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Although a variety of MRI studies investigated the link between body mass index (BMI) and parameters of neural gray matter (GM), the technique applied in most of these studies, voxel-based morphometry (VBM), focusses on the regional GM volume, a macroscopic tissue property. Thus, the studies were not able to exploit the BMI-related information contained in the GM microstructure although PET studies suggest that these factors are important. Here, we used cerebral MR Elastography (MRE) to characterize features of tissue microstructure by evaluating the propagation of shear waves applied to the skull and to assess local tissue viscoelasticity to test the link between this parameter and BMI in 22 lean to overweight males. Unlike the majority of existing MRE studies investigating neural viscoelasticity signals averaged across large brain regions, we used the viscoelasticity of individual voxels for our experiment. Our technique revealed a negative link between BMI and viscoelasticity of two areas of the striatal reward system, i.e., right putamen (t = -8.2; p FWE-corrected  = 0.005) and left globus pallidus (t = -7.1; p FWE  = 0.037) which was independent of GM volume at these coordinates. Finally, comparison of BMI models based on individual voxels vs. on signals averaged across brain atlas regions demonstrates that voxel-based models explain a significantly higher proportion of variance. Consequently, our findings show that cerebral MRE is suitable to identify medically relevant microstructural tissue properties. Using a voxel-wise analysis approach, we were able to utilize the high spatial resolution of MRE for mapping BMI-related information in the brain.

In-vivo brain viscoelasticity measured by magnetic resonance elastography (MRE) is a sensitive imaging marker for long-term biophysical changes in brain tissue due to aging and disease; however, it is still unknown whether MRE can reveal short-term periodic alterations of brain viscoelasticity related to cerebral arterial pulsation (CAP). We developed cardiac-gated steady-state MRE (ssMRE) with spiral readout and stroboscopic sampling of continuously induced mechanical vibrations in the brain at 20, 31.25, and 40 Hz frequencies. Maps of magnitude |G*| and phase ϕ of the complex shear modulus were generated by multifrequency dual visco-elasto inversion with a temporal resolution of 40 ms over 4 s. The method was tested in 12 healthy volunteers. During cerebral systole, |G*| decreased by 6.6 ± 1.9% (56 ± 22 Pa, p  < 0.001, mean ± SD), whereas ϕ increased by 0.5 ± 0.5% (0.006 ± 0.005 rad, p  = 0.002). The effect size of CAP-induced softening slightly decreased with age by 0.10 ± 0.05% per year ( p  = 0.04), indicating lower cerebral vascular compliance in older individuals. Our data show for the first time that the brain softens and becomes more viscous during systole, possibly due to an effect of CAP-induced arterial expansion and increased blood volume on effective-medium tissue properties. This sensitivity to vascular-solid tissue interactions makes ssMRE potentially useful for detection of cerebral vascular disease.

Mechanical properties of biological tissues and, above all, their solid or fluid behavior influence the spread of malignant tumors. While it is known that solid tumors tend to have higher mechanical rigidity, allowing them to aggressively invade and spread in solid surrounding healthy tissue, it is unknown how softer tumors can grow within a more rigid environment such as the brain. Here, we use in vivo magnetic resonance elastography (MRE) to elucidate the role of anomalous fluidity for the invasive growth of soft brain tumors, showing that aggressive glioblastomas (GBMs) have higher water content while behaving like solids. Conversely, our data show that benign meningiomas (MENs), which contain less water than brain tissue, are characterized by fluid-like behavior. The fact that the 2 tumor entities do not differ in their soft properties suggests that fluidity plays an important role for a tumor's aggressiveness and infiltrative potential. Using tissue-mimicking phantoms, we show that the anomalous fluidity of neurotumors physically enables GBMs to penetrate surrounding tissue, a phenomenon similar to Saffman-Taylor viscous-fingering instabilities, which occur at moving interfaces between fluids of different viscosity. Thus, targeting tissue fluidity of malignant tumors might open horizons for the diagnosis and treatment of cancer., Competing Interests: The authors declare no competing interest.

Respiratory arrest is a major life-threatening condition leading to cessation of vital functions and hypoxic-anoxic injury of the brain. The progressive structural tissue changes characterizing the dying brain biophysically are unknown. Here we use noninvasive magnetic resonance elastography to show that biomechanical tissue properties are highly sensitive to alterations in the brain in the critical period before death. Our findings demonstrate that brain stiffness increases after respiratory arrest even when cardiac function is still preserved. Within 5 min of cardiac arrest, cerebral stiffness further increases by up to 30%. This early mechanical signature of the dying brain can be explained by water accumulation and redistribution from extracellular spaces into cells. These processes, together, increase interstitial and intracellular pressure as revealed by magnetic resonance spectroscopy and diffusion-weighted imaging. Our data suggest that the fast response of cerebral stiffness to respiratory arrest enables the monitoring of life-threatening brain pathology using noninvasive in vivo imaging. STATEMENT OF SIGNIFICANCE: Hypoxia-anoxia is a life-threatening condition eventually leading to brain death. Therefore, monitoring vital brain functions in patients at risk is urgently required during emergency care or treatment of acute brain damage due to insufficient oxygen supply. In mouse model of hypoxia-anoxia, we have shown for the first time that biophysical tissue parameters such as brain stiffness changed markedly during the process of death., (Copyright © 2019. Published by Elsevier Ltd.)

Biomechanical cues guide proliferation, growth and maturation of neurons. Yet the molecules that shape the brain's biomechanical properties are unidentified and the relationship between neural development and viscoelasticity of brain tissue remains elusive. Here we combined novel in-vivo tomoelastography and ex-vivo proteomics to investigate whether viscoelasticity of the mouse brain correlates with protein alterations within the critical phase of brain maturation. For the first time, high-resolution atlases of viscoelasticity of the mouse brain were generated, revealing that (i) brain stiffness increased alongside progressive accumulation of microtubular structures, myelination, cytoskeleton linkage and cell-matrix attachment, and that (ii) viscosity-related tissue fluidity decreased alongside downregulated actin crosslinking and axonal organization. Taken together, our results show that brain maturation is associated with a shift of brain mechanical properties towards a more solid-rigid behavior consistent with reduced tissue fluidity. This shift appears to be driven by several molecular processes associated with myelination, cytoskeletal crosslinking and axonal organization. STATEMENT OF SIGNIFICANCE: The viscoelastic properties of brain tissue shape the environment in which neurons proliferate, grow, and mature. In the present study, novel tomoelastography was used to spatially map tissue mechanical properties of the in-vivo mouse brain during maturation. In vivo tomoelastography was also combined with ex vivo mass spectrometry proteomic analysis to identify the molecules which shape the biomechanical properties of brain tissue. With the combined technique, we observed that brain maturation is associated with a shift of brain mechanical properties towards a more solid-rigid behavior consistent with reduced tissue fluidity which is driven by multiple molecular processes. We believe that this shift of brain mechanical properties discovered in our study reflects a fundamental biophysical signature of brain maturation., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

While hypothermia of the brain is used to reduce neuronal damage in patients with conditions such as traumatic brain injury or stroke, little is known about how temperature affects the biophysical properties of in vivo brain tissue. Therefore, we measured shear wave speed (SWS), apparent diffusion coefficient (ADC), and cerebral blood flow (CBF) in the mouse brain at different body temperatures to investigate the relationship between temperature and tissue stiffness, water diffusion, and blood perfusion in the living brain. Multifrequency magnetic resonance elastography (MRE), diffusion-weighted imaging (DWI), and arterial spin labeling (ASL) were performed in seven mice while increasing and recording body temperature from hypothermia (28-30 °C) to normothermia (36-38 °C). SWS, ADC, and CBF were analyzed in regions of whole brain, cortex, hippocampus, and diencephalon. Our results show that SWS decreases while ADC and CBF increase from hypothermia to normothermia (whole brain SWS: -6.2%, ADC: +34.0%, CBF: +80.2%; cortex SWS: -10.1%, ADC: +30.9%, CBF: +82.4%; all p > 0.05). We found a significant inverse correlation between SWS and both ADC and CBF in all analyzed regions except diencephalon (whole brain SWS-ADC: r = -0.8, p < 0.005; SWS-CBF: r = -0.84, p < 0.005; cortex SWS-ADC: r = -0.74, p < 0.05; SWS-CBF: r = -0.65, p < 0.05). These results show that in vivo brain stiffness is inversely correlated with temperature, extracellular water mobility, and microvascular blood flow. Regional differences indicate that cortical areas are more markedly affected by hypothermia than central regions such as diencephalon. Temperature should be considered as a confounder in elastographic measurements, especially in preclinical settings. STATEMENT OF SIGNIFICANCE: Hibernating mammals lower their body temperature and metabolic activity. A hypothermic state can also be induced for medical purposes to reduce the risk of neural damage in patients with neurological disease or injury. However, little is known how physical soft-tissue properties of the in-vivo brain such as water diffusion, blood perfusion or mechanical parameters correlate with each other when temperature changes. Our study demonstrates for the first time that those quantitative imaging markers are tightly linked to changes in body temperature. While water diffusion and blood perfusion are reduced during hypothermia, brain stiffness significantly increases, suggesting that multiparametric quantitative MRI should be used for the noninvasive assessment of brain metabolic activity., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

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., (© 2018 International Society for Magnetic Resonance in Medicine.)

Cerebral stiffness (CS) reflects the biophysical environment in which neurons grow and function. While long-term CS changes can occur in the course of chronic neurological disorders and aging, little is known about acute variations of CS induced by intracranial pressure variations. Current gold standard methods for CS and intracranial pressure such as magnetic resonance elastography and direct pressure recordings are either expensive and slow or invasive. The study objective was to develop a real-time method for in vivo CS measurement and to demonstrate its sensitivity to physiological aging and intracranial pressure variations induced by the Valsalva maneuver in healthy volunteers. We used trans-temporal ultrasound time-harmonic elastography (THE) with external shear-wave stimulation by continuous and superimposed vibrations in the frequency range from 27 to 56 Hz. Multifrequency wave inversion generated maps of shear wave speed (SWS) as a surrogate maker of CS. On average, cerebral SWS was 1.56 ± 0.08 m/s with a tendency to reduce with age (R = -0.76, p < 0.0001) while Valsalva maneuver induced an immediate stiffening of the brain as reflected by a 10.8 ± 2.5% increase (p < 0.0001) in SWS. Our results suggest that CS is tightly linked to intracranial pressure and might be used in the future as non-invasive surrogate marker for intracranial pressure, which otherwise requires invasive measurements.

Objectives: To apply three-dimensional multifrequency MR-elastography (3DMRE) for the measurement of local cerebral viscoelasticity changes in patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP)., Methods: T1-weighted anatomical imaging and 3DMRE were performed in 17 PD and 20 PSP patients as well as 12 controls. Two independent viscoelasticity parameters, |G*| and φ, were reconstructed combining seven harmonic vibration frequencies (30-60 Hz). Spatially averaged values were compared by one-way ANOVA, groups were compared using unpaired t test and Mann-Whitney test, respectively. Correlation between clinical data and parameters of brain elasticity and volume were calculated by Pearson's correlation coefficient., Results: In patients, |G*| was significantly reduced in the frontal and mesencephalic regions (p < 0.05). Beyond that, reduced mesencephalic |G*| discriminated PSP from PD (p < 0.05). Neurodegeneration causes significant brain atrophy (p < 0.01) and is pronounced in PSP patients (p < 0.05 vs. PD). Reduced brain viscoelasticity is correlated with brain atrophy in PSP (r=0.64, p=0.002) and PD (r=0.65, p=0.005) patients but not in controls., Conclusions: MRE-measured viscoelasticity reflects local structural changes of brain tissue in PSP and in PD and provides a useful parameter to differentiate neurodegenerative movement disorders based on imaging examinations., Key Points: • 3D multifrequency MR-elastography reveals diffuse regional changes in brain viscoelasticity in neurodegenerative disorders. • Reduced mesencephalic viscoelasticity separates PD and PSP. • Reduced brain viscoelasticity and brain atrophy as independent hallmarks of neurodegeneration hypothesized.

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Viscoelastic properties of the brain reflect tissue architecture at multiple length scales. However, little is known about the relation between vital tissue functions, such as perfusion, and the macroscopic mechanical properties of cerebral tissue. In this study, arterial spin labelling is paired with magnetic resonance elastography to investigate the relationship between tissue stiffness and cerebral blood flow (CBF) in the in vivo human brain. The viscoelastic modulus, | G*|, and CBF were studied in deep gray matter (DGM) of 14 healthy male volunteers in the following sub-regions: putamen, nucleus accumbens, hippocampus, thalamus, globus pallidus, and amygdala. CBF was further normalized by vessel area data to obtain the flux rate q which is proportional to the perfusion pressure gradient. The striatum (represented by putamen and nucleus accumbens) was distinct from the other DGM regions by displaying markedly higher stiffness and perfusion values. q was a predictive marker for DGM stiffness as analyzed by linear regression | G*| =  q·(4.2 ± 0.6)kPa·s + (0.80 ± 0.06)kPa ( R 2  = 0.92, P = 0.006). These results suggest a high sensitivity of MRE in DGM to perfusion pressure. The distinct mechano-vascular properties of striatum tissue, as compared to the rest of DGM, may reflect elevated perfusion pressure, which could explain the well-known susceptibility of the putamen to hemorrhages.

Purpose: To improve the resolution of elasticity maps by adapting motion and distortion correction methods for phase-based magnetic resonance imaging (MRI) contrasts such as magnetic resonance elastography (MRE), a technique for measuring mechanical tissue properties in vivo., Materials and Methods: MRE data of the brain were acquired with echo-planar imaging (EPI) at 3T (n = 14) and 7T (n = 18). Motion and distortion correction parameters were estimated using the magnitude images. The real and imaginary part of the complex MRE data were corrected separately and recombined. The width of the point-spread function (PSF) and the position variability were calculated. The images were normalized to the Montreal Neurological Institute (MNI) anatomical template. The gray-to-white matter separability of the elasticity maps was tested., Results: Motion correction sharpened the |G*| maps as demonstrated by a narrowing of the PSF by 0.78 ± 0.51 mm at 7T and 0.52 ± 0.63 mm at 3T. The amount of individual head motion during MRE acquisition correlated with the decrease in the width of the PSF at 7T (r = 0.53, P = 0.025) and at 3T (r = 0.69, P = 0.006) and with the increase of gray-to-white matter separability after motion correction at 7T (r = 0.64, P = 0.0039) and at 3T (r = 0.57, P = 0.0319). Improved spatial accuracy after distortion correction results in a significant increase in separability of gray and white matter stiffness (P = 0.0067), especially in inferior parts of the brain suffering from strong B 0 inhomogeneities., Conclusion: We demonstrate that our method leads to sharper images and higher spatial accuracy, raising the prospect of the investigation of smaller brain areas with increased sensitivity in studies using MRE., Level of Evidence: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:134-141., (© 2016 International Society for Magnetic Resonance in Medicine.)

Objectives: Application of multifrequency magnetic resonance elastography (MMRE) of the brain parenchyma in patients with neuromyelitis optica spectrum disorder (NMOSD) compared to age matched healthy controls (HC)., Methods: 15 NMOSD patients and 17 age- and gender-matched HC were examined using MMRE. Two three-dimensional viscoelastic parameter maps, the magnitude |G*| and phase angle φ of the complex shear modulus were reconstructed by simultaneous inversion of full wave-field data in 1.9-mm isotropic resolution at 7 harmonic drive frequencies from 30 to 60 Hz., Results: In NMOSD patients, a significant reduction of |G*| was observed within the white matter fraction (p = 0.017), predominantly within the thalamic regions (p = 0.003), compared to HC. These parameters exceeded the reduction in brain volume measured in patients versus HC (p = 0.02 whole-brain volume reduction). Volumetric differences in white matter fraction and the thalami were not detectable between patients and HC. However, phase angle φ was decreased in patients within the white matter (p = 0.03) and both thalamic regions (p = 0.044)., Conclusions: MMRE reveals global tissue degeneration with accelerated softening of the brain parenchyma in patients with NMOSD. The predominant reduction of stiffness is found within the thalamic region and related white matter tracts, presumably reflecting Wallerian degeneration., Key Points: • Magnetic resonance elastography reveals diffuse cerebral tissue changes in patients with NMOSD. • Premature tissue softening in NMOSD patients indicates tissue degeneration. • Hypothesis of a widespread cerebral neurodegeneration in form of diffuse tissue alteration.

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., (© 2015 Wiley Periodicals, Inc.)

The aim of this study was to introduce remote wave excitation for high-resolution cerebral multifrequency MR elastography (mMRE). mMRE of 25-45-Hz drive frequencies by head rocker stimulation was compared with mMRE by remote wave excitation based on a thorax mat in 12 healthy volunteers. Maps of the magnitude |G*| and phase φ of the complex shear modulus were reconstructed using multifrequency dual elasto-visco (MDEV) inversion. After the scan, the subjects and three operators assessed the comfort and convenience of cerebral mMRE using two methods of stimulating the brain. Images were acquired in a coronal view in order to identify anatomical regions along the spinothalamic pathway. In mMRE by remote actuation, all subjects and operators appreciated an increased comfort and simplified procedural set-up. The resulting strain amplitudes in the brain were sufficiently large to analyze using MDEV inversion, and yielded high-resolution viscoelasticity maps which revealed specific anatomical details of brain mechanical properties: |G*| was lowest in the pons (0.97 ± 0.08 kPa) and decreased within the corticospinal tract in the caudal-cranial direction from the crus cerebri (1.64 ± 0.26 kPa) to the capsula interna (1.29 ± 0.14 kPa). By avoiding onerous mechanical stimulation of the head, remote excitation of intracranial shear waves can be used to measure viscoelastic parameters of the brain with high spatial resolution. Therewith, the new mMRE method is suitable for neuroradiological examinations in the clinic., (Copyright © 2015 John Wiley & Sons, Ltd.)

Magnetic resonance elastography (MRE) is an imaging method that reveals the mechanical properties of tissue, modelled as a combination of " viscosity" and " elasticity" . We recently showed reduced brain viscoelasticity in multiple sclerosis (MS) patients compared with healthy controls, and in the relapsing-remitting disease model experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which these intrinsic tissue properties become altered remain unclear. This study investigates whether distinct regions in the mouse brain differ in their native viscoelastic properties, and how these properties are affected during chronic EAE in C57Bl/6 mice and in mice lacking the cytokine interferon-gamma. IFN-γ(-/-) mice exhibit a more severe EAE phenotype, with amplified inflammation in the cerebellum and brain stem. Brain scans were performed in the sagittal plane using a 7 T animal MRI scanner, and the anterior (cerebral) and posterior (cerebellar) regions analyzed separately. MRE investigations were accompanied by contrast-enhanced MRI scans, and by histopathology and gene expression analysis ex vivo. Compared with the cerebrum, the cerebellum in healthy mice has a lower viscoelasticity, i.e. it is intrinsically " softer" . This was seen both in the wild-type mice and the IFNγ(-/-) mice. During chronic EAE, C57Bl/6 mice did not show altered brain viscoelasticity. However, as expected, the IFNγ(-/-) mice showed a more severe EAE phenotype, and these mice did show altered brain elasticity during the course of disease. The magnitude of the elasticity reduction correlated with F4/80 gene expression, a marker for macrophages/microglia in inflamed central nervous system tissue. Together these results demonstrate that MRE is sensitive enough to discriminate between viscoelastic properties in distinct anatomical structures in the mouse brain, and to confirm a further relationship between cellular inflammation and mechanical alterations of the brain. This study underscores the utility of MRE to monitor pathological tissue alterations in vivo., (Copyright © 2015 John Wiley & Sons, Ltd.)

Purpose: Waveguide elastography (WGE) combines magnetic resonance elastography (MRE), diffusion tensor imaging (DTI), and anisotropic inversions for a determination of the elastic properties of white matter. Previously, the method evaluated the anisotropic elastic properties of the corticospinal tracts (CSTs) of healthy volunteers. Here, the sensitivity of WGE is tested for the detection of pathologic changes in a cohort of patients with Amyotrophic Lateral Sclerosis (ALS)., Methods: MRE and DTI were performed in 14 patients with ALS and 14 healthy, age-matched controls. A comparison was made between three components from WGE and the DTI metrics FA, MD, PD, and RD, for the detection of differences between patients and controls. It was hypothesized that the stiffness values in the CSTs of the patients would be significantly lower due to the known neurodegeneration associated with ALS., Results: Two anisotropic shear moduli polarized parallel and perpendicular to the CSTs were significantly reduced in ALS patients (P < 0.0001), whereas the anisotropic longitudinal modulus polarized parallel to the CSTs showed no significant differences., Conclusion: The results of this study suggest a relatively high sensitivity of two anisotropic shear moduli as noninvasive metrics for the assessment of neuronal degeneration within the CSTs., (© 2013 Wiley Periodicals, Inc.)

Compressibility of biological tissues such as brain parenchyma is related to its poroelastic nature characterized by the geometry and pressure of vasculature and interconnected fluid-filled spaces. Thus, cerebral volumetric strain may be sensitive to intracranial pressure which can be altered under physiological conditions. So far volumetric strain has attained little attention in studies of the mechanical behavior of the brain. This paper reports a study of measuring the in vivo cerebral volumetric strain induced by the Valsalva maneuver (VM) where forced expiration against a closed glottis leads to a transient increase in the intracranial pressure. For this purpose we applied three-dimensional magnetic resonance imaging equipped with a patient-controlled acquisition system to five healthy volunteers. With each volunteer, three experiments were performed: one with VM and two in resting state. i.e. normal ventilation, which were conducted before and after VM. The VM data were registered to reference data by morphology based non-rigid deformation, yielding 3D maps of total displacements and volumetric strain. On average, VM induced volumetric strain correlated to whole-brain dilatation of -3.14±0.87% and -2.80±0.71% compared to the reference states before and after VM, respectively. These values were well reproduced by repetitive experiments during the same scan as well as by repeated measurements in one volunteer on different days. Combined with literature data of intracranial pressure changes, our volumetric strain values can be used to elucidate the static compression modulus of the in vivo human brain. These results add knowledge to the understanding of the brain׳s biomechanical properties under physiological conditions., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Magnetic resonance elastography (MRE) is capable of measuring the viscoelastic properties of brain tissue in vivo. However, MRE is still limited in providing high-resolution maps of mechanical constants. We therefore introduce 3D multifrequency MRE (3DMMRE) at 7T magnetic field strength combined with enhanced multifrequency dual elasto-visco (MDEV) inversion in order to achieve high-resolution elastographic maps of in vivo brain tissue with 1mm(3) resolution. As demonstrated by phantom data, the new MDEV-inversion method provides two high resolution parameter maps of the magnitude (|G*|) and the phase angle (ϕ) of the complex shear modulus. MDEV inversion applied to cerebral 7T-3DMMRE data of five healthy volunteers revealed structures of brain tissue in greater anatomical details than previous work. The viscoelastic properties of cortical gray matter (GM) and white matter (WM) could be differentiated by significantly lower values of |G*| and ϕ in GM (21% [P<0.01]; 8%, [P<0.01], respectively) suggesting that GM is significantly softer and less viscous than WM. In conclusion, 3DMMRE at ultrahigh magnetic fields and MDEV inversion open a new window into characterizing the mechanical structure of in vivo brain tissue and may aid the detection of various neurological disorders based on their effects to mechanical tissue properties., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate the influence of neuronal density on viscoelastic parameters of living brain tissue after ischemic infarction in the mouse using MR elastography (MRE). Transient middle cerebral artery occlusion (MCAO) in the left hemisphere was induced in 20 mice. In vivo 7-T MRE at a vibration frequency of 900 Hz was performed on days 3, 7, 14 and 28 (n = 5 per group) after MCAO, followed by the analysis of histological markers, such as neuron counts (NeuN). MCAO led to a significant reduction in the storage modulus in the left hemisphere relative to contralateral values (p = 0.03) without changes over time. A correlation between storage modulus and NeuN in both hemispheres was observed, with correlation coefficients of R = 0.648 (p = 0.002, left) and R = 0.622 (p = 0.003, right). The loss modulus was less sensitive to MCAO, but correlated with NeuN in the left hemisphere (R = 0.764, p = 0.0001). In agreement with the literature, these results suggest that the shear modulus in the brain is reduced after transient ischemic insult. Furthermore, our study provides evidence that the in vivo shear modulus of brain tissue correlates with neuronal density. In diagnostic applications, MRE may thus have diagnostic potential as a tool for image-based quantification of neurodegenerative processes., (Copyright © 2013 John Wiley & Sons, Ltd.)

Motion-sensitive phase contrast magnetic resonance imaging and magnetic resonance elastography are applied for the measurement of volumetric strain and tissue compressibility in human brain. Volumetric strain calculated by the divergence operator using a biphasic effective-medium model is related to dilatation and compression of fluid spaces during harmonic stimulation of the head or during intracranial passage of the arterial pulse wave. In six volunteers, phase contrast magnetic resonance imaging showed that the central cerebrum expands at arterial pulse wave to strain values of (2.8 ± 1.9)·10(-4). The evolution of volumetric strain agrees well with the magnitude of the harmonic divergence measured in eight volunteers by magnetic resonance elastography using external activation of 25 Hz vibration frequency. Intracranial volumetric strain was proven sensitive to venous pressure altered by abdominal muscle contraction. In eight volunteers, an increase in volumetric strain due to abdominal muscle contraction of approximately 45% was observed (P = 0.0001). The corresponding compression modulus in the range of 9.5-13.5 kPa demonstrated that the compressibility of brain tissue at 25 Hz stimulation is much higher than that of water. This pilot study provides the background for compression-sensitive magnetic resonance imaging with or without external head stimulation. Volumetric strain may be sensitive to fluid flow abnormalities or pressure imbalances between vasculature and parenchyma as seen in hydrocephalus., (Copyright © 2012 Wiley Periodicals, Inc.)

White matter is composed primarily of myelinated axons which form fibrous, organized structures and can act as waveguides for the anisotropic propagation of sound. The evaluation of their elastic properties requires both knowledge of the orientation of these waveguides in space, as well as knowledge of the waves propagating along and through them. Here, we present waveguide elastography for the evaluation of the elastic properties of white matter tracts in the human brain, in vivo, using a fusion of diffusion tensor imaging, magnetic resonance elastography, spatial-spectral filtering, a Helmholtz decomposition, and anisotropic inversions, and apply this method to evaluate the material parameters of the corticospinal tracts of five healthy human volunteers. We begin with an Orthotropic inversion model and demonstrate that redundancies in the solution for the nine elastic coefficients indicate that the corticospinal tracts can be approximated by a Hexagonal model (transverse isotropy) comprised of five elastic coefficients representative of a medium with fibers aligned parallel to a central axis, and provides longitudinal and transverse wave velocities on the order of 5.7 m/s and 2.1 m/s, respectively. This method is intended as a new modality to assess white matter structure and health by means of the evaluation of the anisotropic elasticity tensor of nerve fibers., (Copyright © 2012 Wiley Periodicals, Inc.)

Introduction: Viscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE) is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS) is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS., Methods: We determined viscoelastic parameters of the brain parenchyma in 23 MS patients with primary or secondary chronic progressive disease course in comparison to 38 age- and gender-matched healthy individuals by multifrequency MRE, and correlated the results with clinical data, T2 lesion load and brain volume. Two viscoelastic parameters, the shear elasticity μ and the powerlaw exponent α, were deduced according to the springpot model and compared to literature values of relapsing-remitting MS., Results: In chronic-progressive MS patients, μ and α were reduced by 20.5% and 6.1%, respectively, compared to healthy controls. MR volumetry yielded a weaker correlation: Total brain volume loss in MS patients was in the range of 7.5% and 1.7% considering the brain parenchymal fraction. All findings were significant (P<0.001)., Conclusions: Chronic-progressive MS disease courses show a pronounced reduction of the cerebral shear elasticity compared to early relapsing-remitting disease. The powerlaw exponent α decreased only in the chronic-progressive stage of MS, suggesting an alteration in the geometry of the cerebral mechanical network due to chronic neuroinflammation.

Nearly half a century after the first report of normal pressure hydrocephalus (NPH), the pathophysiological cause of the disease still remains unclear. Several theories about the cause and development of NPH emphasize disease-related alterations of the mechanical properties of the brain. MR elastography (MRE) uniquely allows the measurement of viscoelastic constants of the living brain without intervention. In this study, 20 patients (mean age, 69.1 years; nine men, 11 women) with idiopathic (n = 15) and secondary (n = 5) NPH were examined by cerebral multifrequency MRE and compared with 25 healthy volunteers (mean age, 62.1 years; 10 men, 15 women). Viscoelastic constants related to the stiffness (µ) and micromechanical connectivity (α) of brain tissue were derived from the dynamics of storage and loss moduli within the experimentally achieved frequency range of 25-62.5 Hz. In patients with NPH, both storage and loss moduli decreased, corresponding to a softening of brain tissue of about 20% compared with healthy volunteers (p < 0.001). This loss of rigidity was accompanied by a decreasing α parameter (9%, p < 0.001), indicating an alteration in the microstructural connectivity of brain tissue during NPH. This disease-related decrease in viscoelastic constants was even more pronounced in the periventricular region of the brain. The results demonstrate distinct tissue degradation associated with NPH. Further studies are required to investigate the source of mechanical tissue damage as a potential cause of NPH-related ventricular expansions and clinical symptoms., (Copyright © 2010 John Wiley & Sons, Ltd.)

Physiological aging of the brain is accompanied by ubiquitous degeneration of neurons and oligodendrocytes. An alteration of the cellular matrix of an organ impacts its macroscopic viscoelastic properties which can be detected by magnetic resonance elastography (MRE)--to date the only method for measuring brain mechanical parameters without intervention. However, the wave patterns detected by MRE are affected by atrophic changes in brain geometry occurring in an individual's life span. Moreover, regional variability in MRE-detected age effects is expected corresponding to the regional variation in atrophy. Therefore, the sensitivity of brain MRE to brain volume and aging was investigated in 66 healthy volunteers aged 18-72. A linear decline in whole-brain elasticity was observed (-0.75%/year, R-square = 0.59, p<0.001); the rate is three times that determined by volume measurements (-0.23%/year, R-square = 0.4, p<0.001). The highest decline in elasticity (-0.92%/year, R-square = 0.43, p<0.001) was observed in a region of interest placed in the frontal lobe with minimal age-related shrinkage (-0.1%, R-square = 0.06, p = 0.043). Our results suggest that cerebral MRE can measure geometry-independent viscoelastic parameters related to intrinsic tissue structure and altered by age.

Purpose: To investigate the feasibility of quantitative in vivo ultrahigh field magnetic resonance elastography (MRE) of the human brain in a broad range of low-frequency mechanical vibrations., Materials and Methods: Mechanical vibrations were coupled into the brain of a healthy volunteer using a coil-driven actuator that either oscillated harmonically at single frequencies between 25 and 62.5 Hz or performed a superimposed motion consisting of multiple harmonics. Using a motion sensitive single-shot spin-echo echo planar imaging sequence shear wave displacements in the brain were measured at 1.5 and 7 T in whole-body MR scanners. Spatially averaged complex shear moduli were calculated applying Helmholtz inversion., Results: Viscoelastic properties of brain tissue could be reliably determined in vivo at 1.5 and 7 T using both single-frequency and multifrequency wave excitation. The deduced dispersion of the complex modulus was consistent within different experimental settings of this study for the measured frequency range and agreed well with literature data., Conclusion: MRE of the human brain is feasible at 7 T. Superposition of multiple harmonics yields consistent results as compared to standard single-frequency based MRE. As such, MRE is a system-independent modality for measuring the complex shear modulus of in vivo human brain in a wide dynamic range.

In multiple sclerosis (MS), diffuse brain parenchymal damage exceeding focal inflammation is increasingly recognized to be present from the very onset of the disease, and, although occult to conventional imaging techniques, may present a major cause of permanent neurological disability. Subtle tissue alterations significantly influence biomechanical properties given by stiffness and internal friction, that--in more accessible organs than the brain--are traditionally assessed by manual palpation during the clinical exam. The brain, however, is protected from our sense of touch, and thus our current knowledge on cerebral viscoelasticity is very limited. We developed a clinically feasible magnetic resonance elastography setup sensitive to subtle alterations of brain parenchymal biomechanical properties. Investigating 45 MS patients revealed a significant decrease (13%, P<0.001) of cerebral viscoelasticity compared to matched healthy volunteers, indicating a widespread tissue integrity degradation, while structure-geometry defining parameters remained unchanged. Cerebral viscoelasticity may represent a novel in vivo marker of neuroinflammatory and neurodegenerative pathology., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

Viscoelasticity is a sensitive measure of the microstructural constitution of soft biological tissue and is increasingly used as a diagnostic marker, e.g. in staging liver fibrosis or characterizing breast tumors. In this study, multifrequency magnetic resonance elastography was used to investigate the in vivo viscoelasticity of healthy human brain in 55 volunteers (23 females) ranging in age from 18 to 88 years. The application of four vibration frequencies in an acoustic range from 25 to 62.5 Hz revealed for the first time how physiological aging changes the global viscosity and elasticity of the brain. Using the rheological springpot model, viscosity and elasticity are combined in a parameter mu that describes the solid-fluid behavior of the tissue and a parameter alpha related to the tissue's microstructure. It is shown that the healthy adult brain undergoes steady parenchymal 'liquefaction' characterized by a continuous decline in mu of 0.8% per year (P<0.001), whereas alpha remains unchanged. Furthermore, significant sex differences were found with female brains being on average 9% more solid-like than their male counterparts rendering women more than a decade 'younger' than men with respect to brain mechanics (P=0.016). These results set the background for using cerebral multifrequency elastography in diagnosing subtle neurodegenerative processes not detectable by other diagnostic methods.

The purpose of this work was to develop magnetic resonance elastography (MRE) for the fast and reproducible measurement of spatially averaged viscoelastic constants of living human brain. The technique was based on a phase-sensitive echo planar imaging acquisition. Motion encoding was orthogonal to the image plane and synchronized to intracranial shear vibrations at driving frequencies of 25 and 50 Hz induced by a head-rocker actuator. Ten time-resolved phase-difference wave images were recorded within 60 s and analyzed for shear stiffness and shear viscosity. Six healthy volunteers (six men; mean age 34.5 years; age range 25-44 years) underwent 23-39 follow-up MRE studies over a period of 6 months. Interindividual mean +/- SD shear moduli and shear viscosities were found to be 1.17 +/- 0.03 kPa and 3.1 +/- 0.4 Pas for 25 Hz and 1.56 +/- 0.07 kPa and 3.4 +/- 0.2 Pas for 50 Hz, respectively (P < or = 0.01). The intraindividual range of shear modulus data was 1.01-1.31 kPa (25 Hz) and 1.33-1.77 kPa (50 Hz). The observed modulus dispersion indicates a limited applicability of Voigt's model to explain viscoelastic behavior of brain parenchyma within the applied frequency range. The narrow distribution of data within small confidence intervals demonstrates excellent reproducibility of the experimental protocol. The results are necessary as reference data for future comparisons between healthy and pathological human brain viscoelastic data., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

MR elastography (MRE) enables the noninvasive determination of the viscoelastic behavior of human internal organs based on their response to oscillatory shear stress. An experiment was developed that combines multifrequency shear wave actuation with broad-band motion sensitization to extend the dynamic range of a single MRE examination. With this strategy, multiple wave images corresponding to different driving frequencies are simultaneously received and can be analyzed by evaluating the dispersion of the complex modulus over frequency. The technique was applied on the brain and liver of five healthy volunteers. Its repeatability was tested by four follow-up studies in each volunteer. Five standard rheological models (Maxwell, Voigt, Zener, Jeffreys and fractional Zener model) were assessed for their ability to reproduce the observed dispersion curves. The three-parameter Zener model was found to yield the most consistent results with two shear moduli mu(1) = 0.84 +/- 0.22 (1.36 +/- 0.31) kPa, mu(2) = 2.03 +/- 0.19 (1.86 +/- 0.34) kPa and one shear viscosity of eta = 6.7 +/- 1.3 (5.5 +/- 1.6) Pa s (interindividual mean +/- SD) in brain (liver) experiments. Significant differences between the rheological parameters of brain and liver were found for mu(1) and eta (P < 0.05), indicating that human brain is softer and possesses a higher viscosity than liver.

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. 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. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Highlights from the article: In the Discussion, confusingly, they directly compared their results with both shear modulus measured by magnetic resonance elastography (MRE) ([1], [6]) and Young's modulus measured by intra-operative shear wave elastography ([3]). Consequently, all Young's modulus values reported by Ertl et al. require further validation and should not be interpreted to represent age-matched normal values as suggested by the title of this study. 4 M Ertl N Raasch G Hammel K Harter C Lang Transtemporal investigation of brain parenchyma elasticity using 2-D shear wave elastography: Definition of age-matched normal values Ultrasound Med Biol 44 2018 78 84.

Abstract: Tissue mechanical parameters have been shown to be highly sensitive to disease by elastography. Magnetic resonance elastography (MRE) in the human body relies on the low-dynamic range of tissue mechanics <100Hz. In contrast, MRE suited for investigations of mice or small tissue samples requires vibration frequencies 10–20 times higher than those used in human MRE. The dispersion of the complex shear modulus (G ⁎) prevents direct comparison of elastography data at different frequency bands and, consequently, frequency-independent viscoelastic models that fit to G * over a wide dynamic range have to be employed. This study presents data of G * of samples of agarose gel, liver, brain, and muscle measured by high-resolution MRE in a 7T-animal scanner at 200–800Hz vibration frequency. Material constants μ and α according to the springpot model and related to shear elasticity and slope of the G *-dispersion were determined. Both μ and α of calf brain and bovine liver were found to be similar, while a sample of fibrotic human liver (METAVIR score of 3) displayed about fifteen times higher shear elasticity, similar to μ of bovine muscle measured in muscle fiber direction. α was the highest in fibrotic liver, followed by normal brain and liver, while muscle had the lowest α-values of all biological samples investigated in this study. As expected, the least G *-dispersion was seen in soft gel. The proposed technique of wide-range dynamic MRE can provide baseline data for both human MRE and high-dynamic MRE for better understanding tissue mechanics of different tissue structures. [Copyright &y& Elsevier]