Ultrasonic Sound Speed Estimation for Liver Fat Quantification: A Review by the AIUM-RSNA QIBA Pulse-Echo Quantitative Ultrasound Initiative.

Non-alcoholic fatty liver disease (NAFLD) is a significant cause of diffuse liver disease, morbidity and mortality worldwide. Early and accurate diagnosis of NALFD is critical to identify patients at risk of disease progression. Liver biopsy is the current gold standard for diagnosis and prognosis. However, a non-invasive diagnostic tool is desired because of the high cost and risk of complications of tissue sampling. Medical ultrasound is a safe, inexpensive and widely available imaging tool for diagnosing NAFLD. Emerging sonographic tools to quantitatively estimate hepatic fat fraction, such as tissue sound speed estimation, are likely to improve diagnostic accuracy, precision and reproducibility compared with existing qualitative and semi-quantitative techniques. Various pulse-echo ultrasound speed of sound estimation methodologies have been investigated, and some have been recently commercialized. We review state-of-the-art in vivo speed of sound estimation techniques, including their advantages, limitations, technical sources of variability, biological confounders and existing commercial implementations. We report the expected range of hepatic speed of sound as a function of liver steatosis and fibrosis that may be encountered in clinical practice. Ongoing efforts seek to quantify sound speed measurement accuracy and precision to inform threshold development around meaningful differences in fat fraction and between sequential measurements.

Reverberant magnetic resonance elastographic imaging using a single mechanical driver.

Reverberant elastography provides fast and robust estimates of shear modulus; however, its reliance on multiple mechanical drivers hampers clinical utility. In this work, we hypothesize that for constrained organs such as the brain, reverberant elastography can produce accurate magnetic resonance elastograms with a single mechanical driver. To corroborate this hypothesis, we performed studies on healthy volunteers (n= 3); and a constrained calibrated brain phantom containing spherical inclusions with diameters ranging from 4-18 mm. In both studies (i.e. phantom and clinical), imaging was performed at frequencies of 50 and 70 Hz. We used the accuracy and contrast-to-noise ratio performance metrics to evaluate reverberant elastograms relative to those computed using the established subzone inversion method. Errors incurred in reverberant elastograms varied from 1.3% to 16.6% when imaging at 50 Hz and 3.1% and 16.8% when imaging at 70 Hz. In contrast, errors incurred in subzone elastograms ranged from 1.9% to 13% at 50 Hz and 3.6% to 14.9% at 70 Hz. The contrast-to-noise ratio of reverberant elastograms ranged from 63.1 to 73 dB compared to 65 to 66.2 dB for subzone elastograms. The average global brain shear modulus estimated from reverberant and subzone elastograms was 2.36 ± 0.07 kPa and 2.38 ± 0.11 kPa, respectively, when imaging at 50 Hz and 2.70 ± 0.20 kPa and 2.89 ± 0.60 kPa respectively, when imaging at 70 Hz. The results of this investigation demonstrate that reverberant elastography can produce accurate, high-quality elastograms of the brain with a single mechanical driver.

Pulse-Echo Quantitative US Biomarkers for Liver Steatosis: Toward Technical Standardization.

Excessive liver fat (steatosis) is now the most common cause of chronic liver disease worldwide and is an independent risk factor for cirrhosis and associated complications. Accurate and clinically useful diagnosis, risk stratification, prognostication, and therapy monitoring require accurate and reliable biomarker measurement at acceptable cost. This article describes a joint effort by the American Institute of Ultrasound in Medicine (AIUM) and the RSNA Quantitative Imaging Biomarkers Alliance (QIBA) to develop standards for clinical and technical validation of quantitative biomarkers for liver steatosis. The AIUM Liver Fat Quantification Task Force provides clinical guidance, while the RSNA QIBA Pulse-Echo Quantitative Ultrasound Biomarker Committee develops methods to measure biomarkers and reduce biomarker variability. In this article, the authors present the clinical need for quantitative imaging biomarkers of liver steatosis, review the current state of various imaging modalities, and describe the technical state of the art for three key liver steatosis pulse-echo quantitative US biomarkers: attenuation coefficient, backscatter coefficient, and speed of sound. Lastly, a perspective on current challenges and recommendations for clinical translation for each biomarker is offered.

Comprehensive experimental assessments of rheological models' performance in elastography of soft tissues.

Elastography researchers have utilized several rheological models to characterize soft tissue viscoelasticity over the past thirty years. Due to the frequency-dependent behavior of viscoelastic parameters as well as the different techniques and frequencies employed in various studies of soft tissues, rheological models have value in standardizing disparate techniques via explicit mathematical representations. However, the important question remains: which of the several available models should be considered for widespread adoption within a theoretical framework? We address this by evaluating the performance of three well established rheological models to characterize ex vivo bovine liver tissues: the Kelvin-Voigt (KV) model as a 2-parameter model, and the standard linear solid (SLS) and Kelvin-Voigt fractional derivative (KVFD) models as 3-parameter models. The assessments were based on the analysis of time domain behavior (using stress relaxation tests) and frequency domain behavior (by measuring shear wave speed (SWS) dispersion). SWS was measured over a wide range of frequency from 1 Hz to 1 kHz using three different tests: (i) harmonic shear tests using a rheometer, (ii) reverberant shear wave (RSW) ultrasound elastography scans, and (iii) RSW optical coherence elastography scans, with each test targeting a distinct frequency range. Our results demonstrated that the KVFD model produces the only mutually consistent rendering of time and frequency domain data for liver. Furthermore, it reduces to a 2-parameter model for liver (correspondingly to a 2-parameter "spring-pot" or power-law model for SWS dispersion) and provides the most accurate predictions of the material viscoelastic behavior in time (>98% accuracy) and frequency (>96% accuracy) domains. STATEMENT OF SIGNIFICANCE: Rheological models are applied in quantifying tissues viscoelastic properties. This study is unique in presenting comprehensive assessments of rheological models.

A Preliminary Study of Liver Fat Quantification Using Reported Ultrasound Speed of Sound and Attenuation Parameters.

The quantification of liver fat as a diagnostic assessment of steatosis remains an important priority for non-invasive imaging systems. We derive a framework in which the unknown fat volume percentage can be estimated from a pair of ultrasound measurements. The precise estimation of ultrasound speed of sound and attenuation within the liver is found to be sufficient for estimating fat volume assuming a classic model of the properties of a composite elastic material. In this model, steatosis is represented as a random dispersion of spherical fat vacuoles with acoustic properties similar to those of edible oils. Using values of speed of sound and attenuation from the literature in which normal and steatotic livers were studied near 3.5 MHz, we describe agreement of the new estimation method with independent measures of fat. This framework holds the potential for translation to clinical scanners with which the two ultrasound measurements can be made and used for improved quantitative assessment of steatosis.

Plantar Soft Tissue Characterization Using Reverberant Shear Wave Elastography: A Proof-of-Concept Study.

Plantar soft tissue stiffness provides relevant information on biomechanical characteristics of the foot. Therefore, appropriate monitoring of foot elasticity could be useful for diagnosis, treatment or health care of people with complex pathologies such as a diabetic foot. In this work, the reliability of reverberant shear wave elastography (RSWE) applied to plantar soft tissue was investigated. Shear wave speed (SWS) measurements were estimated at the plantar soft tissue at the first metatarsal head, the third metatarsal head and the heel from both feet in five healthy volunteers. Experiments were repeated for a test-retest analysis with and without the use of gel pad using a mechanical excitation frequency range between 400 and 600 Hz. Statistical analysis was performed to evaluate the reliability of the SWS estimations. In addition, the results were compared against those obtained with a commercially available shear wave-based elastography technique, supersonic imaging (SSI). The results indicate a low coefficient of variation for test-retest experiments with gel pad (median: 5.59%) and without gel pad (median: 5.83%). Additionally, the values of the SWS measurements increase at higher frequencies (median values: 2.11 m/s at 400 Hz, 2.16 m/s at 450 Hz, 2.24 m/s at 500 Hz, 2.21 m/s at 550 Hz and 2.31 m/s at 600 Hz), consistent with previous reports at lower frequencies. The SWSs at the plantar soft tissue at the first metatarsal head, third metatarsal head and heel were found be significantly (p<0.05) different, with median values of 2.42, 2.16 and 2.03 m/s, respectively which indicates the ability of the method to differentiate between shear wave speeds at different anatomical locations. The results indicated better elastographic signal-to-noise ratios with RSWE compared to SSI because of the artifacts presented in the SWS generation. These preliminary results indicate that the RSWE approach can be used to estimate the plantar soft tissue elasticity, which may have great potential to better evaluate changes in biomechanical characteristics of the foot.

Practical settings for shear wave speed estimation using the framework of Reverberant Shear Wave Elastography: A numerical simulation study.

Reverberant shear wave elastography (RSWE) has become a promising approach to quantifying soft tissues' viscoelastic properties by the propagating shear wave speed (SWS) estimation based on the particle velocity autocorrelation. In this work, three different practical settings were evaluated for the SWS estimation by numerical simulations of an isotropic, homogenous, and elastic medium: first, the 2D representation of the particle velocity, second, the spatial autocorrelation computation, and third, the selection of the curve fitting domain. We conclude that the 2D autocorrelation function using the Wiener-Khinchin theorem provides up to 127 times faster results than traditional autocorrelation methods. Additionally, we state that extracting the magnitude and phase from the Fourier transform of the temporal domain, applying the 2D-autocorrelation on a mobile square window sized at least two wavelengths, and fitting the monotonically decreasing part of the autocorrelation profile's central lobe results in more accurate (13.2% of bias) and precise (5.3% of CV) estimations than other practical settings.Clinical relevance- Affections in soft tissues' biomechanical properties are related to pathologies, such as tumor cancer, muscular degenerative diseases, or fibrosis. These changes are quantified by the SWS and its derived viscoelastic parameters. RSWE is a promising approach for their characterization. In this work, we evaluated alternative elections of practical settings within the methodology. Numerical simulations indicate they lead to faster and more reliable local SWS estimations than conventional settings.

Comprehensive Viscoelastic Characterization of Tissues and the Inter-relationship of Shear Wave (Group and Phase) Velocity, Attenuation and Dispersion.

We report shear wave phase and group velocity, dispersion and attenuation in oil-in-gelatin viscoelastic phantoms and in vivo liver data. Moreover, we measured the power law coefficient from each dispersion curve and used it, together with the shear wave velocity, to calculate an approximate value for attenuation that agrees with independent attenuation measurements. Results in phantoms exhibit good agreement for all parameters with respect to independent mechanical measurements. For in vivo data, the livers of 20 patients were scanned. Results were compared with pathology scores obtained from liver biopsies. Across these cases, increases in shear wave dispersion and attenuation were related to increased steatosis score. It was found that shear wave dispersion and attenuation are experimentally linked, consistent with simple predictions based on the rheology of tissues, and can be used individually or jointly to assess tissue viscosity. Thus, this study indicates the possible utility of using shear wave dispersion and attenuation to non-invasively and quantitatively assess steatosis.

Validations of the microchannel flow model for characterizing vascularized tissues.

The microchannel flow model postulates that stress-strain behavior in soft tissues is influenced by the time constants of fluid-filled vessels related to Poiseuille's law. A consequence of this framework is that changes in fluid viscosity and changes in vessel diameter (through vasoconstriction) have a measurable effect on tissue stiffness. These influences are examined through the theory of the microchannel flow model. Then, the effects of viscosity and vasoconstriction are demonstrated in gelatin phantoms and in perfused tissues, respectively. We find good agreement between theory and experiments using both a simple model made from gelatin and from living, perfused, placental tissue ex vivo.

An initial study of complete 2D shear wave dispersion images using a reverberant shear wave field.

Within the field of elastography, a relatively new approach analyzes the limiting case of shear waves established as a reverberant field. In this framework, it is assumed that a distribution of shear waves exists, oriented across all directions in 3D and continuous in time. The simultaneous multi-frequency application of reverberant shear wave fields can be accomplished by applying an array of external sources that can be excited by multiple frequencies within a bandwidth, for example 50, 100, 150, …, 500 Hz, all contributing to the shear wave field produced in the liver or other target organ. This enables the analysis of the dispersion of shear wave speed as it increases with frequency, indicating the viscoelastic and lossy nature of the tissue under study. Furthermore, dispersion images can be created and displayed alongside the shear wave speed images. We report preliminary studies on breast and liver tissues using the multi-frequency reverberant shear wave technique, employing frequencies up to 700 Hz in breast tissue, and robust reverberant patterns of shear waves across the entire liver and kidney in obese patients. Dispersion images are shown to have contrast between tissue types and with quantitative values that align with previous studies.

Attenuation of Shear Waves in Normal and Steatotic Livers.

Shear wave propagation in the liver has been a robust subject of research, with shear wave speed receiving the most attention. The correlation between increased shear wave speed and increased fibrosis in the liver has been established as a useful diagnostic tool. In comparison, the precise mechanisms of shear wave attenuation, and its relation to diseased states of the liver, are less well-established. This study focused on the hypothesis that steatosis adds a viscous (lossy) component to the liver, which increases shear wave attenuation. Twenty patients' livers were scanned with ultrasound and with induced shear wave propagation, and the resulting displacement profiles were analyzed using recently developed estimators to derive both the speed and attenuation of the shear waves within 6-cm2 regions of interest. The results were compared with pathology scores obtained from liver biopsies taken under ultrasound guidance. Across these cases, increases in shear wave attenuation were linked to increased steatosis score. This preliminary study supports the hypothesis and indicates the possible utility of the measurements for non-invasive and quantitative assessment of steatosis.

Group versus Phase Velocity of Shear Waves in Soft Tissues.

Across the varieties of waves that have been studied in physics, it is well established that group velocities can be significantly greater than or less than phase velocities measured within comparable frequency bands, depending on the particular mechanisms involved. The distinction between group and phase velocities is important in elastography, because diagnoses are made based on shear wave speed estimations from a variety of techniques. We review the general definitions of group and phase velocity and examine their specific relations within an important general class of rheological models. For the class of tissues and materials exhibiting power law dispersion, group velocity is significantly greater than phase velocity, and simple expressions are shown to interrelate the commonly measured parameters. Examples are given from phantoms and tissues.

Analysis of Transient Shear Wave in Lossy Media.

The propagation of shear waves from impulsive forces is an important topic in elastography. Observations of shear wave propagation can be obtained with numerous clinical imaging systems. Parameter estimations of the shear wave speed in tissues, and more generally the viscoelastic parameters of tissues, are based on some underlying models of shear wave propagation. The models typically include specific choices of the spatial and temporal shape of the impulsive force and the elastic or viscoelastic properties of the medium. In this work, we extend the analytical treatment of 2-D shear wave propagation in a biomaterial. The approach applies integral theorems relevant to the solution of the generalized Helmholtz equation, and does not depend on a specific rheological model of the tissue's viscoelastic properties. Estimators of attenuation and shear wave speed are derived from the analytical solutions, and these are applied to an elastic phantom, a viscoelastic phantom and in vivo liver using a clinical ultrasound scanner. In these samples, estimated shear wave group velocities ranged from 1.7 m/s in the liver to 2.5 m/s in the viscoelastic phantom, and these are lower-bounded by independent measurements of phase velocity.

Shear Wave Speed Estimation Using Reverberant Shear Wave Fields: Implementation and Feasibility Studies.

Elastography is a modality that estimates tissue stiffness and, thus, provides useful information for clinical diagnosis. Attention has focused on the measurement of shear wave propagation; however, many methods assume shear wave propagation is unidirectional and aligned with the lateral imaging direction. Any deviations from the assumed propagation result in biased estimates of shear wave speed. To address these challenges, directional filters have been applied to isolate shear waves with different propagation directions. Recently, a new method was proposed for tissue stiffness estimation involving creation of a reverberant shear wave field propagating in all directions within the medium. These reverberant conditions lead to simple solutions, facile implementation and rapid viscoelasticity estimation of local tissue. In this work, this new approach based on reverberant shear waves was evaluated and compared with another well-known elastography technique using two calibrated elastic and viscoelastic phantoms. Additionally, the clinical feasibility of this technique was analyzed by assessing shear wave speed in human liver and breast tissues, in vivo. The results indicate that it is possible to estimate the viscoelastic properties in each scanned medium. Moreover, a better approach to estimation of shear wave speed was obtained when only the phase information was taken from the reverberant waves, which is equivalent to setting all magnitudes within the bandpass equal to unity: an idealization of a perfectly isotropic reverberant shear wave field.

H-scan sensitivity to scattering size.

In the H-scan analysis and display, visualization of different scattering sizes and types is enabled by a matched filter approach involving different orders of Gaussian weighted Hermite functions. An important question with respect to clinical applications involves the change in H-scan outputs with respect to small changes in scatterer sizes. The sensitivity of H-scan outputs is analyzed using the theory of backscatter from a compressible sphere. Experimental corroboration is established using mono dispersed spherical scatterers in phantoms. With a 6-MHz center frequency broadband transducer, it is possible to visualize changes in scattering size in the order of 10 to [Formula: see text] in phantoms and also changes in ex vivo bovine liver tissue due to edema caused by hypotonic perfusion.

Reverberant shear wave fields and estimation of tissue properties.

The determination of shear wave speed is an important subject in the field of elastography, since elevated shear wave speeds can be directly linked to increased stiffness of tissues. MRI and ultrasound scanners are frequently used to detect shear waves and a variety of estimators are applied to calculate the underlying shear wave speed. The estimators can be relatively simple if plane wave behavior is assumed with a known direction of propagation. However, multiple reflections from organ boundaries and internal inhomogeneities and mode conversions can create a complicated field in time and space. Thus, we explore the mathematics of multiple component shear wave fields and derive the basic properties, from which efficient estimators can be obtained. We approach this problem from the historic perspective of reverberant fields, a conceptual framework used in architectural acoustics and related fields. The framework can be recast for the alternative case of shear waves in a bounded elastic media, and the expected value of displacement patterns in shear reverberant fields are derived, along with some practical estimators of shear wave speed. These are applied to finite element models and phantoms to illustrate the characteristics of reverberant fields and provide preliminary confirmation of the overall framework.

Shear Wave Speed Measurements Using Crawling Wave Sonoelastography and Single Tracking Location Shear Wave Elasticity Imaging for Tissue Characterization.

Elastography provides tissue stiffness information that attempts to characterize the elastic properties of tissue. However, there is still limited literature comparing elastographic modalities for tissue characterization. This study focuses on two quantitative techniques using different vibration sources that have not been compared to date: crawling wave sonoelastography (CWS) and single tracking location shear wave elasticity imaging (STL-SWEI). To understand each technique's performance, shear wave speed (SWS) was measured in homogeneous phantoms and ex vivo beef liver tissue. Then, the contrast, contrast-to-noise ratio (CNR), and lateral resolution were measured in an inclusion and two-layer phantoms. The SWS values obtained with both modalities were validated with mechanical measurements (MM) which serve as ground truth. The SWS results for the three different homogeneous phantoms (10%, 13%, and 16% gelatin concentrations) and ex vivo beef liver tissue showed good agreement between CWS, STL-SWEI, and MM as a function of frequency. For all gelatin phantoms, the maximum accuracy errors were 2.52% and 2.35% using CWS and STL-SWEI, respectively. For the ex vivo beef liver, the maximum accuracy errors were 9.40% and 7.93% using CWS and STL-SWEI, respectively. For lateral resolution, contrast, and CNR, both techniques obtained comparable measurements for vibration frequencies less than 300 Hz (CWS) and distances between the push beams ( ∆x ) between 3 mm and 5.31 mm (STL-SWEI). The results obtained in this study agree over an SWS range of 1-6 m/s. They are expected to agree in perfectly linear, homogeneous, and isotropic materials, but the SWS overlap is not guaranteed in all materials because each of the three methods have unique features.

Shear Wave Elastography in the Living, Perfused, Post-Delivery Placenta.

The placenta is the critical interface between the mother and the developing fetus and is essential for survival and growth. Despite the widespread use of ultrasound imaging and Doppler in obstetrics and gynecology and the recent growth of elastographic technologies, little is known about the biomechanical (elastic shear wave) properties of the placenta and the range of normal and pathologic parameters that are present. This study uses a well-developed protocol for perfusing whole placentas, post-delivery, to maintain tissue integrity and function for hours. In this model, the placenta is living, whole and maintained within normal physiologic parameters such as flow, arterial pressure and oxygen, throughout examination by ultrasound, Doppler and shear wave elastography. The preliminary results indicate that normal placental tissue on the fetal side has shear wave speeds on the order of 2 m/s, in a range similar to those of animal livers. Some abnormalities are found outside this range, and thus, elastographic measures of the placenta may provide useful assessments related to the state of the tissue.

Crawling Waves Speed Estimation Based on the Dominant Component Analysis Paradigm.

A novel method for estimating the shear wave speed from crawling waves based on the amplitude modulation-frequency modulation model is proposed. Our method consists of a two-step approach for estimating the stiffness parameter at the central region of the material of interest. First, narrowband signals are isolated in the time dimension to recover the locally strongest component and to reject distortions from the ultrasound data. Then, the shear wave speed is computed by the dominant component analysis approach and its spatial instantaneous frequency is estimated by the discrete quasi-eigenfunction approximations method. Experimental results on phantoms with different compositions and operating frequencies show coherent speed estimations and accurate inclusion locations.

Effects of data acquisition parameters on the quality of sonoelastographic imaging.

Sonoelastography is an ultrasonic technique that provides qualitative and quantitative images of tissue elasticity. Even though the Kasai variance estimator is a key part of the sonoelastographic image formation, there are no studies that demonstrate that its performance using discrete time signals and finite sized ensemble lengths is optimal. In this work, the influence of the selection of acquisition parameters (pulse repetition frequency or PRF, vibration frequency, and ensemble length) on the quality of the elastograms is studied. Simulations are carried out to define the optimal PRF and ensemble length given a vibration frequency in order to avoid artifacts which can severely degrade image quality. This empirical criterion is supported by sonoelastography experiments performed using two commercial scanners, where the variability increased from 4% to 42% at the worst selection of acquisition parameters. Although a further mathematical proof of the empirical findings is required, these results suggest that careful selection of PRF, vibration frequency and ensemble lengths is required to ensure unbiased sonoelastograms.