Tensor denoising of quantitative multi-parameter mapping.

PURPOSE: Quantitative multi-parameter mapping (MPM) provides maps of physical quantities representing physiologically meaningful tissue characteristics, which allows to investigate microstructure-function relationships reflecting normal or pathologic processes in the brain. However, the achievable spatial resolution and stability of MPM for basic research or clinical applications is severely constrained by SNR limits of the MR acquisition process, resulting in relatively long acquisition times. To increase SNR, we denoise MPM acquisitions using principal component analysis along tensors exploiting the Marchenko-Pastur law (tMPPCA). METHODS: tMPPCA denoising was applied to three sets of MPM raw data before the quantification of maps of proton density, magnetization transfer saturation, R1, and R2*. The regional SNR gain for high-resolution MPM was investigated as well as reproducibility gains for clinically optimized protocols with moderate and high acceleration factors at different image resolutions. RESULTS: Substantial noise reduction in raw data was achieved, resulting in reduced noise for quantitative mapping up to sixfold without introducing bias of mean values (below 1%). Scan-rescan fluctuations were reduced up to threefold. Denoising allowed to decrease the voxel volume fourfold at the same scan time or reduce the scan time twofold at same voxel volume without loss of sensitivity. CONCLUSIONS: tMPPCA denoising can (a) improve of fine spatial and temporal patterns, (b) considerably reduce scan time for clinical applications, or (c) increase resolution to potentially push cutting-edge MPM protocols from the upper to the lower limit of the mesoscopic scale.

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.

Mechanical behavior of the hippocampus and corpus callosum: An attempt to reconcile ex vivo with in vivo and micro with macro properties.

Mechanical properties of brain tissue are very complex and vary with the species, region, method, and dynamic range, and between in vivo and ex vivo measurements. To reconcile this variability, we investigated in vivo and ex vivo stiffness properties of two distinct regions in the human and mouse brain - the hippocampus (HP) and the corpus callosum (CC) - using different methods. Under quasi-static conditions, we examined ex vivo murine HP and CC by atomic force microscopy (AFM). Between 16 and 40Hz, we investigated the in vivo brains of healthy volunteers by magnetic resonance elastography (MRE) in a 3-T clinical scanner. At high-frequency stimulation between 1000 and 1400Hz, we investigated the murine HP and CC ex vivo and in vivo with MRE in a 7-T preclinical system. HP and CC showed pronounced stiffness dispersion, as reflected by a factor of 32-36 increase in shear modulus from AFM to low-frequency human MRE and a 25-fold higher shear wave velocity in murine MRE than in human MRE. At low frequencies, HP was softer than CC, in both ex vivo mouse specimens (p < 0.05) and in vivo human brains (p < 0.01) while, at high frequencies, CC was softer than HP under in vivo (p < 0.01) and ex vivo (p < 0.05) conditions. The standard linear solid model comprising three elements reproduced the observed HP and CC stiffness dispersions, while other two- and three-element models failed. Our results indicate a remarkable consistency of brain stiffness across species, ex vivo and in vivo states, and different measurement techniques when marked viscoelastic dispersion properties combining equilibrium and non-equilibrium mechanical elements are considered.

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

Purpose: 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 (BMI). Methods: 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 1 day and 1 year to determine intraclass correlation coefficient (ICC) and identify possible long-term changes. Results: White matter shear wave speed (SWS) was slightly higher in 2D-MRE (1.28 ± 0.02 m/s) than 3D-MRE (1.22 ± 0.05 m/s, p < 0.0001), with less variation after 1 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 1 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 BMI. Conclusion: 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.

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.

Multiple motion encoding in phase-contrast MRI: A general theory and application to elastography imaging.

While MRI allows to encode the motion of tissue in the magnetization's phase, it remains yet a challenge to obtain high fidelity motion images due to wraps in the phase for high encoding efficiencies. Therefore, we propose an optimal multiple motion encoding method (OMME) and exemplify it in Magnetic Resonance Elastography (MRE) data. OMME is formulated as a non-convex least-squares problem for the motion using an arbitrary number of phase-contrast measurements with different motion encoding gradients (MEGs). The mathematical properties of OMME are proved in terms of standard deviation and dynamic range of the motion's estimate for arbitrary MEGs combination which are confirmed using synthetically generated data. OMME's performance is assessed on MRE data from in vivo human brain experiments and compared to dual encoding strategies. The unwrapped images are further used to reconstruct stiffness maps and compared to the ones obtained using conventional unwrapping methods. OMME allowed to successfully combine several MRE phase images with different MEGs, outperforming dual encoding strategies in either motion-to-noise ratio (MNR) or number of successfully reconstructed voxels with good noise stability. This lead to stiffness maps with greater resolution of details than obtained with conventional unwrapping methods. The proposed OMME method allows for a flexible and noise robust increase in the dynamic range and thus provides wrap-free phase images with high MNR. In MRE, the method may be especially suitable when high resolution images with high MNR are needed.

Liquid-Liver Phantom: Mimicking the Viscoelastic Dispersion of Human Liver for Ultrasound- and MRI-Based Elastography.

OBJECTIVES: Tissue stiffness can guide medical diagnoses and is exploited as an imaging contrast in elastography. However, different elastography devices show different liver stiffness values in the same subject, hindering comparison of values and establishment of system-independent thresholds for disease detection. There is a need for standardized phantoms that specifically address the viscosity-related dispersion of stiffness over frequency. To improve standardization of clinical elastography across devices and platforms including ultrasound and magnetic resonance imaging (MRI), a comprehensively characterized phantom is introduced that mimics the dispersion of stiffness of the human liver and can be generated reproducibly. MATERIALS AND METHODS: The phantom was made of linear polymerized polyacrylamide (PAAm) calibrated to the viscoelastic properties of healthy human liver in vivo as reported in the literature. Stiffness dispersion was analyzed using the 2-parameter springpot model fitted to the dispersion of shear wave speed of PAAm, which was measured by shear rheometry, ultrasound-based time-harmonic elastography, clinical magnetic resonance elastography (MRE), and tabletop MRE in the frequency range of 5 to 3000 Hz. Imaging parameters for ultrasound and MRI, reproducibility, aging behavior, and temperature dependency were assessed. In addition, the frequency bandwidth of shear wave speed of clinical elastography methods (Aplio i900, Canon; Acuson Sequoia, Siemens; FibroScan, EchoSense) was characterized. RESULTS: Within the entire frequency range analyzed in this study, the PAAm phantom reproduced well the stiffness dispersion of human liver in vivo despite its fluid properties under static loading (springpot stiffness parameter, 2.14 [95% confidence interval, 2.08-2.19] kPa; springpot powerlaw exponent, 0.367 [95% confidence interval, 0.362-0.373]). Imaging parameters were close to those of liver in vivo with only slight variability in stiffness values of 0.5% (0.4%, 0.6%), 4.1% (3.9%, 4.5%), and -0.63% (-0.67%, -0.58%), respectively, between batches, over a 6-month period, and per °C increase in temperature. CONCLUSIONS: The liquid-liver phantom has useful properties for standardization and development of liver elastography. First, it can be used across clinical and experimental elastography devices in ultrasound and MRI. Second, being a liquid, it can easily be adapted in size and shape to specific technical requirements, and by adding inclusions and scatterers. Finally, because the phantom is based on noncrosslinked linear PAAm constituents, it is easy to produce, indicating potential widespread use among researchers and vendors to standardize liver stiffness measurements.

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.

In vivo stiffness of multiple sclerosis lesions is similar to that of normal-appearing white matter.

In 1868, French neurologist Jean-Martin Charcot coined the term multiple sclerosis (MS) after his observation that numerous white matter (WM) glial scars felt like sclerotic tissue. Nowadays, magnetic resonance elastography (MRE) can generate images with contrast of stiffness (CS) in soft in vivo tissues and may therefore be sensitive to MS lesions, provided that sclerosis is indeed a mechanical signature of this disease. We analyzed CS in a total of 147 lesions in patients with relapsing-remitting MS, compared with control regions in contralateral brain regions, and phantom data as well as performed numerical simulations to determine the delineation limits of multifrequency MRE (20 - 40 Hz) in MS. MRE analysis of simulated waves revealed a delineation limit of approximately 10% CS for detecting 9-mm lesions (mean size in our patient population). Due to inversion bias, this limit is reached when true CS is -11% for soft and 35% for stiff lesions. In vivo MRE identified 35 stiffer lesions and 17 softer lesions compared with surrounding WM (mean stiffness: 934±82 Pa). However, a similar pattern was found in the contralateral brain, suggesting that the range of stiffness changes in WM lesions due to MS is within the normal range of WM variability and normal heterogeneity-related CS. Consequently, Charcot's original intuition that MS is a focal sclerotic disease can neither be dismissed nor confirmed by in vivo MRE. However, the observation that MS lesions do not markedly differ in stiffness from surrounding brain tissue suggests that marked tissue sclerosis is not a mechanical signature of MS. STATEMENT OF SIGNIFICANCE: Multiple sclerosis (MS) was named by J.M. Charcot after the sclerotic changes in brain tissue he found in post-mortem autopsies. Since then, nothing has been revealed about the actual stiffening of MS lesions in vivo. Studying the viscoelastic properties of plaques in their natural environment is a major challenge that can only be overcome by MR elastography (MRE). Therefore, we used multifrequency MRE to answer the question whether MS lesions in patients with a relapsing-remitting disease course are mechanically different than surrounding tissue. Our findings suggest that the range of stiffness changes in white matter lesions due to MS is within the normal range of white matter variability and in vivo tissue sclerosis might not be a mechanical signature of MS.

Inversion-recovery MR elastography of the human brain for improved stiffness quantification near fluid-solid boundaries.

PURPOSE: In vivo MR elastography (MRE) holds promise as a neuroimaging marker. In cerebral MRE, shear waves are introduced into the brain, which also stimulate vibrations in adjacent CSF, resulting in blurring and biased stiffness values near brain surfaces. We here propose inversion-recovery MRE (IR-MRE) to suppress CSF signal and improve stiffness quantification in brain surface areas. METHODS: Inversion-recovery MRE was demonstrated in agar-based phantoms with solid-fluid interfaces and 11 healthy volunteers using 31.25-Hz harmonic vibrations. It was performed by standard single-shot, spin-echo EPI MRE following 2800-ms IR preparation. Wave fields were acquired in 10 axial slices and analyzed for shear wave speed (SWS) as a surrogate marker of tissue stiffness by wavenumber-based multicomponent inversion. RESULTS: Phantom SWS values near fluid interfaces were 7.5 ± 3.0% higher in IR-MRE than MRE (P = .01). In the brain, IR-MRE SNR was 17% lower than in MRE, without influencing parenchymal SWS (MRE: 1.38 ± 0.02 m/s; IR-MRE: 1.39 ± 0.03 m/s; P = .18). The IR-MRE tissue-CSF interfaces appeared sharper, showing 10% higher SWS near brain surfaces (MRE: 1.01 ± 0.03 m/s; IR-MRE: 1.11 ± 0.01 m/s; P < .001) and 39% smaller ventricle sizes than MRE (P < .001). CONCLUSIONS: Our results show that brain MRE is affected by fluid oscillations that can be suppressed by IR-MRE, which improves the depiction of anatomy in stiffness maps and the quantification of stiffness values in brain surface areas. Moreover, we measured similar stiffness values in brain parenchyma with and without fluid suppression, which indicates that shear wavelengths in solid and fluid compartments are identical, consistent with the theory of biphasic poroelastic media.

Real-Time Multifrequency MR Elastography of the Human Brain Reveals Rapid Changes in Viscoelasticity in Response to the Valsalva Maneuver.

Modulation of cerebral blood flow and vascular compliance plays an important role in the regulation of intracranial pressure (ICP) and also influences the viscoelastic properties of brain tissue. Therefore, magnetic resonance elastography (MRE), the gold standard for measuring in vivo viscoelasticity of brain tissue, is potentially sensitive to cerebral autoregulation. In this study, we developed a multifrequency MMRE technique that provides serial maps of viscoelasticity at a frame rate of nearly 6 Hz without gating, i.e., in quasi-real time (rt-MMRE). This novel method was used to monitor rapid changes in the viscoelastic properties of the brains of 17 volunteers performing the Valsalva maneuver (VM). rt-MMRE continuously sampled externally induced vibrations comprising three frequencies of 30.03, 30.91, and 31.8 Hz were over 90 s using a steady-state, spiral-readout gradient-echo sequence. Data were processed by multifrequency dual elasto-visco (MDEV) inversion to generate maps of magnitude shear modulus | G∗| (stiffness) and loss angle φ at a frame rate of 5.4 Hz. As controls, the volunteers were examined to study the effects of breath-hold following deep inspiration and breath-hold following expiration. We observed that | G∗| increased while φ decreased due to VM and, less markedly, due to breath-hold in inspiration. Group mean VM values showed an early overshoot of | G∗| 2.4 ± 1.2 s after the onset of the maneuver with peak values of 6.7 ± 4.1% above baseline, followed by a continuous increase in stiffness during VM. A second overshoot of | G∗| occurred 5.5 ± 2.0 s after the end of VM with peak values of 7.4 ± 2.8% above baseline, followed by 25-s sustained recovery until the end of image acquisition. φ was constantly reduced by approximately 2% during the entire VM without noticeable peak values. This is the first report of viscoelasticity changes in brain tissue induced by physiological maneuvers known to alter ICP and detected by clinically applicable rt-MMRE. Our results show that apnea and VM slightly alter brain properties toward a more rigid-solid behavior. Overshooting stiffening reactions seconds after onset and end of VM reveal rapid autoregulatory processes of brain tissue viscoelasticity.

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.

Superviscous properties of the in vivo brain at large scales.

There is growing awareness that brain mechanical properties are important for neural development and health. However, published values of brain stiffness differ by orders of magnitude between static measurements and in vivo magnetic resonance elastography (MRE), which covers a dynamic range over several frequency decades. We here show that there is no fundamental disparity between static mechanical tests and in vivo MRE when considering large-scale properties, which encompass the entire brain including fluid filled compartments. Using gradient echo real-time MRE, we investigated the viscoelastic dispersion of the human brain in, so far, unexplored dynamic ranges from intrinsic brain pulsations at 1 Hz to ultralow-frequency vibrations at 5, 6.25, 7.8 and 10 Hz to the normal frequency range of MRE of 40 Hz. Surprisingly, we observed variations in brain stiffness over more than two orders of magnitude, suggesting that the in vivo human brain is superviscous on large scales with very low shear modulus of 42±13 Pa and relatively high viscosity of 6.6±0.3 Pa∙s according to the two-parameter solid model. Our data shed light on the crucial role of fluid compartments including blood vessels and cerebrospinal fluid (CSF) for whole brain properties and provide, for the first time, an explanation for the variability of the mechanical brain responses to manual palpation, local indentation, and high-dynamic tissue stimulation as used in elastography.