. Application of a 3D-UTE sequence for the detection and characterization of a short-T2-component in skeletal muscle tissue

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Intramuscular connective tissue: epimysium, perimysium and endomysium.

Intramuscular connective tissue (IMCT) is principally composed of fibers of the proteins collagen and elastin, surrounded by a proteoglycan (PG) matrix. The collagen and elastin contents as percentage of dry tissue weight are 1-10% and less than 0.1-2% respectively, varying with age and muscle (6). Within the anatomical relevant structures of the IMCT, besides the endomysial, perimysial and epimysial layers, is the basal lamina, a thin connective tissue sheet linking the fibrous (reticular) layer of the endomysium to the sarcolemma. Between the sarcolemma and the basal lamina there are small mononuclear cells called satellite cells, which play a fundamental role in myofiber regeneration.
The proteins and macromolecules forming the IMCT are immersed in the so called interstitial fluid, which is composed of water, salts and plasma proteins. Figure 1-5 presents electron micrograph images of the cut surface of bovine sternomandibularis muscle after digestion with NaOH to remove muscle cell contents and proteoglycans, leaving the perimysial and endomysial layers of the IMCT clearly visible.

Structural and histological alterations induced by pathology in the skeletal muscle tissue

The goal of this section was to describe the main structural and histological tissue alterations that are commonly observed in NMD, and that are expected to appreciably impact proton (1H) NMR observations, without getting into the details concerning the disease-specific mechanisms underlying such alterations.
Neuromuscular disorders encompass a large number of diseases that impair the functioning of muscles. An important consequence of the disease activity common to most NMDs is injury at the cellular level. The term cell injury refers to the destruction of the integrity of the sarcolemma, which results in an outflow of cellular organelles into the interstitial space leading to myofiber necrosis. Local inflammation takes place as a response to the degeneration of the cell(s) resulting in interstitial oedema and phagocytosis Figure 1-6.

The role of NMR in myology clinical research

The continuous advances of NMR techniques, especially the recent progress on the development and optimization of quantitative examination tools, have driven increased attention to Nuclear Magnetic Resonance Imaging (NMRI) and Nuclear Magnetic Resonance Spectroscopy (NMRS) and extended their applications in the neuromuscular field, from supplementary diagnostic tools to quantitative non-invasive outcome measures in clinical studies.
Muscle NMRI is sensitive to pathology induced changes such as fat degeneration and inflammation, and has been proven capable of revealing disease-specific patterns of selective muscle involvement (12–16), lending itself well for guiding genetic tests and for optimal muscle selection for biopsy (17), improving the diagnostic workup (18). Furthermore, progressive characterization of such patterns shall help to better understand the pathogenesis of neuromuscular disease.
Quantitative NMR methods have provided non-invasive outcome measures for NMD, offering the possibility of realising longitudinal studies for the follow-up of therapeutic trials and disease progression (19–24), which was just not feasible with purely qualitative techniques, incapable of detecting short duration changes in slow progressing diseases. Moreover, detailed description of disease progression may elucidate still unknown aspects of onset and progression of pathology. Besides NMRI, Nuclear Magnetic Resonance Spectroscopy (NMRS) techniques have also demonstrated their utility in the clinical field of NMD, as it is a consolidated non-invasive tool for quantifying pathology induced metabolic alterations (25, 26). With correct manipulation, NMR techniques can be made sensitive to different tissue-characteristic physical properties and physiological processes, making it an important investigative tool for studying the physiological mechanisms underlying disease activity.

NMR outcome measures currently available for skeletal muscle studies

An adult human body is mainly composed of water (60-70 %), proteins (15-25 %) and lipids (5-15%), and these components are distributed at different relative fractions within each type of tissue in the body. Hydrogen nuclei are present in all molecules forming these components and are the most abundant atoms in the human body, which makes it them nuclei of choice for most NMRI applications. In practice, the signal from hydrogen (proton) in proteins is not observable with usual NMRI techniques due to its extremely short T2-relaxation time (T2) (~ 10 μs) (see 2.4), so that most of the signal that is processed in 1H-NMRI techniques comes only from protons in water and lipids. The relaxation of water in tissue is very different from the relaxation of pure water, and is usually dominated by the interactions of the water molecules with the macromolecules constituting the tissue. As a consequence, there will be three independent sources of contrast in magnetic resonance images: (i) the volumetric density of detectable protons; (ii) the different intrinsic NMR parameters characterizing water and lipids; and (iii) the different tissue-characteristic NMR parameters of water protons, which are determined by the chemical composition and structure of the tissue. The different tissues or structures that are identified in standard clinical NMRI of SKM are: muscle, fat, fascia and cortical bone (Figure 1-9); the two last being recognizable by a characteristic lack of signal.

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Magnetization excitation and the resonance phenomenon

Let’s define the non-zero net-magnetization aligned to the external magnetic field, ⃗⃗⃗⃗ , by ⃗⃗⃗ ∫ ⃗⃗⃗ ⃗ We will call magnetization excitation the process of breaking the thermal equilibrium of a system by tipping the net magnetization vector away from the ⃗⃗⃗⃗ direction. This might be done by applying a second magnetic field, ⃗⃗⃗⃗ , orthogonal to ⃗⃗⃗⃗ . In practice | ⃗⃗⃗⃗ || ⃗⃗⃗⃗ | , and it is easy to notice that a static field ⃗⃗⃗⃗ will only bring the system to a second thermal equilibrium state with ⃗⃗ ( ⃗⃗⃗⃗ ⃗⃗⃗⃗ ). As the field ⃗⃗⃗⃗⃗⃗⃗⃗ ⃗⃗⃗⃗ ⃗⃗⃗⃗ ⃗⃗⃗⃗ , practically nothing will change. If instead, an oscillating transverse ⃗⃗⃗⃗ is applied at the Larmor precession frequency, , i.e., in resonance with the precessing magnetization, for a duration , the net magnetization will be tipped away by an angle | ⃗⃗⃗⃗ | . To see this, let’s observe the system from a referential rotating at the Larmor frequency (Figure 2-2). From this point of view the ⃗⃗⃗⃗ field will be static and no precession of ⃗⃗ around ⃗⃗⃗⃗ would ever be observed. It follows that in this referential ⃗⃗⃗⃗⃗⃗⃗⃗ ⃗⃗⃗⃗ and, from Eq. 2.6 .

Table of contents :

Table of Contents
List of Figures
List of Tables
1. General Introduction
1.1. Skeletal muscle structure and histology
1.1.1. Striated muscle architecture
1.1.2. Muscle cell (Myofiber)
1.1.3. Intramuscular connective tissue: epimysium, perimysium and endomysium.
1.1.4. Structural and histological alterations induced by pathology in the skeletal muscle tissue
1.2. The role of NMR in myology clinical research
1.2.1. NMR outcome measures currently available for skeletal muscle studies
1.3. Thesis overview and contributions
2. Basic Concepts of Nuclear Magnetic Resonance
2.1. The spin magnetic moment and the precession equation
2.2. Magnetic polarization (Magnetization)
2.3. Magnetization excitation and the resonance phenomenon
2.4. Relaxation and the Bloch equations
2.5. Nuclear magnetic resonance spectroscopy
2.6. Nuclear magnetic resonance imaging
2.7. Characterization of tissue NMR parameters and NMRI contrasts
2.7.1. The spin echo
2.7.2. The gradient echo
2.7.3. Magnetization from repeated RF-pulses and the steady state
2.7.4. Diffusion effects and T2 measurement
2.8. The issue of B1 in-homogeneity in practical NMRI applications at high field
3. A Spin-echo-based Method for T2-Mapping in Fat-infiltrated Muscles
3.1. Quantitative characterization of muscle inflammation
3.2. Separation of 1H-NMR signals from lipids and water
3.2.1. Spectral fat-water separation methods
3.2.2. Relaxation-based methods for fat-water separation
3.3. Validation of an MSE-based method for quantification of muscle water T2 in fat-infiltrated skeletal muscle
3.3.1. Methodology Data acquisition Data treatment
3.3.2. Results
3.3.3. Discussion and Conclusions
4. A Steady-state-based Method for T2-Mapping in Fat-infiltrated Muscles
4.1. Introduction
4.1.1. Context
4.1.2. Theory The original T2-pSSFP method The extended T2-pSSFP method
4.2. Methodology
4.3. Results
4.4. Discussion
4.5. Conclusion
5. Significance of T2 Relaxation of 1H-NMR Signals in Human Skeletal Muscle 
5.1. Relaxation in biological tissues
5.2. Multiexponential muscle water T2-relaxation and compartmentation hypotheses
5.3. New insights on human skeletal muscle tissue compartments revealed by in vivo T2 relaxometry
5.3.1. Methodology Data acquisition Data treatment
5.3.2. Results
5.3.3. Discussion
5.3.4. Conclusions
5.4. Insights on the T2-relaxometry of diseased skeletal muscle tissue
5.4.1. Methodology Simulations In-vivo data acquisition
5.4.2. Results
5.4.3. Discussion and conclusions
6. Application of Ultra-short Time to Echo Methods to Study Short-T2-components in Skeletal Muscle Tissue
6.1. The NMR signal from connective tissues
6.2. The UTE method
6.3. Application of a 3D-UTE sequence for the detection and characterization of a short-T2-component in skeletal muscle tissue
6.3.1. Methodology
6.3.2. Results
6.3.3. Discussion
6.4. UTE applications for imaging of short-T2-components in SKM tissue
6.5. In-vivo NMRI of short-T2-components in SKM tissue
6.5.1. Methodology
6.5.2. Results
6.5.3. Discussion and conclusions
7. Conclusions and Perspectives


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