatible torque
cell to measure isometric moments and allowing for passive
joint positioning.29,36
Examples of the positioning, loading, and force measurement devices and
drivers are shown in Figure 2.
An increase in shear stiffness was observed when the muscles were
isometrically contracting. For example, when the volunteers extended their
proximal legs at 10% of MVC, there was a significant increase (p<0.05) in
the shear stiffness of the vastus lateralis. At 20% of MVC, there was a
significant increase in the shear stiffness of the vastus medials.36
Repeatability of Magnetic Resonance Elastography
Imaging on Skeletal Muscles
The repeatability of muscle MRE acquisition was assessed in the biceps
brachii and lateral gastrocnemius. Repeat data were collected in the
relaxed biceps brachii of two volunteers over seven days. The mean and
standard deviations of the stiffness values of the repeat trials were
calculated. Repeat data were collected from nine volunteers in the
relaxed lateral gastrocnemius. The co-efficient of variation was 15.7%,
which was comparable to the standard deviations reported in the biceps
brachii. When the lateral gastrocnemius was contracted, the co-efficient
of variation increased to 19.4%.37
I: spine of scapular; II: magnetic resonance elastography (MRE) stiffness image superimposed;
III. taut band region imaged by MRE; IV. cervical spine.
Blue indicates ‘stiffer’ region and purple indicates ‘softer’ region. Red line indicates the location
of the taut band identified through the palpation examination.
Source: Chen et al., 2008.39
displacement. A pneumatic driver is easy to construct, free of artifacts, and
low-cost, and has good frequency response. In focused ultrasound, the
ultrasound beam is temporally modulated to create cyclic variation in
acoustic radiation pressure at the focus of the ultrasound source, which
can be localized deep within an object. Regardless of the type of driver
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Assessing Pathological Muscle with
Magnetic Resonance Elastography
In vivo MRE examinations on the stiffness of the proximal lower limb muscle
(vastus medialis) have been shown to be capable of detecting differences in
stiffness between healthy and hyperthyroid subjects. Mechanical vibration was
applied to the proximal lower limb via a pneumatic tube driver, and muscle
contracture was monitored by the MR-compatible torque cell assembled to the
foot plate.29 MRE scans on the patients with hyperthyroid myopathy showed a
lower shear stiffness in the relaxed condition (2.11±0.61kPa) compared with
the shear stiffness following treatment of hyperthyroidism (5.52±1.52kPa).
Pre-treatment muscle stiffness was also significantly lower than that of the
age-matched healthy volunteers (4.56±0.40kPa)36 (see Figure 3).
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Characterization of Skeletal Muscle Elasticity Using Magnetic Resonance Elastography
Because of its ability to differentiate tissue stiffness, MRE has been
proposed as an imaging method to objectively detect the location
and quantify the stiffness of myofascial taut band, thereby facilitating the
diagnosis of myofascial pain. First, the myofascial pain patients
underwent manual palpatory examination by an experienced physician,
and the location of the myofascial taut band detected by palpation was
marked. An MRE scan was then performed on the patients. Mechanical
vibration (planar wave) was applied on the muscle–tendon junction at
spin of scapula, allowing a shear wave to propagate through the upper
trapezius, one of the most frequent locations of myofascial taut band
and trigger point.30,39 MRE phase images showed a chevron-shaped wave
front in the vicinity of myofascial taut band detected by manual
palpation. Stiffness images showed a statistically significant 50–100%
(p=0.01) increase of shear stiffness (8.4kPa) in the taut band regions of
the involved subjects (see Figure 4) relative to that of the controls
(4.2kPa) or in nearby uninvolved muscle (4.8kPa).30
Conclusions
MRE has gained popularity in biomechanical imaging of skeletal muscles.
Combining in vivo MRE stiffness measurements and commonly used
clinical measures such as muscle biopsy and subjective scales would
facilitate the understanding of how changes in the skeletal muscle tissues
by pathology alter their function. In vitro MRE imaging of appropriate
models of ECM damaging and/or changes would help us to gain further
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insight into the role of ECM in the mechanical properties of muscles.
MRE can also be used to objectively evaluate the efficacy of treatments
for muscles altered by pathologies and injury. Primary technical
Magnetic resonance elastography is a
non-invasive phase-contrast technique
that directly visualizes and quantitatively
measures propagating shear waves in
tissue-like materials subject to harmonic
mechanical excitation.
challenges for MRE imaging on skeletal muscles include: further
development of MRE pulse sequences to allow fast or realtime image
data acquisition; improvement of stiffness inversion to be more robust
and to handle material anisotropy; and more advanced design and
instrumentation of drivers that more efficiently deliver mechanical
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