Heterogeneous multifrequency direct inversion (HMDI) for magnetic resonance elastography with application to a clinical brain exam

A new viscoelastic wave inversion method for MRE, called Heterogeneous Multifrequency Direct Inversion (HMDI), was developed which accommodates heterogeneous elasticity within a direct inversion (DI) by incorporating first-order gradients and combining results from a narrow band of multiple frequencies. The method is compared with a Helmholtz-type DI, Multifrequency Dual Elasto-Visco inversion (MDEV), both on ground-truth Finite Element Method simulations at varied noise levels and a prospective in vivo brain cohort of 48 subjects ages 18–65. In simulated data, MDEV recovered background material within 5% and HMDI within 1% of prescribed up to SNR of 20 dB. In vivo HMDI and MDEV were then combined with segmentation from SPM to create a fully automated “brain palpation” exam for both whole brain (WB), and brain white matter (WM), measuring two parameters, the complex modulus magnitude |G*| , which measures tissue “stiffness”, and the slope of |G*| values across frequencies, a measure of viscous dispersion. |G*| values for MDEV and HMDI were comparable to the literature (for a 3-frequency set centered at 50 Hz, WB means were 2.17 and 2.15 kPa respectively, and WM means were 2.47 and 2.49 kPa respectively). Both methods showed moderate correlation to age in both WB and WM, for both |G*| and |G*| slope, with Pearson’s r ≥ 0.4 in the most sensitive frequency sets. In comparison to MDEV, HMDI showed better preservation of recovered target shapes, more noise-robustness, and stabler recovery values in regions with rapid property change, however summary statistics for both methods were quite similar. By eliminating homogeneity assumptions within a fast, fully automatic, regularization-free direct inversion, HMDI appears to be a worthwhile addition to the MRE image reconstruction repertoire. In addition to supporting the literature showing decrease in brain viscoelasticity with age, our work supports a wide range of inter-individual variation in brain MRE results

Cerebral tomoelastography based on multifrequency MR elastography in two and three dimensions

Magnetic resonance elastography (MRE) generates quantitative maps of the mechanical properties of biological soft tissues. However, published values obtained by brain MRE vary largely and lack detail resolution, due to either true biological effects or technical challenges. We here introduce cerebral tomoelastography in two and three dimensions for improved data consistency and detail resolution while considering aging, brain parenchymal fraction (BPF), systolic blood pressure, and body-mass-index. Multifrequency MRE with 2D- and 3D-tomoelastography postprocessing was applied to the brains of 31 volunteers (age range: 22-61 years) for analyzing the coefficient of variation (CV) and effects of biological factors. Eleven volunteers were rescanned after one day and one year to determine intraclass correlation coefficient (ICC) and identify possible long-term changes. White matter shear-wave-speed (SWS) was slightly higher in 2D-MRE (1.28±0.02m/s) than 3D-MRE (1.22±0.05m/s, p<0.0001), with less variation after one day in 2D (0.33±0.32%) than in 3D (0.96±0.66%, p=0.004), which was also reflected in a slightly lower CV and higher ICC in 2D (1.84%, 0.97 [0.88-0.99]) than in 3D (3.89%, 0.95 [0.76-0.99]). Remarkably, 3D-MRE was sensitive to a decrease in white matter SWS within only one year, whereas no change in white matter volume was observed during this follow-up period. Across volunteers, stiffness correlated with age and BPF, but not with blood pressure and body-mass-index. Cerebral tomoelastography provides high-resolution viscoelasticity maps with excellent consistency. Brain MRE in 2D shows less variation across volunteers in shorter scan times than 3D-MRE, while 3D-MRE appears to be more sensitive to subtle biological effects such as aging

Viscoelasticity Imaging of Biological Tissues and Single Cells Using Shear Wave Propagation

Changes in biomechanical properties of biological soft tissues are often associated with physiological dysfunctions. Since biological soft tissues are hydrated, viscoelasticity is likely suitable to represent its solid-like behavior using elasticity and fluid-like behavior using viscosity. Shear wave elastography is a non-invasive imaging technology invented for clinical applications that has shown promise to characterize various tissue viscoelasticity. It is based on measuring and analyzing velocities and attenuations of propagated shear waves. In this review, principles and technical developments of shear wave elastography for viscoelasticity characterization from organ to cellular levels are presented, and different imaging modalities used to track shear wave propagation are described. At a macroscopic scale, techniques for inducing shear waves using an external mechanical vibration, an acoustic radiation pressure or a Lorentz force are reviewed along with imaging approaches proposed to track shear wave propagation, namely ultrasound, magnetic resonance, optical, and photoacoustic means. Then, approaches for theoretical modeling and tracking of shear waves are detailed. Following it, some examples of applications to characterize the viscoelasticity of various organs are given. At a microscopic scale, a novel cellular shear wave elastography method using an external vibration and optical microscopy is illustrated. Finally, current limitations and future directions in shear wave elastography are presented

Entwicklung der multifrequenten Magnetresonanz-Elastographie zur Quantifizierung der biophysikalischen Eigenschaften von menschlichem Hirngewebe

Magnetic resonance elastography (MRE) is an emerging technique for the quantitative imaging of the biophysical properties of soft tissues in humans. Following its successful clinical application in detecting and characterizing liver fibrosis, the scientific community is investigating the use of viscoelasticity as a biomarker for neurological diseases. Clinical implementation requires a thorough understanding of brain tissue mechanics in conjunction with innovative techniques in new research areas. Therefore, three in vivo studies were conducted to analyze the inherent stiffness dispersion of brain tissue over a wide frequency range, to investigate real-time MRE in monitoring the viscoelastic response of brain tissue during the Valsalva maneuver (VM), and to study mechanical alterations of small lesions in multiple sclerosis (MS). Ultra-low frequency MRE with profile-based wave analysis was developed in 14 healthy subjects to determine large-scale brain stiffness, from pulsation-induced shear waves (1 Hz) to ultra-low frequencies (5 – 10 Hz) to the conventional range (20 – 40 Hz). Furthermore, multifrequency real-time MRE with a frame rate of 5.4 Hz was introduced to analyze stiffness and fluidity changes in response to respiratory challenges and cerebral autoregulation in 17 healthy subjects. 2D and 3D wavenumber-based stiffness reconstruction of the brain was established for conventional MRE in 12 MS patients. MS lesions were analyzed in terms of mechanical contrast with surrounding tissue in relation to white matter (WM) heterogeneity. We found superviscous properties of brain tissue at large scales with a strong stiffness dispersion and a relatively high model-based viscosity of η = 6.6 ± 0.3 Pa∙s. The brain’s viscoelasticity was affected by perfusion changes during VM, which was associated with an increase in brain stiffness of 6.7% ± 4.1% (p<.001), whereas fluidity decreased by -2.1 ± 1.4% (p<.001). In the diseased brain, the analysis of 147 MS lesions revealed 46% of lesions to be softer and 54% of lesions to be stiffer than surrounding tissue. However, due to the heterogeneity of WM stiffness, the results provide no significant evidence for a systematic pattern of mechanical variations in MS. Nevertheless, the results may explain, for the first time, the gap between static ex vivo and dynamic in vivo methods. Fluidity-induced dispersion provides rich information on the structure of tissue compartments. Moreover, viscoelasticity is affected by perfusion during cerebral autoregulation and thus may be sensitive to intracranial pressure modulation. The overall heterogeneity of stiffness obscures changes in MS lesions, and MS may not exhibit sclerosis as a mechanical signature. In summary, this thesis contributes to the field of human brain MRE by presenting new methods developed in studies conducted in new research areas using state-of-the-art technology. The results advance clinical applications and open exciting possibilities for future in vivo studies of human brain tissue.Die Magnetresonanz-Elastographie (MRE) ist ein Verfahren zur quantitativen Darstellung der viskoelastischen Eigenschaften von Weichgewebe. Nach der erfolgreichen klinischen Anwendung in der Leberdiagnostik wird versucht, Viskoelastizität als Biomarker für neurologische Krankheiten zu nutzen. Hierzu bedarf es einer genauen Analyse der Gewebemechanik und innovativen Anwendungsgebieten. Daher, wurden drei Studien durchgeführt, um die Steifigkeitsdispersion von Hirngewebe zu analysieren, das viskoelastische Verhalten während des Valsalva Manövers (VM) abzubilden, und die mechanischen Veränderungen in Läsionen bei Multipler Sklerose (MS) zu untersuchen. Niedrigfrequenz-MRE mit profilbasierter Wellenanalyse wurde in 14 Probanden entwickelt, um die Steifigkeit des Gesamthirns von pulsationsinduzierten Scherwellen (1 Hz) über ultraniedrige Frequenzen (5 – 10 Hz) bis hin zum konventionellen Bereich (20 – 40 Hz) zu bestimmen. Außerdem wurde die multifrequente Echtzeit-MRE mit einer Bildfrequenz von 6.4 Hz eingeführt, um die viskoelastische Antwort des Gehirns auf respiratorische Herausforderungen bei 17 gesunden Probanden zu untersuchen. Neue 2D- und 3D-Wellenzahl-basierte Steifigkeitsrekonstruktionen für das Gehirn wurden in 12 MS Patienten und konventioneller MRE entwickelt. Die Steifigkeitsänderungen in MS-Läsionen wurden mit umliegender weißer Substanz und dessen Heterogenität verglichen. Wir fanden superviskose Eigenschaften des Hirngewebes mit einer starken Dispersion und relativ hohen, modellbasierten Viskosität von η = 6,6 ± 0,3 Pa∙s. Die mechanischen Gewebeeigenschaften wurden durch Perfusionsänderungen während VM beeinflusst und die Hirnsteifigkeit erhöhte sich um 6,7 ± 4,1% (p<.001) wobei sich die Fluidität um -2,1 ± 1,4% (p<.001) verringerte. Die Analyse von 147 MS-Läsionen ergab, dass 54% bzw. 46% der Läsionen steifer bzw. weicher sind als das umgebende Gewebe. Aufgrund der Heterogenität der WM-Steifigkeit konnte jedoch kein Hinweis auf ein systematisches Muster mechanischer Veränderungen in MS-Läsionen gefunden werden. Die Ergebnisse können zum ersten Mal die Lücke zwischen statischen ex vivo und dynamischen in vivo Methoden erklären. Die fluiditätsinduzierte Dispersion liefert interessante Informationen über die zugrundeliegende Gewebestruktur. Darüber hinaus wird die Viskoelastizität durch die Perfusion während der zerebralen Autoregulation beeinflusst und kann daher empfindlich auf intrakranielle Druckschwankungen reagieren. Die allgemeine Heterogenität der Steifigkeit überschattet die Veränderungen in MS-Läsionen, und somit ist Sklerose möglicherweise kein prominentes Merkmal von MS. Zusammenfassend lässt sich festhalten, dass diese Dissertation einen Beitrag zum Gebiet der MRE leistet, indem neue Methoden und Anwendungen in neuen Forschungsgebieten mit modernster Technologie dargestellt werden. Hierdurch wird die klinische Translation gefördert und spannende Möglichkeiten für zukünftige Studien eröffnet

The MRE inverse problem for the elastic shear modulus

Magnetic resonance elastography (MRE) is a powerful technique for noninvasive determination of the biomechanical properties of tissue, with important applications in disease diagnosis. A typical experimental scenario is to induce waves in the tissue by time-harmonic external mechanical oscillation and then measure the tissue's displacement at fixed spatial positions 8 times during a complete time-period, extracting the dominant frequency signal from the discrete Fourier transform in time. Accurate reconstruction of the tissue's elastic moduli from MRE data is a challenging inverse problem, and we derive and analyze two new methods which address different aspects. The first of these concerns the time signal: using only the dominant frequency component loses information for noisy data and typically gives a complex value for the (real) shear modulus, which is then hard to interpret. Our new reconstruction method is based on the Fourier time-interpolant of the displacement: it uses all the measured information and automatically gives a real value of shear modulus up to rounding error. This derivation is for homogeneous materials, and our second new method (stacked frequency wave inversion, SFWI) concerns the inhomogeneous shear modulus in the time-harmonic case. The underlying problem is ill-conditioned because the coefficient of the shear modulus in the governing equations can be zero or small, and the SFWI approach overcomes this by combining approximations at different frequencies into a single overdetermined matrix--vector equation. Careful numerical tests confirm that both these new algorithms perform well

Aging brain mechanics: Progress and promise of magnetic resonance elastography

Neuroimaging techniques that can sensitivity characterize healthy brain aging and detect subtle neuropathologies have enormous potential to assist in the early detection of neurodegenerative conditions such as Alzheimer's disease. Magnetic resonance elastography (MRE) has recently emerged as a reliable, high-resolution, and especially sensitive technique that can noninvasively characterize tissue biomechanical properties (i.e., viscoelasticity) in vivo in the living human brain. Brain tissue viscoelasticity provides a unique biophysical signature of neuroanatomy that are representative of the composition and organization of the complex tissue microstructure. In this article, we detail how progress in brain MRE technology has provided unique insights into healthy brain aging, neurodegeneration, and structure-function relationships. We further discuss additional promising technical innovations that will enhance the specificity and sensitivity for brain MRE to reveal considerably more about brain aging as well as its potentially valuable role as an imaging biomarker of neurodegeneration. MRE sensitivity may be particularly useful for assessing the efficacy of rehabilitation strategies, assisting in differentiating between dementia subtypes, and in understanding the causal mechanisms of disease which may lead to eventual pharmacotherapeutic development