Cortical matrix remodeling as a hallmark of relapsing-remitting neuroinflammation in MR elastography and quantitative MRI.

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that involves both white and gray matter. Although gray matter damage is a major contributor to disability in MS patients, conventional clinical magnetic resonance imaging (MRI) fails to accurately detect gray matter pathology and establish a clear correlation with clinical symptoms. Using magnetic resonance elastography (MRE), we previously reported global brain softening in MS and experimental autoimmune encephalomyelitis (EAE). However, it needs to be established if changes of the spatiotemporal patterns of brain tissue mechanics constitute a marker of neuroinflammation. Here, we use advanced multifrequency MRE with tomoelastography postprocessing to investigate longitudinal and regional inflammation-induced tissue changes in EAE and in a small group of MS patients. Surprisingly, we found reversible softening in synchrony with the EAE disease course predominantly in the cortex of the mouse brain. This cortical softening was associated neither with a shift of tissue water compartments as quantified by T2-mapping and diffusion-weighted MRI, nor with leukocyte infiltration as seen by histopathology. Instead, cortical softening correlated with transient structural remodeling of perineuronal nets (PNNs), which involved abnormal chondroitin sulfate expression and microgliosis. These mechanisms also appear to be critical in humans with MS, where tomoelastography for the first time demonstrated marked cortical softening. Taken together, our study shows that neuroinflammation (i) critically affects the integrity of PNNs in cortical brain tissue, in a reversible process that correlates with disease disability in EAE, (ii) reduces the mechanical integrity of brain tissue rather than leading to water accumulation, and (iii) shows similar spatial patterns in humans and mice. These results raise the prospect of leveraging MRE and quantitative MRI for MS staging and monitoring treatment in affected patients.

Comparison of inversion methods in MR elastography: An open-access pipeline for processing multifrequency shear-wave data and demonstration in a phantom, human kidneys, and brain.

PURPOSE: Magnetic resonance elastography (MRE) maps the viscoelastic properties of soft tissues for diagnostic purposes. However, different MRE inversion methods yield different results, which hinder comparison of values, standardization, and establishment of quantitative MRE markers. Here, we introduce an expandable, open-access, webserver-based platform that offers multiple inversion techniques for multifrequency, 3D MRE data. METHODS: The platform comprises a data repository and standard MRE inversion methods including local frequency estimation (LFE), direct-inversion based multifrequency dual elasto-visco (MDEV) inversion, and wavenumber-based (k-) MDEV. The use of the platform is demonstrated in phantom data and in vivo multifrequency MRE data of the kidneys and brains of healthy volunteers. RESULTS: Detailed maps of stiffness were generated by all inversion methods showing similar detail of anatomy. Specifically, the inner renal cortex had higher shear wave speed (SWS) than renal medulla and outer cortex without lateral differences. k-MDEV yielded higher SWS values than MDEV or LFE (full kidney/brain k-MDEV: 2.71 ± 0.19/1.45 ± 0.14 m/s, MDEV: 2.14 ± 0.16/0.99 ± 0.11 m/s, LFE: 2.12 ± 0.15/0.89 ± 0.06 m/s). CONCLUSION: The freely accessible platform supports the comparison of MRE results obtained with different inversion methods, filter thresholds, or excitation frequencies, promoting reproducibility in MRE across community-developed methods.

Microscopic multifrequency MR elastography for mapping viscoelasticity in zebrafish.

PURPOSE: The zebrafish (Danio rerio) has become an important animal model in a wide range of biomedical research disciplines. Growing awareness of the role of biomechanical properties in tumor progression and neuronal development has led to an increasing interest in the noninvasive mapping of the viscoelastic properties of zebrafish by elastography methods applicable to bulky and nontranslucent tissues. METHODS: Microscopic multifrequency MR elastography is introduced for mapping shear wave speed (SWS) and loss angle (φ) as markers of stiffness and viscosity of muscle, brain, and neuroblastoma tumors in postmortem zebrafish with 60 µm in-plane resolution. Experiments were performed in a 7 Tesla MR scanner at 1, 1.2, and 1.4 kHz driving frequencies. RESULTS: Detailed zebrafish viscoelasticity maps revealed that the midbrain region (SWS = 3.1 ± 0.7 m/s, φ = 1.2 ± 0.3 radian [rad]) was stiffer and less viscous than telencephalon (SWS = 2.6 ± 0. 5 m/s, φ = 1.4 ± 0.2 rad) and optic tectum (SWS = 2.6 ± 0.5 m/s, φ = 1.3 ± 0.4 rad), whereas the cerebellum (SWS = 2.9 ± 0.6 m/s, φ = 0.9 ± 0.4 rad) was stiffer but less viscous than both (all p < .05). Overall, brain tissue (SWS = 2.9 ± 0.4 m/s, φ = 1.2 ± 0.2 rad) had similar stiffness but lower viscosity values than muscle tissue (SWS = 2.9 ± 0.5 m/s, φ = 1.4 ± 0.2 rad), whereas neuroblastoma (SWS = 2.4 ± 0.3 m/s, φ = 0.7 ± 0.1 rad, all p < .05) was the softest and least viscous tissue. CONCLUSION: Microscopic multifrequency MR elastography-generated maps of zebrafish show many details of viscoelasticity and resolve tissue regions, of great interest in neuromechanical and oncological research and for which our study provides first reference values.

Reduction of breathing artifacts in multifrequency magnetic resonance elastography of the abdomen.

PURPOSE: With abdominal magnetic resonance elastography (MRE) often suffering from breathing artifacts, it is recommended to perform MRE during breath-hold. However, breath-hold acquisition prohibits extended multifrequency MRE examinations and yields inconsistent results when patients cannot hold their breath. The purpose of this work was to analyze free-breathing strategies in multifrequency MRE of abdominal organs. METHODS: Abdominal MRE with 30, 40, 50, and 60 Hz vibration frequencies and single-shot, multislice, full wave-field acquisition was performed four times in 11 healthy volunteers: once with multiple breath-holds and three times during free breathing with ungated, gated, and navigated slice adjustment. Shear wave speed maps were generated by tomoelastography inversion. Image registration was applied for correction of intrascan misregistration of image slices. Sharpness of features was quantified by the variance of the Laplacian. RESULTS: Total scan times ranged from 120 seconds for ungated free-breathing MRE to 376 seconds for breath-hold examinations. As expected, free-breathing MRE resulted in larger organ displacements (liver, 4.7 ± 1.5 mm; kidneys, 2.4 ± 2.2 mm; spleen, 3.1 ± 2.4 mm; pancreas, 3.4 ± 1.4 mm) than breath-hold MRE (liver, 0.7 ± 0.2 mm; kidneys, 0.4 ± 0.2 mm; spleen, 0.5 ± 0.2 mm; pancreas, 0.7 ± 0.5 mm). Nonetheless, breathing-related displacement did not affect mean shear wave speed, which was consistent across all protocols (liver, 1.43 ± 0.07 m/s; kidneys, 2.35 ± 0.21 m/s; spleen, 2.02 ± 0.15 m/s; pancreas, 1.39 ± 0.15 m/s). Image registration before inversion improved the quality of free-breathing examinations, yielding no differences in image sharpness to uncorrected breath-hold MRE in most organs (P > .05). CONCLUSION: Overall, multifrequency MRE is robust to breathing when considering whole-organ values. Respiration-related blurring can readily be corrected using image registration. Consequently, ungated free-breathing MRE combined with image registration is recommended for multifrequency MRE of abdominal organs.

Real-time MR elastography for viscoelasticity quantification in skeletal muscle during dynamic exercises.

PURPOSE: To develop and test real-time MR elastography for viscoelastic parameter quantification in skeletal muscle during dynamic exercises. METHODS: In 15 healthy participants, 6 groups of lower-leg muscles (tibialis anterior, tibialis posterior, peroneus, extensor digitorum longus, soleus, gastrocnemius) were investigated by real-time MR elastography using a single-shot, steady-state spiral gradient-echo pulse sequence and stroboscopic undersampling of harmonic vibrations at 40 Hz frequency. One hundred and eighty consecutive maps of shear-wave speed and loss angle (φ) covering 30.6 s of total acquisition time at 5.9-Hz frame rate were reconstructed from 360 wave images encoding 2 in-plane wave components in an interleaved manner. The experiment was carried out twice to investigate 2 exercises-isometric plantar flexion and isometric dorsiflexion-each performed over 10 s between 2 resting periods. RESULTS: Activation of lower-extremity muscles was associated with increasing viscoelastic parameters shear-wave speed and φ, both reflecting properties related to the transverse direction relative to fiber orientation. Major viscoelastic changes were observed in soleus muscle during plantar flexion (shear-wave speed: 20.0% ± 3.6%, φ: 41.3% ± 12.0%) and in the tibialis anterior muscle during dorsiflexion (41.8% ± 10.2%, φ: 27.9% ± 2.8%; all P < .0001). Two of the muscles analyzed were significantly activated by plantar flexion and 4 by dorsiflexion based on shear-wave speed, whereas φ changed significantly in 5 muscles during both exercises. CONCLUSION: Real-time MR elastography allows mapping of dynamic, nonperiodic viscoelasticity changes in soft tissues such as voluntary muscle with high spatial and temporal resolution. Real-time MR elastography thus opens new horizons for the in vivo study of physiological processes in soft tissues toward functional elastography.

Diagnostic performance of tomoelastography of the liver and spleen for staging hepatic fibrosis.

OBJECTIVES: To determine the diagnostic performance, cut-off values, and optimal drive frequency range for staging hepatic fibrosis using tomoelastography by multifrequency MR elastography of the liver and spleen. METHODS: This prospective study consecutively enrolled a total of 61 subjects between June 2014 and April 2017: 45 patients with chronic liver disease and proven stage of fibrosis and 16 healthy volunteers. Tomoelastography was performed at 1.5 T using six drive frequencies from 35 to 60 Hz. Cut-off values and AUC were calculated. Shear wave speed (in m/s) of the liver and spleen was assessed separately and in combination as a surrogate of stiffness. RESULTS: For compound multifrequency processing of the liver, cut-off and AUC values by fibrosis stage were as follows: F1, 1.52 m/s and 0.89; F2, 1.55 m/s and 0.94; F3, 1.67 m/s and 0.98; and F4, 1.72 m/s and 0.98. Diagnostic performance of the best single drive frequencies (45 Hz, 55 Hz, 60 Hz) was similar (mean AUC = 0.95, respectively). Combined analysis of the liver and spleen slightly improved performance at 60 Hz in F4 patients (mean AUC = 0.97 vs. 0.95, p = 0.03). Full-field-of-view elastograms displayed not only the liver and spleen but also small anatomical structures including the pancreas and major vessels. CONCLUSION: Tomoelastography provides full-field-of-view elastograms with unprecedented detail resolution and excellent diagnostic accuracy for staging hepatic fibrosis. Our analysis of single-frequency tomoelastography suggests that scan time can be further reduced in future studies, making tomoelastography easier to implement in clinical routine. KEY POINTS: • Tomoelastography provides full-field-of-view elastograms of the abdomen with unprecedented detail resolution and excellent diagnostic accuracy for staging hepatic fibrosis. • Diagnostic performance of single-frequency tomoelastography at higher frequencies (45 Hz, 55 Hz, 60 Hz) and compound multifrequency processing are equivalent for staging hepatic fibrosis. • Combined assessment of hepatic and splenic stiffness slightly improves diagnostic performance for staging hepatic fibrosis.

US Time-Harmonic Elastography for the Early Detection of Glomerulonephritis.

Background Glomerulonephritis refers to renal diseases characterized by glomerular and tubulointerstitial fibrosis. Multifrequency US time-harmonic elastography enables the noninvasive quantification of tissue elasticity. Purpose To assess the diagnostic performance of US time-harmonic elastography for the early detection of glomerulonephritis. Materials and Methods From August 2016 through May 2017, study participants with biopsy-proven glomerulonephritis were prospectively examined with US time-harmonic elastography. Participants were subdivided according to chronic kidney disease (CKD) stage. All participants underwent elastography of both kidneys to generate full-field-of-view maps of renal shear wave speed (SWS). SWS was determined separately for the whole renal parenchyma, cortex, and medulla and was correlated with quantitative B-mode findings such as renal length and parenchymal thickness. Diagnostic performance of renal elastography was assessed with receiver operating characteristic curve analysis. Results Fifty-three participants with glomerulonephritis (mean age ± standard deviation, 49 years ± 14) and 30 healthy volunteers (mean age, 37 years ± 11) were evaluated. Age-adjusted renal SWS was lower in participants with glomerulonephritis than in healthy volunteers in the parenchyma, cortex, and medulla, with mean values of 1.55 m/sec (95% confidence interval [CI]: 1.51 m/sec, 1.59 m/sec) and 1.69 m/sec (95% CI: 1.64 m/sec, 1.74 m/sec; P < .001), respectively, in parenchyma, 1.80 m/sec (95% CI: 1.75 m/sec, 1.84 m/sec) and 2.08 m/sec (95% CI: 2.02 m/sec, 2.13 m/sec; P < .001) in cortex, and 1.25 m/sec (95% CI: 1.21 m/sec, 1.29 m/sec) and 1.33 (95% CI: 1.27 m/sec, 1.38 m/sec; P = .03) in medulla. Age-adjusted renal cortex SWS was lower in participants with glomerulonephritis and stage 1 CKD (preserved renal function) than in healthy volunteers (mean, 1.88 [95% CI: 1.81, 1.96] vs 2.08 [95% CI: 2.02, 2.13]; P < .001). In participants with CKD, renal cortex SWS values showed a positive association with estimated glomerular filtration rate (n = 39; r = 0.56; P < .001). Exploratory diagnostic performance of US time-harmonic elastography (area under the receiver operating characteristic curve [AUC], 0.89; 95% CI: 0.82, 0.97) outperformed that of B-mode parameters such as parenchymal thickness (AUC, 0.64; 95% CI: 0.51, 0.77; P < .001) and renal length (AUC, 0.55; 95% CI: 0.40, 0.68; P < .001) in identifying glomerulonephritis. Conclusion US time-harmonic elastography depicts abnormal renal stiffness in glomerulonephritis, particularly among patients with early disease and preserved renal function. Advanced chronic kidney disease is associated with further cortical softening. Time-harmonic elastography outperforms B-mode-based size quantification. © RSNA, 2019 Online supplemental material is available for this article.

Fast tomoelastography of the mouse brain by multifrequency single-shot MR elastography.

PURPOSE: To introduce in vivo multifrequency single-shot magnetic resonance elastography for full-FOV stiffness mapping of the mouse brain and to compare in vivo stiffness of neural tissues with different white-to-gray matter ratios. METHODS: Viscous phantoms and 10 C57BL-6 mice were investigated by 7T small-animal MRI using a single-shot spin-echo planar imaging magnetic resonance elastography sequence with motion-encoding gradients positioned before the refocusing pulse. Wave images were acquired over 10 minutes for 6 mechanical vibration frequencies between 900 and 1400 Hz. Stiffness maps of shear wave speed (SWS) were computed using tomoelastography data processing and compared with algebraic Helmholtz inversion (AHI) for signal-to-noise ratio (SNR) analysis. Different brain regions were analyzed including cerebral cortex, corpus callosum, hippocampus, and diencephalon. RESULTS: In phantoms, algebraic Helmholtz inversion-based SWS was systematically biased by noise and discretization, whereas tomoelastography-derived SWS was consistent over the full SNR range analyzed. Mean in vivo SWS of the whole brain was 3.76 ± 0.33 m/s with significant regional variation (hippocampus = 4.91 ± 0.49 m/s, diencephalon = 4.78 ± 0.78 m/s, cerebral cortex = 3.53 ± 0.29 m/s, and corpus callosum = 2.89 ± 0.17 m/s). CONCLUSION: Tomoelastography retrieves mouse brain stiffness within shorter scan times and with greater detail resolution than classical algebraic Helmholtz inversion-based magnetic resonance elastography. The range of SWS values obtained here indicates that mouse white matter is softer than gray matter at the frequencies investigated.

Collagen networks determine viscoelastic properties of connective tissues yet do not hinder diffusion of the aqueous solvent.

Collagen accounts for the major extracellular matrix (ECM) component in many tissues and provides mechanical support for cells. Magnetic Resonance (MR) Imaging, MR based diffusion measurements and MR Elastography (MRE) are considered sensitive to the microstructure of tissues including collagen networks of the ECM. However, little is known whether water diffusion interacts with viscoelastic properties of tissues. This study combines highfield MR based diffusion measurements, novel compact tabletop MRE and confocal microscopy in collagen networks of different cross-linking states (untreated collagen gels versus additional treatment with glutaraldehyde). The consistency of bulk rheology and MRE within a wide dynamic range is demonstrated in heparin gels, a viscoelastic standard for MRE. Additional crosslinking of collagen led to an 8-fold increased storage modulus, a 4-fold increased loss modulus and a significantly decreased power law exponent, describing multi-relaxational behavior, corresponding to a pronounced transition from viscous-soft to elastic-rigid properties. Collagen network changes were not detectable by MR based diffusion measurements and microscopy which are sensitive to the micrometer scale. The MRE-measured shear modulus is sensitive to collagen fiber interactions which take place on the intrafiber level such as fiber stiffness. The insensitivity of MR based diffusion measurements to collagen hydrogels of different cross-linking states alludes that congeneric collagen structures in connective tissues do not hinder extracellular diffusive water transport. Furthermore, the glutaraldehyde induced rigorous changes in viscoelastic properties indicate that intrafibrillar dissipation is the dominant mode of viscous dissipation in collagen-dominated connective tissue.

Non-invasive structure-function assessment of the liver by 2D time-harmonic elastography and the dynamic Liver MAximum capacity (LiMAx) test.

BACKGROUND AND AIM: Accurate assessment of structural and functional characteristics of the liver could improve the diagnosis and the clinical management of patients with chronic liver diseases. However, the structure-function relationship in the progression of chronic liver disease remains elusive. The aim of this study is the combined measurement of liver function by the 13 C-methacetin Liver MAximum capacity (LiMAx) test and tissue-structure related stiffness by 2D time-harmonic elastography for the assessment of liver disease progression. METHODS: LiMAx test and time-harmonic elastography were applied, and the serological scores fibrosis 4 index and aspartate aminotransferase to platelet ratio index were calculated in patients with chronic liver diseases (n = 75) and healthy control subjects (n = 22). In 47 patients who underwent surgery, fibrosis was graded by histological examination of the resected liver tissue. RESULTS: LiMAx values correlated negatively with liver stiffness (r = -0.747), aminotransferase to platelet ratio index (r = -0.604), and fibrosis 4 (r = -0.573). Median (interquartile range) LiMAx values decreased with fibrosis progression from 395 µg/kg/h (371-460 µg/kg/h) in participants with no fibrosis to 173 µg/kg/h (126-309 µg/kg/h) in patients with severe fibrosis. Median liver stiffness increased progressively with the stage of fibrosis from no fibrosis (1.56 m/s [1.52-1.63 m/s]) to moderate fibrosis (1.60 m/s [1.54-1.67 m/s]) to severe fibrosis (1.85 m/s [1.76-1.92 m/s]). CONCLUSION: Our findings show that structural changes in the liver due to progressing liver diseases and reflected by increased tissue stiffness correlate with a functional decline of the organ as reflected by a decreased metabolic capacity of the liver.

US Time-Harmonic Elastography: Detection of Liver Fibrosis in Adolescents with Extreme Obesity with Nonalcoholic Fatty Liver Disease.

Purpose To measure in vivo liver stiffness by using US time-harmonic elastography in a cohort of pediatric patients who were overweight to extremely obese with nonalcoholic fatty liver disease (NAFLD) and to evaluate the diagnostic value of time-harmonic elastography for differentiating stages of fibrosis associated with progressive disease. Materials and Methods In this prospective study, 67 consecutive adolescents (age range, 10-17 years; mean body mass index, 34.7 kg/m2; range, 21.4-50.4 kg/m2) with biopsy-proven NAFLD were enrolled. Liver stiffness was measured by using time-harmonic elastography based on externally induced continuous vibrations of 30 Hz to 60 Hz frequency and real-time B-mode-guided wave profile analysis covering tissue depths of up to 14 cm. The diagnostic accuracy of time-harmonic elastography in staging liver fibrosis was assessed with area under the receiver operating characteristic curve (AUC) analysis. Liver stiffness cutoffs for the differentiation of fibrosis stages were identified based on the highest Youden index. Results Time-harmonic elastography was feasible in all patients (0% failure rate), including 70% (n = 47) of individuals with extreme obesity (body mass index above the 99.5th percentile). AUC analysis for the detection of any fibrosis (≥ stage F1), moderate fibrosis (≥ stage F2), and advanced fibrosis (≥ stage F3) was 0.88 (95% confidence interval [CI]: 0.80, 0.96), 0.99 (95% CI: 0.98, 1.00), and 0.88 (95% CI: 0.80, 0.96), respectively. The best liver stiffness cutoffs were 1.52 m/sec for at least stage F1, 1.62 m/sec for at least stage F2, and 1.64 m/sec for at least stage F3. Conclusion US time-harmonic elastography allows accurate detection of moderate fibrosis even in pediatric patients with extreme obesity. Larger clinical trials are warranted to confirm the accuracy of US time-harmonic elastography.

A compact 0.5 T MR elastography device and its application for studying viscoelasticity changes in biological tissues during progressive formalin fixation.

PURPOSE: To develop a method of compact tabletop magnetic resonance elastography (MRE) for rheological tests of tissue samples and to measure changes in viscoelastic powerlaw constants of liver and brain tissue during progressive fixation. METHODS: A 10-mm bore, 0.5-T permanent-magnet-based MRI system was equipped with a gradient-amplifier-controlled piezo-actuator and motion-sensitive spin echo sequence for inducing and measuring harmonic shear vibrations in cylindrical samples. Shear modulus dispersion functions were acquired at 200-5700 Hz in animal tissues at different states of formalin fixation and fitted by the springpot powerlaw model to obtain shear modulus µ and powerlaw exponent α. RESULTS: In a frequency range of 300-1500 Hz, unfixed liver tissue was softer and less dispersive than brain tissue with µ = 1.68 ± 0.17 kPa and α = 0.51 ± 0.06 versus µ = 2.60 ± 0.68 kPa and α = 0.68 ± 0.03. Twenty-eight hours of formalin fixation yielded a 400-fold increase in liver µ, 25-fold increase in brain µ, and two-fold reduction in α of both tissues. CONCLUSION: Compact 0.5-T MRE facilitates automated measurement of shear modulus dispersion in biological tissue at low costs. Formalin fixation changes the viscoelastic properties of tissues from viscous-soft to elastic-stiff more markedly in liver than brain. Magn Reson Med 79:470-478, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Tomoelastography of the native kidney: Regional variation and physiological effects on in vivo renal stiffness.

PURPOSE: To measure normal renal stiffness in adults, taking into account regional variation, hydration, and urinary status. METHODS: Thirty-six healthy volunteers were examined by tomoelastography based on MR elastography at four frequencies, from 40 to 70 Hz and multifrequency shear wave speed recovery. Regional wave speeds were derived for the medulla, cortex (inner cortex and outer cortex), and renal pelvis, and examined for age-related effects. Subgroups were repeatedly examined for reproducibility, amount of prior water drinking, and urinary status. Variations in renal perfusion were simulated ex vivo using a porcine kidney subjected to venous water inflow at different pressures. RESULTS: Shear wave speed (stiffness) of renal parenchyma was 2.46 ± 0.12 m/s (inner cortex: 2.91 ± 0.17 m/s; outer cortex: 2.52 ± 0.11 m/s; medulla: 2.15 ± 0.08 m/s) without side differences and a tendency toward softening with age (P = 0.028). Corresponding intraclass correlation for reproducibility coefficients were 0.78 (inner cortex: 0.80; outer cortex: 0.81; medulla: 0.80). Water drinking resulted in slightly higher values in inner cortex and lower values in medulla (both P = 0.039), which was consistent with the results in perfused specimens. A full bladder led to higher renal pelvis stiffness (P = 0.004), whereas renal parenchyma remained uninfluenced. Stiffness of the porcine renal cortex increased with venous inflow pressure, whereas medulla stiffness decreased. CONCLUSIONS: Tomoelastography provides full field of view maps of renal stiffness with highly detailed resolution and sensitivity to physiological effects related to age and fluid-solid tissue interactions. These basic data could be used to compare pathological conditions in the future. Magn Reson Med 79:2126-2134, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Tomoelastography of the abdomen: Tissue mechanical properties of the liver, spleen, kidney, and pancreas from single MR elastography scans at different hydration states.

PURPOSE: To develop a compact magnetic resonance elastography (MRE) protocol for abdomen and to investigate the effect of water uptake on tissue stiffness in the liver, spleen, kidney, and pancreas. METHODS: Nine asymptomatic volunteers were investigated by MRE before and after 1 liter water uptake. Shear-wave excitation at four frequencies was transferred to the abdomen from anterior and posterior directions using pressurized air drivers. Tomographic representations of shear-wave speed were produced by analysis of multifrequency wave numbers in axial and coronal images acquired within four breath-holds or under free breathing, respectively. RESULTS: Pre and post water, stiffness of the spleen (pre/post: 2.20 ± 0.10/2.06 ± 0.18 m/s) and kidney (pre/post: 1.93 ± 0.22/1.97 ± 0.23 m/s) was higher than in the liver (pre/post: 1.36 ± 0.10/1.38 ± 0.13 m/s) and pancreas (pre/post: 1.20 ± 0.12/1.20 ± 0.08 m/s), all P < 0.01. Accounting for four drive frequencies, water drinking only changed the splenic stiffness (-6%, P = 0.03), whereas in the frequency range from 50 to 60 Hz the effect became significant also in the pancreas (-6%, P = 0.04) and liver (+3%, P = 0.03). Elastograms of the kidney in coronal view clearly depicted higher stiffness in cortex than in medulla. CONCLUSION: Tomoelastography reveals sensitivity of tissue mechanical properties to the hydration state of multiple abdominal organs within one scan and in unprecedented resolution of anatomical details. Magn Reson Med 78:976-983, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Physiologic Reduction of Hepatic Venous Blood Flow by the Valsalva Maneuver Decreases Liver Stiffness.

OBJECTIVES: Liver stiffness increases after intake of food or water, suggesting that hepatic venous blood flow affects the results of elastographic measurements. This study investigated the correlation between in vivo liver stiffness and hepatic blood flow using the Valsalva maneuver for reducing intrahepatic venous blood flow. METHODS: Intrahepatic changes in venous blood flow were assessed by sonography based on the pulsed wave Doppler velocity, vessel diameter assessment, and blood flow volume measurements in the portal vein and right hepatic vein. Time-harmonic elastography at 7 harmonic driving frequencies (30-60 Hz) was used to measure liver stiffness in the right liver lobe of 15 healthy volunteers. RESULTS: The right hepatic vein diameter, flow volume, and peak pulsed wave velocity decreased during the Valsalva maneuver from mean ± SD values of 8.64 ± 1.85 to 6.55 ± 1.84 mm (P = .002), 0.53 ± 0.23 to 0.37 ± 0.26 L/min (P = .037), and 22.14 ± 4.87 to 17.38 ± 5.41 cm/s (P = .01), respectively. This maneuver decreased liver stiffness in all volunteers by a mean of approximately 13% from 1.71 ± 0.22 to 1.48 ± 0.22 m/s (P = .00006). CONCLUSIONS: Our results demonstrate that liver stiffness is sensitive to altered venous blood flow, which is of clinical importance when using elastography for evaluation of portal hypertension. Furthermore, our results indicate that accurate measurement of liver stiffness requires standardized breathing conditions to rule out effects of changes in hepatic blood flow on elastographic findings.

In vivo wideband multifrequency MR elastography of the human brain and liver.

PURPOSE: To demonstrate the feasibility of in vivo wideband MR elastography (wMRE) using continuous, time-harmonic shear vibrations in the frequency range of 10-50 Hz. THEORY AND METHODS: The method was tested in a gel phantom with marked mechanical loss. The brains and livers of eight volunteers were scanned by wMRE using multislice, single-shot MRE with optimized fractional encoding and synchronization of sequence acquisition to vibration. Multifrequency three-dimensional inversion was used to reconstruct compound maps of magnitude |G*| and phase φ of the complex shear modulus. A new phase estimation, φ*, was developed to avoid systematic bias due to noise. RESULTS: In the phantom, G*-dispersion measured by wMRE agreed well with oscillatory shear rheometry. |G*| and φ* measured at vibrations of 10-25 HZ, 25-35 HZ, and 40-50 HZ were 0.62 ± 0.08, 1.56 ± 0.16, 2.18 ± 0.20 kPa and 0.09 ± 0.17, 0.39 ± 0.16, 0.20 ± 0.13 rad in brain and 0.89 ± 0.11, 1.67 ± 0.20, 2.27 ± 0.35 kPa and 0.15 ± 0.10, 0.24 ± 0.05, 0.26 ± 0.05 rad in liver. Elastograms including all frequencies showed the best resolution of anatomical detail with |G*| = 1.38 ± 0.12 kPa, φ* = 0.24 ± 0.10 rad (brain) and |G*| = 1.79 ± 0.23 kPa, φ* = 0.24 ± 0.05 rad (liver). CONCLUSION: wMRE reveals highly dispersive G* properties of the brain and liver, and our results suggest that the influence of large-scale structures such as fluid-filled vessels and sulci on the MRE-measured parameters increases at low vibration frequencies. Magn Reson Med 76:1116-1126, 2016. © 2015 Wiley Periodicals, Inc.

Explorative study using ultrasound time-harmonic elastography for stiffness-based quantification of skeletal muscle function.

Time-harmonic elastography (THE) is an emerging ultrasound imaging technique that allows full-field mapping of the stiffness of deep biological tissues. THE's unique ability to rapidly capture stiffness in multiple tissues has never been applied for imaging skeletal muscle. Therefore, we addressed the lack of data on temporal changes in skeletal muscle stiffness while simultaneously covering stiffness of different muscles. Acquiring repeated THE scans every five seconds we quantified shear-wave speed (SWS) as a marker of stiffness of the long head (LHB) and short head (SHB) of biceps brachii and of the brachialis muscle (B) in ten healthy volunteers. SWS was continuously acquired during a 3-min isometric preloading phase, a 3-min loading phase with different weights (4, 8, and 12 kg), and a 9-min postloading phase. In addition, we analyzed temporal SWS standard deviation (SD) as a marker of muscle contraction regulation. Our results (median [min, max]) showed both SWS at preloading (LHB: 1.04 [0.94, 1.12] m/s, SHB: 0.86 [0.78, 0.94] m/s, B: 0.96 [0.87, 1.09] m/s, p < 0.001) and the increase in SWS with loading weight to be muscle-specific (LHB: 0.010 [0.002, 0.019] m/s/kg, SHB: 0.022 [0.017, 0.042] m/s/kg, B: 0.039 [0.019, 0.062] m/s/kg, p < 0.001). Additionally, SWS during loading increased continuously over time by 0.022 [0.004, 0.051] m/s/min (p < 0.01). Using an exponential decay model, we found an average relaxation time of 27 seconds during postloading. Analogously, SWS SD at preloading was also muscle-specific (LHB: 0.018 [0.011, 0.029] m/s, SHB: 0.021 [0.015, 0.027] m/s, B: 0.024 [0.018, 0.037] m/s, p < 0.05) and increased by 0.005 [0.003, 0.008] m/s/kg (p < 0.01) with loading. SWS SD did not change over loading time and decreased immediately in the postloading phase. Taken together, THE of skeletal muscle is a promising imaging technique for in vivo quantification of stiffness and stiffness changes in multiple muscle groups within seconds. Both the magnitude of stiffness changes and their temporal variation during isometric exercise may reflect the functional status of skeletal muscle and provide additional information to the morphological measures obtained by conventional imaging modalities.

On the relationship between viscoelasticity and water diffusion in soft biological tissues.

Magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) are complementary imaging techniques that detect disease based on viscoelasticity and water mobility, respectively. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering the clinical translation of combined DWI-MRE markers. We used DWI-MRE to study 129 biomaterial samples including native and cross-linked collagen, glycosaminoglycans (GAGs) with different sulfation levels, and decellularized specimens of pancreas and liver, all with different proportions of solid tissue, or solid fractions. We developed a theoretical framework of the relationship between mechanical loss and tissue-water mobility based on two parameters, solid and fluid viscosity. These parameters revealed distinct DWI-MRE property clusters characterizing weak, moderate, and strong water-network interactions. Sparse networks interacting weakly with water, such as collagen or diluted decellularized tissue, resulted in marginal changes in water diffusion over increasing solid viscosity. In contrast, dense networks with larger solid fractions exhibited both free and hindered water diffusion depending on the polarity of the solid components. For example, polar and highly sulfated GAGs as well as native soft tissues hindered water diffusion despite relatively low solid viscosity. Our results suggest that two fundamental properties of tissue networks, solid fraction and network polarity, critically influence solid and fluid viscosity in biological tissues. Since clinical DWI and MRE are sensitive to these viscosity parameters, the framework we present here can be used to detect tissue remodeling and architectural changes in the setting of diagnostic imaging. STATEMENT OF SIGNIFICANCE: The viscoelastic properties of biological tissues provide a wealth of information on the vital state of cells and host matrix. Combined measurement of viscoelasticity and water diffusion by medical imaging is sensitive to tissue microarchitecture. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering full exploitation of these properties as a combined clinical biomarker. Therefore, we analyzed the parameter space accessible by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) and developed a theoretical framework for the relationship between water mobility and mechanical parameters in biomaterials. Our theory of solid material properties related to particle motion can be translated to clinical radiology using clinically established MRE and DWI.

Stiffness pulsation of the human brain detected by non-invasive time-harmonic elastography.

Introduction: Cerebral pulsation is a vital aspect of cerebral hemodynamics. Changes in arterial pressure in response to cardiac pulsation cause cerebral pulsation, which is related to cerebrovascular compliance and cerebral blood perfusion. Cerebrovascular compliance and blood perfusion influence the mechanical properties of the brain, causing pulsation-induced changes in cerebral stiffness. However, there is currently no imaging technique available that can directly quantify the pulsation of brain stiffness in real time. Methods: Therefore, we developed non-invasive ultrasound time-harmonic elastography (THE) technique for the real-time detection of brain stiffness pulsation. We used state-of-the-art plane-wave imaging for interleaved acquisitions of shear waves at a frequency of 60 Hz to measure stiffness and color flow imaging to measure cerebral blood flow within the middle cerebral artery. In the second experiment, we used cost-effective lineby-line B-mode imaging to measure the same mechanical parameters without flow imaging to facilitate future translation to the clinic. Results: In 10 healthy volunteers, stiffness increased during the passage of the arterial pulse wave from 4.8% ± 1.8% in the temporal parenchyma to 11% ± 5% in the basal cisterns and 13% ± 9% in the brain stem. Brain stiffness peaked in synchrony with cerebral blood flow at approximately 180 ± 30 ms after the cardiac R-wave. Line-by-line THE provided the same stiffness values with similar time resolution as high-end plane-wave THE, demonstrating the robustness of brain stiffness pulsation as an imaging marker. Discussion: Overall, this study sets the background and provides reference values for time-resolved THE in the human brain as a cost-efficient and easy-touse mechanical biomarker associated with cerebrovascular compliance.

The influence of static portal pressure on liver biophysical properties.

The liver is a highly vascularized organ where fluid properties, including vascular pressure, vessel integrity and fluid viscosity, play a critical role in gross mechanical properties. To study the effects of portal pressure, liver confinement, fluid viscosity, and tissue crosslinking on liver stiffness, water diffusion, and vessel size, we applied multiparametric magnetic resonance imaging (mpMRI), including multifrequency magnetic resonance elastography (MRE) and apparent diffusion coefficient (ADC) measurements, to ex vivo livers from healthy male rats (13.6±1.6 weeks) at room temperature. Four scenarios including altered liver confinement, tissue crosslinking, and vascular fluid viscosity were investigated with mpMRI at different portal pressure levels (0-17.5 cmH2O). Our experiments demonstrated that, with increasing portal pressure, rat livers showed higher water content, water diffusivity, and increased vessel sizes quantified by the vessel tissue volume fraction (VTVF). These effects were most pronounced in native, unconfined livers (VTVF: 300±120%, p<0.05, ADC: 88±29%, p<0.01), while still significant under confinement (confined: VTVF: 53±32%, p<0.01, ADC: 28±19%, p<0.05; confined-fixed: VTVF: 52±20%, p<0.001, ADC: 11±2%, p<0.01; confined-viscous: VTVF: 210±110%, p<0.01, ADC: 26±9%, p<0.001). Softening with elevated portal pressure (-12±5, p<0.05) occurred regardless of confinement and fixation. However, the liver stiffened when exposed to a more viscous inflow fluid (11±4%, p<0.001). Taken together, our results elucidate the complex relationship between macroscopic-biophysical parameters of liver tissue measured by mpMRI and vascular-fluid properties. Influenced by portal pressure, vascular permeability, and matrix crosslinking, liver stiffness is sensitive to intrinsic poroelastic properties, which, alongside vascular architecture and water diffusivity, may aid in the differential diagnosis of liver disease. STATEMENT OF SIGNIFICANCE: Using highly controllable ex vivo rat liver phantoms, hepatic biophysical properties such as tissue-vascular structure, stiffness, and water diffusivity were investigated using multiparametric MRI including multifrequency magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI). Through elaborate tuning of the experimental conditions such as the static portal pressure, flow viscosity, amount and distribution of fluid content in the liver, we identified the contributions of the fluid component to the overall imaging-based biophysical properties of the liver. Our finding demonstrated the sensitivity of liver stiffness to the hepatic poroelastic properties, which may aid in the differential diagnosis of liver diseases.