Outcomes/Objectives
· Summarize quantitative biomarkers of skeletal muscle function (specifically relaxometry and diffusion-weighted imaging) that access novel physiologic properties
· Describe the role of quantitative modeling for increased specificity
· Describe examples of exercise as a controlled clinical challenge
· Summarize quantitative biomarkers of skeletal muscle function (specifically relaxometry and diffusion-weighted imaging) that access novel physiologic properties
· Describe the role of quantitative modeling for increased specificity
· Describe examples of exercise as a controlled clinical challenge
DWI, which measures water motion and its hindrance or enhancement in biological tissue, has many variants to highlight features of skeletal muscle. One is diffusion tensor imaging (DTI) (1), which measures the directional bias of water diffusion and provides metrics of the value and anisotropy of diffusion. Myofiber anisotropy is a natural feature for characterization by diffusion tensor imaging (DTI) in healthy (2-4) and pathological muscle (5,6), such as inflammation (6), ischemia, fatty infiltration, compartment syndrome (7,8) or injuries (5,9). Fiber tractography has also been applied to muscle as a means for noninvasive estimation of connectivity, fiber length, and pennation angles (10-13). In fact, particular adaptation of DTI for muscle is growing. Since the approximate diameter of the myofiber membrane (50 mm) is much larger than typical the diffusion lengths (10 mm), restriction effects are moderate. Several studies have thus used stimulated echo preparations with longer diffusion times to increase muscle DTI contrast (7,8,14-21). Several studies have begun to incorporate DTI into biological models for enhanced specificity. In one example (random permeable barrier model (RPBM)) based on topological representation of myofiber membranes, the continuous variation of diffusion time provides estimates of fiber size and permeability (8,22,23). In another case, a combination of T2-weighting and diffusion-weighting coupled with a two water pool model (intracellular and endomysial spaces) supports differentiating a variety of microstructural scenarios (atrophy, edema, fibrosis) (24). Another approach analyzed muscle DTI data alone with a similar two-compartment description (25) in which insights on fiber ellipticity were found, similar to prior work (26).
Intravoxel incoherent motion (IVIM) separately quantifies myofiber microstructure and microvascularity through two-compartment analysis of a range of diffusion-weightings (6,27,28). Histology also confirms that a large fraction of microvasculature in skeletal muscle surrounds and is aligned with each individual myofiber. The muscle IVIM signature is correspondingly anisotropic (27). Diffusion kurtosis imaging (DKI), an extension of DWI probing microstructural complexity, has recently been explored in skeletal muscle (20,29-31). Initial results suggest kurtosis to be an additive and complementary biomarker to those of DTI. It has also been pointed out that IVIM and DKI effects may be mutually confounding if not quantified separately (30).
Diffusion biomarkers in muscle are often useful not only at rest but after exercise challenge. Skeletal muscle water transport is transiently altered by exercise due to a combination of water exchange, myofiber swelling, and increased perfusion. Correspondingly, exercise response of diffusion-weighted contrast has been observed, (32-34). Static DTI studies (7,8) and dynamic DTI studies (34-39) performed before and after exercise have revealed anisotropic increases in diffusion metrics in calf and thigh muscle. IVIM is a powerful probe of the response of microcirculation to challenge, which is a key element in pathologies. IVIM studies in the forearm (28,34), calf (40), back (34), shoulder (41), and thigh (42) have shown increases in both microstructural and microvascular parameters in activated muscle.
Finally, another type of biomarker has emerged from what was thought to be an artifact. Specifically, seemingly stochastic signal voids in DWI are now believed (through correlation with electromyography (43), connectivity from DTI tractography (44), and direct electrical stimulation (45)) to relate of fasciculation of individual motor units within skeletal muscle. Applications of this approach (such as to amyotrophic lateral sclerosis (45)) are at very early stages in this novel area.
The crucial role of oxygenation in muscle function has led to a significant application of blood-oxygen-level-dependent (BOLD) MRI for muscle characterization (46), in the form of T2* weighted imaging or T2* mapping. Furthermore, in analogy to the use of BOLD for neuroimaging, physical challenge (exercise, cuff compression) is typically introduced to modulate the BOLD signal and monitor the kinetics of its subsequent return to equilibrium (47-52). Given the number of possible contributing factors (blood volume, oxygenation, microarchitecture) sophisticated modeling is increasingly pursued to understand the BOLD signal.
Transverse relaxation (T2) mapping also has been applied extensively to muscle(53) to probe pathologic processes (injury, denervation, inflammation). The technique is employed both in single component (monoexponential) T2 measurement in multicompartment measurements as in early measurements (54,55). Technical improvements have included consideration of fat fraction as well as RF pulse imperfections on T2 quantification. Pathologic populations of Duchenne muscular dystrophy (56,57) and inflammatory myopathies (58,59) have been studied with T2 mapping. Elevated muscle signal intensity on T2-weighted imaging following exercise is well-documented (54,60,61). Exercise challenge has also been used in conjunction with T2-mapping for additional specificity (55). T1 mapping has also been increasingly explored as means to quantitatively track fat infiltration and probe the change in macromolecular dynamics in neuromuscular disease (58,62), as well as quantify exercise response (63).
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