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Stroke is commonly caused by thromboembolic events originating from atherosclerotic plaques in the carotid vasculature. To improve stroke risk prediction by delineating vulnerable plaque features, our group has developed ARFI Variance of Acceleration log(VoA) imaging. We herein evaluate the ability of trained, blinded readers to interpret in vivo ARFI log(VoA) images of human carotid plaques, with validation by matched histology. Patients undergoing carotid endarterectomy were imaged using a Siemens S3000 and a 9L4 transducer. From 21 plaques, one was excluded due to specimen damage during surgery. Parametric 2D images of ARFI log(VoA) were rendered and evaluated by 3 neuroradiologists, 1 abdominal radiologist, 1 sonographer, and 1 pathologist, all blinded to the histological gold standard. Receiver operating characteristic (ROC) curve analysis was performed, and area under the curve (AUC) was taken as a metric of performance for detecting lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), collagen (COL), and calcium (CAL). Reader log(VoA) outcomes were compared to those achieved using ARFI peak displacement (PD) in a comparable prior study. Average AUC performance for plaque features were as follows: CAL, 0.77; COL, 0.76; LRNC, 0.79; IPH, 0.82. Grouping the stiff (COL and CAL) and soft (LRNC and IPH) features together increased average AUCs to 0.86 for stiff and 0.87 for soft. These log(VoA) AUC outcomes were higher than those achieved by blinded readers evaluating ARFI PD images. This study shows the relevance of ARFI log(VoA) imaging, as interpreted by trained, blinded readers, to delineating the structure and composition of carotid atherosclerotic plaque in humans, in vivo.

Rupture potential of atherosclerotic plaques in carotid arteries is conferred by both composition and structure of plaques. Previous studies have shown that from in vivo collected data, carotid plaque components such as collagen, calcium, necrotic core and intraplaque hemorrhage can be automatically detected by an ARFI imaging-derived machine learning classifier. Automatic classification considered normalized cross-correlation measurements of ARFI-induced displacement, signal-to-noise ratio and cross-correlation coefficients from an on-axis ARFI acquisition. We now extend our prior work by hypothesizing that using multiple ARFI data forms improves plaque feature detection and FC thickness measurement in human carotid plaques, relative to a single form of ARFI data. Carotid plaques were imaged in vivo prior to surgery in 20 patients undergoing carotid endarterectomy (CEA), and extracted plaque specimens were harvested after CEA for histological processing. ARFI data were acquired with cardiac gating to diastole with push (DP) and to systole without push (SNP) using fundamental low (FL), fundamental high (FH), and harmonic (H) tracking frequencies. Combinations of the resulting displacement profiles were used as inputs to the SVM classifier. The classifier was evaluated by 5-fold cross-validation, with the histological samples acting as gold standards. From the output SVM likelihood matrices, ROC curves were calculated for separating collagen from calcium and lipid-rich necrotic core from intraplaque hemorrhage. For all examined plaques, DP+FH+H achieved the highest average AUC of 0.926 (Sensitivity = 0.932, Specificity = 0.915) but required 2 acquisitions. The best data combination requiring only one acquisition (DP+FH) achieved an AUC of 0.917 (Sensitivity = 0.902, Specificity = 0.880). These results suggest that using multiple forms of frequency and gating of ARFI data as inputs to an automatic classifier improves discrimination of carotid plaque components, relevant for rupture vulnerability assessment.

The kidney is an anisotropic organ, with higher elasticity along versus across nephrons. The degree of mechanical anisotropy in the kidney may be diagnostically relevant if properly exploited; however, if improperly controlled, anisotropy may confound stiffness measurements. The purpose of this study is to demonstrate the clinical feasibility of acoustic radiation force (ARF)-induced peak displacement (PD) measures for both exploiting and obviating mechanical anisotropy in the cortex of human kidney allografts, in vivo . Validation of the imaging methods is provided by preclinical studies in pig kidneys, in which ARF-induced PD values were significantly higher ( $p , Wilcoxon) when the transducer executing asymmetric ARF was oriented across versus along the nephrons. The ratio of these PD values obtained with the transducer oriented across versus along the nephrons strongly linearly correlated ( $R^{2} = 0.95$ ) to the ratio of shear moduli measured by shear wave elasticity imaging. On the contrary, when a symmetric ARF was implemented, no significant difference in PD was observed ( $p > 0.01$ ). Similar results were demonstrated in vivo in the kidney allografts of 14 patients. The symmetric ARF produced PD measures with no significant difference ( $p > 0.01$ ) between along versus across alignments, but the asymmetric ARF yielded PD ratios that remained constant over a six-month observation period post-transplantation, consistent with stable serum creatinine level and urine protein-to-creatinine ratio in the same patient population ( $p> 0.01$ ). The results of this pilot in vivo clinical study suggest the feasibility of 1) implementing symmetrical ARF to obviate mechanical anisotropy in the kidney cortex when anisotropy is a confounding factor and 2) implementing asymmetric ARF to exploit mechanical anisotropy when mechanical anisotropy is a potentially relevant biomarker.

While in vivo acoustic radiation force impulse (ARFI)-induced peak displacement (PD) has been demonstrated to have high sensitivity and specificity for differentiating soft from stiff plaque components in patients with carotid plaque, the parameter exhibits poorer performance for distinguishing between plaque features with similar stiffness. To improve discrimination of carotid plaque features relative to PD, we hypothesize that signal correlation and signal-to-noise ratio (SNR) can be combined, outright or via displacement variance. Plaque feature detection by displacement variance, evaluated as the decadic logarithm of the variance of acceleration and termed “log(VoA),” was compared to that achieved by exploiting SNR, cross correlation coefficient, and ARFI-induced PD outcome metrics. Parametric images were rendered for 25 patients undergoing carotid endarterectomy, with spatially matched histology confirming plaque composition and structure. On average, across all plaques, log(VoA) was the only outcome metric with values that statistically differed between regions of lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), collagen (COL), and calcium (CAL). Further, log(VoA) achieved the highest contrast-to-noise ratio (CNR) for discriminating between LRNC and IPH, COL and CAL, and grouped soft (LRNC and IPH) and stiff (COL and CAL) plaque components. More specifically, relative to the previously demonstrated ARFI PD parameter, log(VoA) achieved 73% higher CNR between LRNC and IPH and 59% higher CNR between COL and CAL. These results suggest that log(VoA) enhances the differentiation of LRNC, IPH, COL, and CAL in human carotid plaques, in vivo , which is clinically relevant to improving stroke risk prediction and medical management.

Our group has previously found that in silico, mechanical anisotropy may be interrogated by exciting transversely isotropic materials with geometrically asymmetric acoustic radiation force excitations and then monitoring the associated induced displacements in the region of excitation. We now translate acoustic radiation force-based anisotropy assessment to human muscle in vivo and investigate its clinical relevance to monitoring muscle degeneration in Duchenne muscular dystrophy (DMD). Clinical anisotropy assessments were performed using Viscoelastic Response ultrasound, with a degree of anisotropy reflected by the ratios of Viscoelastic Response relative elasticity (RE) or relative viscosity (RV) measured with the asymmetric radiation force oriented parallel versus perpendicular to muscle fiber alignment. In vivo results from rectus femoris and gastrocnemius muscles of boys aged ∼7.9–10.4 y indicate that RE and RV anisotropy ratios in rectus femoris muscles of boys with DMD were significantly higher than those of healthy control boys (RE: DMD = 1.51 ± 0.87, control = 0.99 ± 0.69, p = 0.04, Wilcoxon rank sum test; RV: DMD = 1.04 ± 0.71, control = 0.74 ± 0.22, p = 0.02). In the gastrocnemius muscle, only the RV anisotropy ratio was significantly higher in dystrophic than control patients (DMD = 1.23 ± 0.35, control = 0.88 ± 0.31, p = 0.04). In the dystrophic rectus femoris muscle, the RE anisotropy ratio was inversely correlated (slope = –0.03/lbf, r = –0.43, p = 0.07, Pearson correlation) with quantitative muscle testing functional output measures but was not correlated with quantitative muscle testing in the dystrophic gastrocnemius. These results suggest that Viscoelastic Response RE and RV measures reflect differences in mechanical anisotropy associated with functional impairment with dystrophic degeneration that are relevant to monitoring DMD clinically.

Acoustic Radiation Force Impulse (ARFI) imaging employs sound impulses to induce and track tissue motion that conveys mechanical property. In application to carotid atherosclerotic plaque, ARFI noninvasively delineates features that convey risk for ischemic stroke: intraplaque hemorrhage, lipid-rich necrotic core, thin or ruptured fibrous cap, diffuse collagen, and calcium deposits. This talk will feature recent advances to in vivo ARFI atherosclerosis imaging technology, including the use of machine learning for automated feature classification, which are validated histologically in patients undergoing carotid endarterectomy. New developments, including incorporating vector blood flow estimation for combined shear strain assessment, will be highlighted.

Many biological tissues, including muscle or kidney, are mechanically anisotropic, and the degree of anisotropy (DoA) in mechanical properties is diagnostically relevant. DoA can be assessed either using the ratio of shear wave velocities (SWVs) or acoustic radio forced impulse (ARFI)-induced peak displacements (PD) measured longitudinal over transverse orientations. Whether using SWV or PD as a basis, DoA expressed as the ratio of values requires 90° transducer rotation when a linear array is employed. This large rotation angle is prone to misalignment errors. One solution is the use of a fully sampled matrix array for electronic rotation of point spread function (PSF). However, the challenges of matrix array are its high fabrication cost and complicated fabrication procedures. The cheaper and simpler alternative of matrix array is the use of a row–column array. A $3\times64$ elements 1.5-D array with a row–column excitation mode is proposed to assess DoA in mechanical properties using the PD ratio. Different numbers of elements in elevational and lateral directions were selected to have orthogonal ARFI excitation beams without rotating the transducer. A custom-designed flex circuit was used to fabricate the array with a simpler electrode connection than a fully sampled matrix array. The performance of the array was evaluated in Field II simulation and experiment. The output pressure was 0.57-MPa output under a 40- ${V}_{\text {pp}}$ excitation with a −6-dB point spread dimension of $14\times4$ mm2 in orthogonal directions. The PD was measured to be $1.4~\mu \text{m}$ in an isotropic elastic phantom with Young’s modulus of 5.4 kPa. These results suggest that the array is capable of assessing DoA using PD ratio without physical rotation of the transducer. The array has the potential to reduce the misalignment errors for DoA assessment.

Many tissues, such as muscle, kidney, and breast, are mechanically anisotropic. Appropriately exploited, mechanical anisotropy can be a clinically relevant target for noninvasive imaging. An imaging method's potential for interrogating mechanical anisotropy can be experimentally evaluated using tissue-mimicking materials, also known as phantoms. The objective of this work is to demonstrate the feasibility of constructing mechanically anisotropic phantoms using 3D-printed polylactic acid (PLA) fibers embedded in gelatin hydrogel or polyvinyl alcohol (PVA) cryogel. Four identical fiber sets were printed; two were embedded in gelatin and two in PVA. Acoustic Radiation Force Impulse (ARFI) imaging was performed on the constructed phantoms, with data acquisitions at 0°, 30°, 60°, and 90° concentric orientations, where 0° and 90° corresponded to the long-axis of the spatially asymmetric ARF excitation being aligned across and along the fibers, respectively. Degree of anisotropy (DoA) was calculated as the ratio of peak displacements achieved at 90° versus 0° orientations. While both gelatin and PVA embedded fibers demonstrated elastic anisotropy, DoA values were 32% higher in gelatin. These pilot experimental results demonstrate that phantoms constructed of 3D-printed PLA fibers embedded in gelatin or PVA exhibit mechanical anisotropy as assessed by ARFI ultrasound.

Viscoelastic Response (VisR) ultrasound is a noninvasive method for interrogating the viscoelastic properties of tissue by observing, in the region of excitation, tissue displacement in response to successive acoustic radiation force impulses. Recent VisR technology advancements now enable estimation of mechanical anisotropy and texture as well as, via machine learning approaches, quantitative evaluation of elastic and viscous moduli (as in Quantitative VisR (QVisR)). The diagnostic relevance of VisR outcome measures have been demonstrated for monitoring renal transplant status, differentiating malignant from benign breast masses, and delineating dystrophic muscle degeneration. For the latter two applications, method and pilot clinical results are reviewed herein. VisR-derived relative elasticity (RE) and relative viscosity (RV) mechanical anisotropy measures differentiated malignant from benign breast masses in women with sensitivities of 0.94 and specificities of 1.00, with accuracies of 0.96. In dystrophic muscle, QVisR-derived longitudinal shear elastic modulus in rectus femoris, vastus lateralus, sartorius, and gastrocnemius muscles statistically different between dystrophic and control for ages less than six years (Wilcoxon, p

Double-profile intersection (DoPIo) ultrasound is a new acoustic radiation force (ARF) imaging technique that exploits scatterer shearing under two different tracking point spread functions to estimate shear elastic moduli. Previous versions of DoPIo used an empirically derived model to relate the time where two displacement profiles, each measuring displacement in identical positions using different aperture sizes. We herein propose an alternative, machine learning-based approach that obviates the need for an empirically-derived model by replacing it with a support vector machine that uses paired displacement profiles in their entirety. In this work, we describe the implementation of such a model, validate its ability in shear modulus for simulated materials, and deploy it to image a calibrated phantom.

We present a quantitative extension of Viscoelastic Response (VisR) ultrasound that estimates shear elastic and viscous moduli from on-axis VisR displacement profiles in silico. Isotropic, homogeneous, linearly viscoelastic materials ranging from 1.57-33.33 kPa shear elasticity and 0.0033-2.34 Pa.s shear viscosity subject to a VisR beamsequence at 26 focal depths were simulated. Multi-target regression machine learning models were used to estimate shear elasticity and shear viscosity given the displacement profile, focal depth, and axial depth. The best performing models achieve a shear elasticity RMSE of 0.29 kPa and a shear viscosity RMSE of 0.13 Pa.s when predictions were made on the test set. These results suggest that machine learning methods can be used to quantitatively estimate viscoelasticity from VisR displacement profiles.

Differentiating malignant from benign breast lesions remains a challenge that may be met by a new imaging biomarker: lesion-to-background mechanical anisotropy assessed by VisR ultrasound. VisR is an ultrasound imaging method that uses 2 consecutive acoustic radiation force excitations, separated in time and delivered to the same region of excitation, to directionally interrogate peak displacement (PD), relative elasticity (RE), and relative viscosity (RV). From these directional measurements, mechanical degree of anisotropy is measured. In a pilot clinical study involving 29 women with BIRADS-4 or −5 breast masses, VisR PD, RE, and RV were measured in lesions and in surrounding tissue at 0°, 30°, 60°, and 90° concentric orientations. From these measurements, lesion DoA (LDoA), surrounding tissue DoA (SDoA), and log(LDoA/SDoA) were assessed per parameter and compared between biopsy-confirmed malignant versus benign masses. Across all patients, PD-, RE-, and RV-based LDoA or SDoA alone did not achieve statistical difference between malignant and benign masses (Wilcoxon, $\mathrm{p} > 0.05$ ). However, PD-, RE-, and RV-based log(LDoA/SDoA) statistically differentiated malignant from benign masses (Wilcoxon, $\mathrm{p} ), with AUC values of 0.96 for PD-based, and 0.94 for RE- and RV-based outcomes. These results demonstrate the relevance of lesion-to-background mechanical anisotropy assessed by VisR ultrasound for differentiating malignant from benign breast masses in women, in vivo.

Stroke is often caused by carotid plaque rupture, with rupture potential indicated by plaque structure and composition. Delineating carotid plaque components that confer rupture risk is vital to stoke prevention. We have previously shown that ARFI Log Variance of Acceleration, log(VoA), discriminates intraplaque hemorrhage (IPH) from lipid-rich necrotic core (LRNC) and collagen (COL) from calcium (CAL) in vivo in humans, while ARFI peak displacement does not. We hypothesize that log(VoA) performance will be further improved by harmonic tracking of ARF-induced displacement. In a pilot clinical study of six carotid plaques imaged in vivo in patients undergoing carotid endarterectomy (CEA), plaque component contrast-to-noise ratio (CNR) achieved by harmonic log(VoA) was compared to that achieved by tracking at fundamental low (4.0 MHz, FL) and high (8.89 MHz, FH) frequencies with validation by spatially-matched histology derived from the extracted plaque specimens. Over all examined plaques, harmonic and both fundamental low and high log(VoA) distributions statistically differentiated plaque components (Wilcoxon, $\mathrm{p} , panel iv). Harmonic log(VoA) achieved the highest CNR between COL and LRNC, which is relevant to fibrous cap delineation, but FH tracking yielded the highest CNR between LRNC and IPH and between COL and CAL. These results suggest that combined harmonic and FH tracking could improve ARFI log(VoA) characterization of carotid plaque components that are correlated to rupture.

Direct ultrasonic imaging of arterial and venous thrombi could aid in diagnosis and treatment planning by providing rapid and cost-effective measurements of thrombus volume and elastic modulus. Toward this end, it was demonstrated that open-air magnetomotive ultrasound (MMUS) provides specific contrast to superparamagnetic iron oxide-labeled model thrombi embedded in gelatin-based blood vessel-mimicking flow phantoms. MMUS was performed on model thrombi in the presence of pulsatile flow that mimics cardiac-induced motion found in real vasculature. The MMUS signal and contrast-to-noise ratio (CNR) were measured across a range of physiologically relevant thrombus volumes and elastic moduli. Model thrombus volumes as small as 0.5 ml were shown to be detectable (CNR > 1) over the entire range of elastic moduli tested (3.5–40 kPa). It was also found that MMUS signal and CNR are increased with increasing thrombus volume ( $r = 0.99$ ) and decreasing elastic modulus ( $r = -0.81$ ), while variations in pulsatile flow rate had little effect. These findings demonstrate that MMUS has promise as a direct in vivo thrombosis imaging modality for quantifying thrombus volume and stiffness.

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p 0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics.

Degree of mechanical anisotropy in renal cortex can be assessed by evaluating the ratio of viscoelastic response (VisR) parameters achieved when the long axis of a spatially asymmetric ARF excitation PSF is aligned along versus across nephrons. In this work, intra-observer reproducibility and variability in VisR derived DoA assessment in renal cortex due to donor type, sex, race, and BMI is evaluated in healthy human kidney allografts, in vivo. Transcutaneous, in vivo VisR imaging was performed in 20 kidney allografts 2 months post-transplantation using a Siemens Acuson Antares™ imaging system and a VF7-3 linear array transducer. Ratios of VisR derived relative elasticity (RE), relative viscosity (RV), and peak displacement (PD) obtained with the ARF short-axis aligned along versus across nephrons were calculated. Patients were divided based on their sex (male: N=14 versus female: N=6), race (African American: N = 6 versus Caucasian: N=14), donor type (living: N=14 versus deceased: N =6), and BMI (BMI >30: N= 8 versus BMI 0.05) due to sex, race, donor types, or BMI. The median absolute percent difference in (PD, RE, RV) ratios were (23, 13, 23) due to sex, (5, 3, 3) due to race, (0.35, 14, 13) due to donor type, and 8.6, 6, 12) due to BMI. Ratios of PD, RE, and RV were not statistically different between 1st and 2nd imaging events with mean percent difference in (PD, RE, and RV) ratios of (-0.04, -0.11, and - 0.01). These findings suggest that VisR outcome measures are robust to potentially confounding demographic factors and reproducible by a trained practitioner.

Low blood SNR makes detecting small vessels, measuring slow flow rates, and assessing blood perfusion without contrast administration challenging. A potential approach is to use Variance of Acceleration (VoA) imaging, which has been demonstrated previously in humans in vivo for monitoring subcutaneous bleeding and delineating intraplaque hemorrhage. We hypothesize that, without the addition of contrast agents, VoA can detect slow flow in small vessels for perfusion assessment. Experiments were performed on an ATS 700-D 527 calibrated flow phantom (vessel diameter of 1 mm, flow rates of 0-53 cm/s) and in the surgically exteriorized right kidneys of 3 pigs (2M/1F, mean body weight of 74.4 ± 9.3 kg) at baseline and after inducing ischemia. In the phantom, logVoA increased in the vessel with increasing flow rate, and it remained constant in the background. LogVoA values were higher in the background with versus without the ARF excitation. Similarly, logVoA values were higher in the vessel, particularly for flow rates < 12 cm/s, with versus without ARF excitation. Vessel CNR by logVoA was higher with versus without ARF excitation for flow rates < 12 cm/s, and CNR by logVoA was greater than CNR by power Doppler for all flow rates. Additionally, logVoA was statistically significantly greater at baseline than ischemia in all three in vivo pig kidneys. Finally, logVoA delineates a 1.25 mm-diameter vessel in a pig renal cortex in vivo, while power Doppler does not. These results suggest that logVoA could support contrast-free detection of slow blood flow in small vessels and in vivo perfusion assessment.

Tissue elasticity can be measured by applying an acoustic radiation force (ARF) excitation and tracking mechanical responses like deformation or shear wave propagation via displacement tracking. However, tissue displacements tracked by ultrasound is underestimated due to the shearing of scatterers under the tracking point-spread function. While such displacement underestimation is a source of error in conventional elasticity approaches, we herein present an alternative method that exploits displacement underestimation: double-profile intersection (DoPIo) elastography. We hypothesize that DoPIo can quantify material elasticity in silico.

Mechanical property changes associated with inflammation, necrosis, fibrosis, and fatty deposition in dystrophic muscle may be quantitatively evaluated by Quantitative Viscoelastic Response (QVisR) ultrasound. QVisR uses a machine learning (ML) framework that takes as input tissue displacement in response to two consecutive and co-located acoustic radiation force (ARF) excitations and yields as output estimates of shear elastic and shear viscous moduli. QVisR imaging was performed in the vastus lateralis (VL) muscles of 11 boys with Duchenne muscular dystrophy (DMD) aged 5 to 12 years and of 8 age-matched boys with no known neuromuscular disorders, who served as controls. QVisR measures of elastic moduli differed between DMD and control VL in boys aged less than six years and six-to-seven years. Similarly, QVisR measures of viscous moduli differed between DMD and control VL in boys aged six-to-seven years. These results demonstrate that QVisR measures of elastic and viscous moduli differentiate dystrophic from control muscle. The findings suggest that QVisR may be relevant to monitoring dystrophic muscle degeneration and response to intervention, particularly in early stages when interventions are most likely to be impactful.

Chronic kidney disease is associated with progressive inflammation and fibrosis, which is conventionally assessed by invasive biopsy. A noninvasive alternative to biopsy may be interrogating elastic and viscous anisotropy. This work evaluates the feasibility of using in vivo Viscoelastic Response (VisR) ultrasound for detecting changes in the elastic and viscous degree of anisotropy (DoA) associated with fibrosis after chronic ischemia-reperfusion injury (IRI) in pig kidney. Histology was used to validate VisR DoA measurements, which were compared to those derived using Shear Wave Elasticity Imaging (SWEI) and Shearwave Dispersion Ultrasound Vibrometry (SDUV). In the injured and contralateral (control) kidneys of 8 pigs, VisR, SWEI, and SDUV-derived elastic DoA, evaluated as the ratio of longitudinal over transverse shear elasticity, was significantly (p

Breast cancer screening is beneficial when it averts progression of disease to metastasis, but adverse effects to patients and unnecessary medical expense may result downstream from false positives. Achieving early breast cancer detection with high sensitivity and specificity remains a challenge that may be met by using acoustic radiation force to assess the mechanical properties of tissue. The objective of this study is to evaluate in vivo the diagnostic relevance of Viscoelastic Response (VisR)-derived metrics for mechanical anisotropy. We compare our in vivo human results against biopsy findings. This study analyzed 9 breast lesions (4 malignant, 5 benign) imaged in vivo in women with BIRADS-4 or -5 ratings after standard screening. VisR relative elasticity (RE), relative viscosity (RV), and peak displacement (PD) were measured for each transducer orientation, and fit to a sinusoid by least-squares minimization, extrapolating to 360°. The fits were phase-aligned, and the point-wise differences in each parameter between lesion and background were integrated over angle. Finally, the ratio of the maximum to the minimum parameter value was calculated to reflect the degree of anisotropy (DoA). DoAs by PD, RE, and RV were statistically significantly greater in background than in lesion for all malignant cases but statistically significantly smaller in background than in lesion for all benign cases (Wilcoxon, p < 0.05). Additionally, differences between lesion and background integrated over angle by RE, RV and PD were statistically significantly different (Wilcoxon, p < 0.05) for malignant and benign lesions across all examined patients. These results suggest that VisR-derived mechanical anisotropy assessment could be diagnostically relevant for discriminating malignant from benign breast lesions.

Quantitative Viscoelastic Response (QVisR) ultrasound is a new machine learning-based elasticity imaging method in which elastic and viscous moduli are estimated from tissue deformation in response to two consecutive acoustic radiation force (ARF) excitations. The estimated moduli are rendered into two-dimensional parametric images of elastic and viscous modulus. From QVisR images, the spatial distribution of elastic and viscous properties may be evaluated using established computational texture analysis tools. In this study, computational texture analysis by the omnidirectional gray-level run-length matrix (GLRLM) was applied to QVisR images. The images were obtained in the vastus lateralis (VL) muscles of 11 boys with Duchenne muscular dystrophy, aged 5-12 years, and 8 age-matched boys with no known neuromuscular disorders, who served as controls. GLRLM-derived elastic entropy in QVisR images was statistically higher (Wilcoxin, p

Chronic kidney disease is associated with progressive inflammation, which is conventionally assessed by invasive biopsy. A noninvasive alternative is to interrogate the mechanical property alterations that occur with inflammation. This work evaluates the feasibility of using in vivo Viscoelastic Response (VisR) ultrasound for detecting differences in mechanical degree of anisotropy (DoA) associated with inflammation after ischemia-reperfusion injury (IRI) in pig kidney. VisR measurements were validated by histology, Shear Wave Elasticity Imaging (SWEI), and Shearwave Dispersion Ultrasound Vibrometry (SDUV) derived DoA. In 6 pigs, data were acquired in vivo in the kidney following IRI and in the contralateral kidney, which did not undergo IRI and served as a control. VisR (relative elasticity (RE), relative viscosity (RV), and peak displacement (PD)), SWEI (shear elastic modulus $(\mu))$ , and SDUV (shear elastic $(\mu_{1})$ and viscous $(\mu_{2})$ moduli) outcomes were evaluated alone and as ratios to reflect DoA (longitudinal over transverse). VisR PD and RE, SWEI $\mu$ , and SDUV $\mu_{1}$ demonstrated significantly increased DoA (p $\mu$ in cortex). Notably, while elastic DoA increased in both medulla and cortex, the underlying causes differed (cortex: diminished transverse modulus v. medulla: elevated longitudinal modulus). VisR RV indicated decreased viscous DoA in the medulla after IRI. Spatially matched histology indicated mild inflammation in the injured, but not the control, kidneys. These results suggest that VisR noninvasively detects changes in DoA associated with inflammation induced by IRI in a pig model. VisR may be diagnostically relevant to delineating inflammation in human kidney.

Vulnerable atherosclerotic plaques have high risk for rupture, with rupture potential related to plaque composition and structure. We have previously shown that soft (intraplaque hemorrhage IPH, and lipid rich necrotic core LRNC) are differentiated from stiff (collagen COL, and calcium CAL) plaque elements in human carotid plaques by Acoustic Radiation Force Impulse (ARFI)-derived peak displacement (PD). However, PD had lower performance for differentiating between features with similar stiffness. Here we evaluate an alternative method to improve intraplaque feature delineation by using machine learning methods. From ARFI imaging data, SNR, cross-correlation coefficient, and displacement were used as inputs to random forests (RaF) and support vector machines (SVM) algorithms. The algorithms were trained to identify IPH, LRNC, COL and CAL by 5-fold cross-validation with ground truth identified from histology. From output likelihood matrices, CNR between plaque components were calculated and compared to the corresponding CNR achieved by ARFI PD and VoA. Results showed that both RaF and SVM achieved higher CNRs for distinguishing between features than ARFI outputs alone. These results suggest that, relative to PD, machine learning improves ARFI discrimination of carotid plaque components that are correlated to vulnerability for rupture.

In transversely isotropic (TI) materials, mechanical properties differ along versus across the axis of symmetry (AoS). The degree of these directional differences has been interrogated as the ratio of ARFI peak displacements (PD) acquired when the long axis of the ARFI excitation point spread function (PSF) was aligned along versus across the AoS. When performed using a conventional linear array transducer, such measurements require a 90° transducer rotation, which can be cumbersome and prone to misalignment errors. Rather than 90°, we hypothesize that smaller rotation angles via electronic steering can be used to assess mechanical anisotropy. This hypothesis was tested in silico using finite-element method (FEM) models and Field II simulation. ARFI Imaging was simulated in thirty-four TI elastic materials using a 3×192 (elevational x lateral) elements multi-D array transducer with elevational elements width >> wavelength of ultrasound. The longitudinal versus transverse shear moduli ratios and Young's moduli ratios were varied from 1.0 to 5.0 and from 1.0 to 4.0, respectively. Via electronic steering, ARFI excitation PSF was rotated at 0°and 59°and was asymmetric at focal depth with long over short axis lengths of 2.7. PD ratio (PD 0 /PD 59 ) increased with increasing shear moduli ratio and did not statistically vary with Young's moduli ratio (p>0.05, Wilcoxon ranksum). PD ratio distinguished simulated materials with greater than 25% difference in shear moduli ratio (p < 0.05). These results suggest that elastic anisotropy may be interrogated by PD ratios acquired via electronically rotating PSF instead of manually rotating transducer, which could facilitate data acquisitions and improve the reproducibility of elastic anisotropy assessment.

In Golden Retriever Muscular Dystrophy (GRMD) dogs, a relevant animal model of human Duchenne muscular dystrophy (DMD), skeletal muscles progressively inflame, necrose, and undergo fibrous and fatty deposition. These degenerative changes alter the composition and structure of muscle, which affects the degree of directional variation, or anisotropy, in tissue mechanical properties. Further, such degenerative changes alter the spatial distribution of mechanical property across muscles. In this work we investigate the relevance of mechanical anisotropy and texture, estimated using Viscoelastic Response (VisR) ultrasound, to tracking progressive dystrophic muscle degeneration in GRMD dogs, in vivo. In a year-long study of 20 dogs, degree of shear elastic anisotropy (DoA), was significantly higher in the GRMD semitendinosus (ST) muscle compared to control ST (GRMD: 1.23 +- 0.25, Control 1.13 +- 0.27, p

In this work, we present preliminary characterization results from a 32 x 32 row-column (RC) addressed 2D capacitive micromachined ultrasonic transducer (CMUT) array. The device was fabricated using anodic bonding on a borosilicate glass substrate, which eliminates the substrate - bottom electrode coupling previously observed in traditional CMUT RC arrays fabricated on silicon substrates. The characterization results were compared for the top and bottom electrodes and include impedance measurements, pulseecho impulse responses, and 2D scans of the pressure field using a calibrated hydrophone. The results showed that the array elements behave similarly when ground and hot electrodes were switched between the top and bottom electrodes for all of the measured parameters including device capacitance, center frequency, and pulse-echo response amplitude. The pressure scans verified the highly customizable nature of RC arrays by showing multiple active element configurations. A sample cross-sectional image of a metal target was also demonstrated.

In transversely isotropic (TI) materials, mechanical properties differ along versus across the axis of symmetry (AoS). The degree of these directional differences has been interrogated by ultrasound-based measures of shear wave velocity (SWV) and ARFI peak displacements (PD) acquired along versus across the AoS. When performed using a conventional linear array transducer, such measurements require a 90o transducer rotation, which can be cumbersome and prone to misalignment errors. Rather than 90o, we hypothesize that smaller rotation angles can be used to assess mechanical anisotropy. This hypothesis was tested in silico using finite-element method (FEM) models and Field II. ARFI and Shear Wave Elasticity Imaging (SWEI) were simulated in five TI elastic materials with longitudinal versus transverse shear elastic modulus ratios (SRs) of 1.22 to 5.44. The simulated rotation angles were 15o, 30o, and 90o. The ratio of PD was measured with the long-axis of the ARF PSF aligned along the AoS versus long-axis rotated by 90o, 30o, or 15o from the AoS. The ratio of SWV was measured along the AoS versus 90o, 30o, or 15o rotation from the AoS. For a 90o rotation angle, both SWV and PD ratios were statistically different (2-sample t-test, p

Previous work has shown that the degree of anisotropy in tissue can be assessed using Acoustic Radiation Force Impulse (ARFI) imaging performed with a geometrically asymmetric excitation. In this work, we investigate the clinical relevance of mechanical anisotropy in Duchenne muscular dystrophy (DMD). Anisotropy assessment was performed using relative elasticity (RE) and relative viscosity (RV) parameters measured by Viscoelastic Response (VisR) ultrasound. These parameters were evaluated as the ratio of their respective values obtained with two orthogonal transducer orientations, i.e. parallel and perpendicular to the muscle fiber direction, to represent the transverse over the longitudinal RE or RV. In a pilot clinical feasibility study performed in six, 7.9–10.4 year-old boys with (DMD) and five age-matched boys with no known neuromuscular disorders, VisR anisotropy imaging was performed in vivo in the rectus femoris (RF) serially for a total of 22 time points in DMD and 12 time points in control boys. Both the RE and RV anisotropy ratios in the RF muscles of boys with DMD were significantly higher (Wilcoxon, p

While skeletal muscle is often assumed to be structurally transversely isotropic (TI), its mechanical anisotropy is not well characterized in vivo. VisR ultrasound, a technique that provides information about the viscoelastic mechanical response of tissue, can be used for such in vivo characterization. Specifically, VisR-derived Relative Elasticity (RE) provides directionally dependent information about the shear modulus of materials. We hypothesize that VisR RE can be used in healthy older adults and in stroke patients to 1) assess the degree of anisotropy (DoA) of the biceps brachii (BB) and 2) characterize the effect of passive loading on the BB. VisR imaging was performed in the BB long head of 2 healthy controls and 1 stroke patient. The subjects' arms were imaged in full extension and approximately 90° flexion at rest. Data were acquired in the transverse and longitudinal imaging planes at the medial location of the BB. The ratio of RE obtained in the transverse to the longitudinal muscle views was found to reflect the DoA in shear modulus, where DoA = 1 indicates perfect isotropy. In control subjects, RE values for flexion and extension in the transverse imaging plane (previously shown to reflect the longitudinal shear modulus, μL) were higher than the RE values in the longitudinal imaging plane (which, primarily reflects the transverse shear modulus, μT). Additionally, both the longitudinal and transverse shear moduli increased in extension vs. flexion. Both the magnitude and direction of anisotropy appeared to change in the stroke patient compared to the healthy controls. This work indicates VisR can be used to assess DoA in skeletal muscle of older adults and examine effects of passive loading on mechanical properties, in vivo, which may be clinically relevant to studying impairment post stroke.

In Duchenne muscular dystrophy (DMD), muscle fiber necrosis and subsequent progressive replacement of muscle by fibrous tissue and fat impacts the degree of anisotropy (DoA) in mechanical properties. Mechanical DoA can be assessed in skeletal muscle using Viscoelastic Response (VisR) ultrasound. We hypothesize that in vivo VisR DoA measures in the rectus femoris (RF) muscles of boys with DMD statistically differ from those in control boys. Further, we hypothesize that VisR DoA is correlated to RF functional output.

Tissue mechanical anisotropy has been shown to be diagnostically relevant in numerous clinical applications. Anisotropy can be assessed using acoustic radiation force-based techniques, including Acoustic Radiation Force Impulse (ARFI) and Viscoelastic Response (VisR) ultrasound. In this work, ARFI peak displacement (PD), as well as VisR relative elasticity (RE) and relative viscosity (RV), were implemented to image mechanical anisotropy in ex vivo porcine posas major muscle. Two psoas major samples were imaged in this work. The first sample was imaged whole. The second sample was sectioned into a 1 cm-diameter cylinder (with cylinder height oriented along the muscle fibers) and embedded into an isotropic gelatin phantom for imaging. ARFI and VisR were performed on both muscle samples using a linear array transducer mounted to a translation and rotation stage. By rotating the transducer 90o as it stepped across a 2D imaging field of view, PD, RE, and RV were measured along and across muscle fibers. Then, the ratios of PD, RE, and RV measurements made along versus across the muscle fibers were calculated, and these ratios were parametrically rendered in to 2D images representing degree of anisotropy. In the whole psoas major, PD anisotropy ratio was 1.08 +− 0.11, the RE anisotropy ratio was 0.94 +− 0.09 and the RV ratio was 0.94 +− 0.08. These PD and RE anisotropy ratios suggest that the longitudinal shear elastic modulus was greater than the transverse shear elastic modulus, which agrees with previous studies on muscle anisotropy. The RV results suggest that the longitudinal viscous modulus was greater than the transverse viscous modulus. Similar PD, RE, and RV anisotropy ratios were measured in the embedded psoas major section, and contrast ratios were 0.21, 0.14, and 0.30 for PD, RE and RV 2D anisotropy images, respectively. CNR for PD, RE, and RV anisotropy images were 3.26, 2.09 and 2.41, respectively. These results demonstrate that ARFI and VisR anisotropy imaging are relevant for delineating the spatial distribution of anisotropic features in tissue.

Degree of anisotropy (DoA) has been evaluated for clinical significance in several organs. In skeletal muscle, mechanical DoA has been shown to increase with passive extension, i.e. the shear modulus parallel to muscle fibers (μ l ) increases relative to that perpendicular (μ t ). Imaging such variations in DoA could facilitate diagnosing and monitoring muscle pathologies. We have previously demonstrated the feasibility of imaging DoA with VisR ultrasound, in silico. The purpose of this work is to experimentally demonstrate VisR DoA imaging ex vivo in pig and in vivo in human muscles. We hypothesize that 2D VisR anisotropy images represent mechanical anisotropy in muscle.

The kidney is an anisotropic organ, with higher elasticity along versus across nephrons. The degree of elastic anisotropy in kidney may be diagnostically relevant if properly exploited; however, if improperly controlled, anisotropy may confound stiffness measurements. The purpose of this study is to demonstrate a novel method for selectively exploiting or obviating elastic anisotropy in kidney using Acoustic Radiation Force Impulse (ARFI)-induced peak displacement (PD). The kidneys of three pigs were imaged in vivo at baseline, with venous ligation, and with arterial ligation, and then kidneys were extracted and imaged ex vivo. Imaging was performed with ARF excitation impulses having F/1.5 or F/5.0 focal configurations, and data were acquired with the transducer oriented along and across nephrons alignment in the renal cortex. In addition to ARFI PD, shear wave velocity was measured along and across nephrons to estimate longitudinal and transverse shear elastic moduli. Elastic anisotropy was then assessed as the ratio of PD across versus along nephrons, and as the ratio of shear moduli along versus across nephrons. PD ratio using the F/1.5 ARF linearly correlated with shear moduli ratio (R2 = 0.95). However, PD ratio using the F/5.0 ARF was approximately 1.0 and had weak correlation to shear moduli ratio (R2= 0.56). Further, the average difference in PD measured along versus across nephrons was 2.91 μm for the F/1.5 ARF but was 0.2 μm for the F/5.0 ARF. These results suggest that the F/1.5 ARF excitation exploited elastic anisotropy in the renal cortex, while the F/5.0 ARF excitation obviated it.

Stroke is commonly caused by thromboembolic events originating from ruptured carotid plaque, with rupture potential related to plaque composition. We have previously shown that soft (intraplaque hemorrhage/necrotic core) and stiff (collagen/calcium) plaque components are differentiated with high sensitivity and specificity by peak displacement (PD) in Acoustic Radiation Force Impulse (ARFI) imaging. However, PD showed low performance for distinguishing between soft and between stiff features. We hypothesize that soft and stiff feature delineation will be improved using a new ARFI outcome metric — the variance of acceleration (VoA). We test our hypothesis using histological validation.

Stroke is commonly caused by thromboembolic events originating from a ruptured carotid plaque. Histological studies have shown that plaque rupture potential is related to plaque composition rather than degree of stenosis. The use of Acoustic Radiation Force Impulse (ARFI) ultrasound imaging has enabled assessment of carotid plaque composition and structure. In particular, a previous study has shown that ARFI-derived peak displacement (PD) can differentiate between soft (intraplaque hemorrhage/necrotic core) and stiff (collagen/calcium) plaque components with high sensitivity and specificity. However, PD showed low performance for distinguishing between soft and between stiff features. This study evaluates an alternative ARFI-derived parameter, variance of acceleration (VoA), for intraplaque feature delineation. This study analyzed 20 carotid plaques imaged in vivo in patients undergoing carotid endarterectomy (CEA). After imaging, CEA specimens were harvested for histological validation. VoA was statistically significantly different (Wilcoxon, p < 0.01) between all examined plaque features, including between intraplaque hemorrhage and necrotic core and between collagen and calcium. Results suggest that VoA analysis improves ARFI discrimination between soft and between stiff carotid plaque components that are related to vulnerability for rupture.

In transversely isotropic (TI) materials, mechanical properties (Young’s modulus, shear modulus, and Poisson’s ratio) are different along versus across the axis of symmetry (AoS). In this paper, the feasibility of interrogating such directional mechanical property differences using acoustic radiation force impulse (ARFI) imaging is investigated. We herein test the hypotheses that: 1) ARFI-induced peak displacements (PDs) vary with TI material orientations when an asymmetrical ARFI excitation point spread function (PSF) is used, but not when a symmetrical ARFI PSF is employed and 2) the ratio of PDs induced with the long axis of an asymmetrical ARFI PSF oriented along versus across the material’s AoS is related to the degree of anisotropy of the material. These hypotheses were tested in silico using finite-element method (FEM) models and Field II. ARFI excitations had F/1.5, 3, 4, or 5 focal configurations, with the F/1.5 and F/5 cases having the most asymmetrical and symmetrical PSFs at the focal depth, respectively. These excitations were implemented for ARFI imaging in 52 different simulated TI materials with varying degrees of anisotropy, and the ratio of ARFI-induced PDs was calculated. The change in the ratio of PDs with respect to the anisotropy of the materials was highest for the F/1.5, indicating that PD was most strongly impacted by the material orientation when the ARFI excitation was the most asymmetrical. On the contrary, the ratio of PDs did not depend on the anisotropy of the material for the F/5 ARFI excitation, suggesting that PD did not depend on material orientation when the ARFI excitation was symmetrical. Finally, the ratio of PDs achieved using asymmetrical ARFI PSF reflected the degree of anisotropy in TI materials. These results support that symmetrical ARFI focal configurations are desirable when the orientation of the ARFI excitation to the AoS is not specifically known and measurement standardization is important, such as for longitudinal or cross-sectional studies of anisotropic organs. However, asymmetrical focal configurations are useful for exploiting anisotropy, which may be diagnostically relevant. Feasibility for future experimental implementation is demonstrated by simulating ultrasonic displacement tracking and by varying the ARF duration.

Viscoelastic response (VisR) imaging is presented as a new acoustic radiation force (ARF)-based elastographic imaging method. Exploiting the Voigt model, VisR imaging estimates displacement in only the ARF region of excitation from one or two successive ARF impulses to estimate τσ, the relaxation time for constant stress. Double-push VisR τσ estimates were not statistically significantly different (p

Duchenne muscular dystrophy (DMD) is a genetic disorder that causes progressive muscle degeneration involving necrosis and inflammation, with subsequent replacement of muscle fibers by fibrosis and fatty tissue. These compositional changes underlie mechanical property alterations in affected muscles, which may be assessed using Viscoelastic Response (VisR) ultrasound. We hypothesize that VisR will delineate differences in the viscoelastic properties of lower limb skeletal muscles in boys with versus without DMD. VisR imaging was performed in the vastus intermedius (VI), rectus femoris (RF), sartorius (SM) and gastrocnemius (GM) muscles of seven boys (4 DMD, 3 control) aged 7.9 – 10.4 years. Parametric images of relative elasticity (RE) and relative viscosity (RV) were rendered. From the parametric images, percent muscle area with relatively high RE or RV value was calculated and compared (Wilcoxon rank-sum) between DMD and control on a per-muscle basis. In the VI, RF and SM, percent muscle with relatively high RV was larger (VI: 17.7% v. 13.1% RF: 98.9% v. 93.7%, SM: 43.2% v. 40.6% p < 0.05) in DMD than control muscles. In the VI, percent muscle with relatively high RE was larger (32.8% v. 29.5%, p < 0.05) in DMD muscles. No significant differences were observed in the GM between DMD and control. VisR results were consistent with temporally-matched functional testing using a hand-held dynamometer, which showed 40.5% to 70.0% lower force output in DMD RF, VL and SM - and only 21.8% lower force output in DMD GM - relative to the corresponding control muscles. These results suggest that VisR imaging is relevant to delineating viscoelastic property alterations that are associated with dystrophic muscle degeneration in boys with DMD, in vivo.

Stroke is commonly caused by thromboembolic events originating from vulnerable atherosclerotic plaque in the carotid vasculature. The purpose of this study was to evaluate the ability of acoustic radiation force impulse (ARFI) imaging, a noninvasive elastography imaging technique, to assess the composition of carotid artery plaques using histologic examination as the gold standard. Twenty-five patients undergoing carotid endarterectomy (CEA) were enrolled and imaged with ARFI. After surgery, extracted specimens were histologically processed and matched to the ultrasound imaging plane. Parametric 2D ARFI images of peak displacement (PD) were evaluated by three radiologists blinded to the histology result. Receiver operating characteristic (ROC) curve analysis was performed, and area under the ROC curve (AUC) was taken as a metric of performance for detecting plaque features such as necrotic core (NC), intraplaque hemorrhage (IPH), collagen (COL), and calcium (CAL). Additionally, linear regression was performed on fibrous cap (FC) thickness measurements. Areas of plaque with NC and IPH were observed to have substantially increased ARFI PD (2× to 4×) compared to areas of plaque with COL or CAL. Median AUC for detecting soft plaque features (NC/IPH) was 0.887 (range: 0.867 – 0.924) and stiff plaque features (COL/CAL) was 0.859 (range: 0.771 – 0.929). FC thickness measured by two of the three radiologists matched closely with histology (reader 1: R2 = 0.64; reader 2: R2 = 0.89). This study suggests that ARFI is capable of distinguishing soft from stiff compositional elements of atherosclerotic plaques and may be relevant to improving plaque risk assessment.

Acute cerebrovascular accidents are associated with the rupture of vulnerable atherosclerotic plaques in the carotid arteries. Fibrous cap thickness has been shown to be an important predictor of plaque rupture, but has been challenging to measure accurately with clinical noninvasive imaging modalities. The goals of this investigation were first, to evaluate the feasibility of using transcutaneous acoustic radiation force impulse (ARFI) ultrasound to quantify fibrous cap thickness and second, to optimize both imaging and motion tracking parameters to support such measurements. Fibrous caps with varying thickness (0.1 – 1.0 mm) were simulated using a simple layered geometry, and their mechanical response to an impulse of radiation force was solved using finite element method (FEM) modeling. Ultrasound tracking of FEM displacements was performed in Field II utilizing three center frequencies (6, 9, and 12 MHz) and eight motion tracking kernel lengths (0.5λ – 4λ). Additionally, fibrous cap thickness in two carotid plaques imaged in vivo was measured with ARFI and compared to matched histology. The results of this study demonstrate that 1) tracking pulse frequencies around 12 MHz are necessary to resolve caps around 0.2 mm, 2) large motion-tracking kernel sizes introduce bias into thickness measurements and overestimate the true cap thickness, and 3) color saturation settings on ARFI peak displacement images can impact thickness measurement accuracy substantially.

Objective Stroke is commonly caused by thromboembolic events originating from ruptured carotid plaque with vulnerable composition. This study assessed the performance of acoustic radiation force impulse (ARFI) imaging, a noninvasive ultrasound elasticity imaging method, for delineating the composition of human carotid plaque in vivo with histologic validation. Methods Carotid ARFI images were captured before surgery in 25 patients undergoing clinically indicated carotid endarterectomy. The surgical specimens were histologically processed with sectioning matched to the ultrasound imaging plane. Three radiologists, blinded to histology, evaluated parametric images of ARFI-induced peak displacement to identify plaque features such as necrotic core (NC), intraplaque hemorrhage (IPH), collagen (COL), calcium (CAL), and fibrous cap (FC) thickness. Reader performance was measured against the histologic standard using receiver operating characteristic curve analysis, linear regression, Spearman correlation (ρ), and Bland-Altman analysis. Results ARFI peak displacement was two-to-four-times larger in regions of NC and IPH relative to regions of COL or CAL. Readers detected soft plaque features (NC/IPH) with a median area under the curve of 0.887 (range, 0.867-0.924) and stiff plaque features (COL/CAL) with median area under the curve of 0.859 (range, 0.771-0.929). FC thickness measurements of two of the three readers correlated with histology (reader 1: R 2 = 0.64, ρ = 0.81; reader 2: R 2 = 0.89, ρ = 0.75). Conclusions This study suggests that ARFI is capable of distinguishing soft from stiff atherosclerotic plaque components and delineating FC thickness.

In this second of a two part series, we present pilot clinical data demonstrating Acoustic Radiation Force Impulse (ARFI) ultrasound for monitoring the onset of subcutaneous hemostasis at femoral artery puncture sites (arteriotomies), in vivo. We conducted a randomized, reader-blinded investigation of 20 patient volunteers who underwent diagnostic percutaneous coronary catheterization. After sheath removal (6 French), patients were randomized to treatment with either standard of care manual compression alone or, to expedite hemostasis, manual compression augmented with a p-GlcNAc fiber-based hemostatic dressing (Marine Polymer Technologies, Danvers MA). Concurrent with manual compression, serial ARFI imaging began at the time of sheath removal and continued every minute for 15 min. Serial data sets were processed with custom software to (1) estimate the time of hemostasis onset, and (2) render hybrid ARFI/B-Mode images to highlight displacements considered to correspond to extravasted blood. Images were read by an observer blinded to the treatment groups. Average estimated times to hemostasis in patient volunteers treated with manual compression alone ( n = 10) and manual compression augmented by hemostatic dressing ( n = 9) were, respectively, 13.00 ± 1.56 and 9.44 ± 3.09 min, which are statistically significantly different ( p = 0.0065, Wilcoxon two-sample test). Example images are shown for three selected patient volunteers. These pilot data suggest that ARFI ultrasound is relevant to monitoring subcutaneous bleeding from femoral arteriotomies clinically and that time to hemostasis was significantly reduced by use of the hemostatic dressing.

Acoustic radiation force impulse (ARFI) Surveillance of Subcutaneous Hemorrhage (ASSH) has been previously demonstrated to differentiate bleeding phenotype and responses to therapy in dogs and humans, but to date, the method has lacked experimental validation. This work explores experimental validation of ASSH in a poroelastic tissue-mimic and in vivo in dogs. The experimental design exploits calibrated flow rates and infusion durations of evaporated milk in tofu or heparinized autologous blood in dogs. The validation approach enables controlled comparisons of ASSH-derived bleeding rate (BR) and time to hemostasis (TTH) metrics. In tissue-mimicking experiments, halving the calibrated flow rate yielded ASSH-derived BRs that decreased by 44% to 48%. Furthermore, for calibrated flow durations of 5.0 minutes and 7.0 minutes, average ASSH-derived TTH was 5.2 minutes and 7.0 minutes, respectively, with ASSH predicting the correct TTH in 78% of trials. In dogs undergoing calibrated autologous blood infusion, ASSH measured a 3-minute increase in TTH, corresponding to the same increase in the calibrated flow duration. For a measured 5% decrease in autologous infusion flow rate, ASSH detected a 7% decrease in BR. These tissue-mimicking and in vivo preclinical experimental validation studies suggest the ASSH BR and TTH measures reflect bleeding dynamics.

In this work, we evaluate if directional differences in the mechanical properties of transversely anisotropic (TI) materials may be interrogated using Acoustic Radiation Force Impulse (ARFI) imaging. We hypothesize that ARFI-induced peak displacements (PDs) will vary depending on the orientation of the ARFI excitation to the TI material's axis of symmetry (AoS) when an asymmetrical ARFI excitation is employed, but not when a symmetrical ARFI excitation is used. We further hypothesize that the ratio of the PDs induced with the long axis of an asymmetrical ARFI excitation oriented along versus across the material AoS will be related to the degree of anisotropy of the material. These hypothesizes were tested in silico using finite element method (FEM) models and Field II. ARFI excitations had F/1.5, 3, 4, or 5 focal configurations, with the F/1.5 case having the most asymmetrical and the F/5 case having the most symmetrical point spread function (2D PSF) at the focal depth. These excitations were implemented for ARFI imaging in 18 different TI materials with varying degrees of anisotropy. The ratio of PDs at the focal depth when the AoS was oriented along versus across the long axis of the ARFI-2D PSF was calculated. The degree of anisotropy in the materials was represented by the ratio of the longitudinal and transverse shear modulus and by the ratio of the longitudinal and transverse Young's modulus. To describe the relationship between the ratio of PDs and material anisotropy, piecewise linear regression of the ratio of PDs versus the ratio of shear moduli and of the ratio of PDs versus the ratio of Young's moduli were calculated. The slopes were highest for the F/1.5 ARFI excitation, indicating that the ratio of PDs was most strongly impacted by the material orientation when the ARFI impulse was most asymmetrical. On the contrary, the slope was roughly zero for the F/5 ARFI excitation, which indicates that PD did not depend on the orientation of the material when the ARFI excitation was symmetrical. These results suggest that symmetrical ARFI focal configurations are desirable when the orientation of the ARFI excitation to the AoS is not specifically known and standardization of measurement is important, such as for longitudinal or cross-sectional studies of anisotropic organs. However, asymmetrical focal configurations are useful for exploiting anisotropy. Finally, the ratio of PDs reflects degree of anisotropy in TI materials.

ARFI Surveillance of Subcutaneous Hemorrhage (ASSH) is a method for noninvasively detecting and monitoring subcutaneous bleeding, in vivo. It has been implemented in relevant animal models and in patients undergoing percutaneous coronary catheterization to monitor hemorrhage at sites of vascular injury. In ASSH, regions of hemorrhage are identified by elevated variance in measured ARF-induced tissue acceleration profiles. However, it is well known that increased variance, or ℌjitterℍ, can be caused by a number of factors nonspecific for the presence of hemorrhage, such as low ultrasonic signal-to-noise ratio (SNR) or small tracking kernel size. To explore the sources of jitter in ASSH, a model of low-reflection-amplitude, untethered scatterers (mimicking red blood cells) within a viscoelastic medium under ARF excitation is developed using FEM simulation and Field II. ASSH profiles are generated with a range of system SNR levels, tracking kernel sizes, and untethered scatterer concentrations and displacement magnitudes. The optimal thresholds for detecting the untethered scatterers are determined using receiver operating characteristic (ROC) curve analysis. The results suggest that, given adequate system SNR (≤ 40 dB) and optimal threshold and kernel selection, ASSH can achieve high performance (≤ 0.9 area under the ROC curve) for detecting untethered scatterers.

Acoustic radiation force impulse (ARFI) ultrasound is an elasticity imaging technique that has the potential to identify vulnerable atherosclerotic plaque characteristics. Previous studies have shown that regions of high ARFI-induced displacement correspond to lipid/necrotic areas in plaques, whereas regions of low displacement correspond with fibrotic/calcified areas. In this work, we continue our analysis of ARFI images captured from patients undergoing carotid endarterectomy. ARFI imaging of carotid plaque was performed prior to surgery, and extracted specimens were histologically processed and matched to the ultrasound imaging plane. ARFI images and histological slides were annotated independently for various features including necrotic core, calcification, fibrosis and fibrous cap, and wide hemorrhage. Results are presented for a number of advanced plaque types (Va, Vb, and VI), and ARFI-derived fibrous cap thickness measurements are compared quantitatively to histology. Results suggest ARFI is capable of measuring fibrous cap thickness with a mean positive bias of 0.09 ± 0.12 mm, and may be capable of identifying ruptured plaque.

Viscoelastic Response (VisR) imaging is an acoustic radiation force (ARF)-based ultrasonic technique for estimating the viscoelastic properties of tissue. It has been proposed as a method for monitoring degeneration in the skeletal muscles of boys with Duchenne muscular dystrophy (DMD). DMD causes progressive inflammation, necrosis, fibrosis and fatty deposition in muscle, all of which will alter the elasticity and viscosity of the tissue. The motivation of this work is to investigate VisR's potential as method for monitoring dystrophic muscle degeneration, in vivo, in boys with DMD. In an ongoing longitudinal clinical study, muscles in the lower limbs of boys affected with DMD and age-matched healthy control boys are imaged using VisR thrice yearly for four years. A case study of serial imaging results in the Medial Gastrocnemius (GM) muscle of one boy with DMD is herein presented. Beginning at age 6.2 years, parametric VisR images of τ, or the ratio of viscosity to elasticity, show a growing region of high τ (>1.2 ms) over the span of one year. This result is consistent with expected progressive inflammation and fatty deposition early in the GM's degenerative cycle. Over the course of the next four months, the area of high τ decreases, which is in agreement with the expected onset of muscle fibrosis. Then, at age 8.3 years, small and diffusely distributed high τ regions are observed in the muscle, consistent with expected distributed fatty depositions. These results suggest that VisR, a noninvasive ultrasound imaging method, may be clinically viable for monitoring local muscular compositional and structural changes associated with dystrophic degeneration, in vivo.