Mouse brain elastography changes with sleep/wake cycles, aging, and Alzheimer's disease.

Understanding the physiological processes in aging and how neurodegenerative disorders affect cognitive function is a high priority for advancing human health. One specific area of recently enabled research is the in vivo biomechanical state of the brain. This study utilized reverberant optical coherence elastography, a high-resolution elasticity imaging method, to investigate stiffness changes during the sleep/wake cycle, aging, and Alzheimer's disease in murine models. Four-dimensional scans of 44 wildtype mice, 13 mice with deletion of aquaporin-4 water channel, and 12 mice with Alzheimer-related pathology (APP/PS1) demonstrated that (1) cortical tissue became softer (on the order of a 10% decrease in shear wave speed) when young wildtype mice transitioned from wake to anesthetized, yet this effect was lost in aging and with mice overexpressing amyloid-ß or lacking the water channel AQP4. (2) Cortical stiffness increased with age in all mice lines, but wildtype mice exhibited the most prominent changes as a function of aging. The study provides novel insight into the brain's biomechanics, the constraints of fluid flow, and how the state of brain activity affects basic properties of cortical tissues.

Breast Ultrasound Volume Sweep Imaging: A New Horizon in Expanding Imaging Access for Breast Cancer Detection.

OBJECTIVE: The majority of people in the world lack basic access to breast diagnostic imaging resulting in delay to diagnosis of breast cancer. In this study, we tested a volume sweep imaging (VSI) ultrasound protocol for evaluation of palpable breast lumps that can be performed by operators after minimal training without prior ultrasound experience as a means to increase accessibility to breast ultrasound. METHODS: Medical students without prior ultrasound experience were trained for less than 2 hours on the VSI breast ultrasound protocol. Patients presenting with palpable breast lumps for standard of care ultrasound examination were scanned by a trained medical student with the VSI protocol using a Butterfly iQ handheld ultrasound probe. Video clips of the VSI scan imaging were later interpreted by an attending breast imager. Results of VSI scan interpretation were compared to the same-day standard of care ultrasound examination. RESULTS: Medical students scanned 170 palpable lumps with the VSI protocol. There was 97% sensitivity and 100% specificity for a breast mass on VSI corresponding to 97.6% agreement with standard of care (Cohen's κ = 0.95, P < .0001). There was a detection rate of 100% for all cancer presenting as a sonographic mass. High agreement for mass characteristics between VSI and standard of care was observed, including 87% agreement on Breast Imaging-Reporting and Data System assessments (Cohen's κ = 0.82, P < .0001). CONCLUSIONS: Breast ultrasound VSI for palpable lumps offers a promising means to increase access to diagnostic imaging in underserved areas. This approach could decrease delay to diagnosis for breast cancer, potentially improving morbidity and mortality.

Diagnostic Performance of an Artificial Intelligence System in Breast Ultrasound.

OBJECTIVES: We study the performance of an artificial intelligence (AI) program designed to assist radiologists in the diagnosis of breast cancer, relative to measures obtained from conventional readings by radiologists. METHODS: A total of 10 radiologists read a curated, anonymized group of 299 breast ultrasound images that contained at least one suspicious lesion and for which a final diagnosis was independently determined. Separately, the AI program was initialized by a lead radiologist and the computed results compared against those of the radiologists. RESULTS: The AI program's diagnoses of breast lesions had concordance with the 10 radiologists' readings across a number of BI-RADS descriptors. The sensitivity, specificity, and accuracy of the AI program's diagnosis of benign versus malignant was above 0.8, in agreement with the highest performing radiologists and commensurate with recent studies. CONCLUSION: The trained AI program can contribute to accuracy of breast cancer diagnoses with ultrasound.

Burr, Lomax, Pareto, and Logistic Distributions from Ultrasound Speckle.

After 100 years of theoretical treatment of speckle patterns from coherent illumination, there remain some open questions about the nature of ultrasound speckle from soft vascularized tissues. A recent hypothesis is that the fractal branching vasculature is responsible for the dominant echo pattern from organs such as the liver. In that case, an analysis of cylindrical scattering structures arranged across a power law distribution of sizes is warranted. Using a simple model of echo strength and basic transformation rules from probability, we derive the first order statistics of speckle considering the amplitude, the intensity, and the natural log of amplitude. The results are given by long tailed distributions that have been studied in the statistics literature for other fields. Examples are given from simulations and animal studies, and the theoretical fit to these preliminary data support the overall framework as a plausible model for characterizing ultrasound speckle statistics.

Monitoring Early Breast Cancer Response to Neoadjuvant Therapy Using H-Scan Ultrasound Imaging: Preliminary Preclinical Results.

OBJECTIVE: H-scan imaging is a new ultrasound technique used to visualize the relative size of acoustic scatterers. The purpose of this study was to evaluate the use of H-scan ultrasound imaging for monitoring early tumor response to neoadjuvant treatment using a preclinical breast cancer animal model. METHODS: Real-time H-scan ultrasound imaging was implemented on a programmable ultrasound scanner (Vantage 256; Verasonics Inc., Kirkland, WA) equipped with an L11-4v transducer. Bioluminescence and H-scan ultrasound was used to image luciferase-positive breast cancer-bearing mice at baseline and at 24, 48, and 168 hours after administration of a single dose of neoadjuvant (paclitaxel) or sham treatment. Animals were euthanized at 48 or 168 hours, and tumors underwent histologic processing to identify cancer cell proliferation and apoptosis. RESULTS: Baseline H-scan ultrasound images of control and therapy group tumors were comparable, but the latter exhibited significant changes over the 7-day study (P < .05). At termination, there was a marked difference between the H-scan ultrasound images of control and treated tumors (P < .05). Specifically, H-scan ultrasound images of treated tumors were more blue in hue than images obtained from control tumors. There was a significant linear correlation between the predominance of the blue hue found in the H-scan ultrasound images and intratumoral apoptotic activity (R2 > 0.40, P < .04). CONCLUSION: Preliminary preclinical results suggest that H-scan ultrasound imaging is a new and promising tissue characterization modality. H-scan ultrasound imaging may provide prognostic value when monitoring early tumor response to neoadjuvant treatment.

The first order statistics of backscatter from the fractal branching vasculature.

The issue of speckle statistics from ultrasound images of soft tissues such as the liver has a long and rich history. A number of theoretical distributions, some related to random scatterers or fades in optics and radar, have been formulated for pulse-echo interference patterns. This work proposes an alternative framework in which the dominant echoes are presumed to result from Born scattering from fluid-filled vessels that permeate the tissue parenchyma. These are modeled as a branching, fractal, self-similar, multiscale collection of cylindrical scatterers governed by a power law distribution relating to the number of branches at each radius. A deterministic accounting of the echo envelopes across the scales from small to large is undertaken, leading to a closed form theoretical formula for the histogram of the envelope of the echoes. The normalized histogram is found to be related to the classical Burr distribution, with the key power law parameter directly related to that of the number density of vessels vs diameter, frequently reported in the range of 2 to 4. Examples are given from liver scans to demonstrate the applicability of the theory.

The nonlinear ultrasound needle pulse.

Recent work has established an analytical formulation of broadband fields which extend in the axial direction and converge to a narrow concentrated line. Those unique (needle) fields have their origins in an angular spectrum configuration in which the forward propagating wavenumber of the field ( kz ) is constant across any z plane for all of the propagated frequencies. A 3 MHz-based, finite amplitude distorted simulation of such a field is considered here in a water path scenario relevant to medical imaging. That nonlinear simulation had its focal features compared to those of a comparable Gaussian beam. The results suggest that the unique convergence of the needle pulse to a narrow but extended axial line in linear propagation is also inherited by higher harmonics in nonlinear propagation. Furthermore, the linear needle field's relatively short duration focal pulses, and the asymptotic declines of its radial profiles, also hold for the associated higher harmonics. Comparisons with the Gaussian field highlight some unique and potentially productive features of needle fields.

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.

Longitudinal iso-phase condition and needle pulses.

We study the properties of pulsed solutions to the scalar and vector wave equations composed of plane-waves with equal longitudinal spatial frequency. This condition guarantees that, at all times, the field profile is invariant in the longitudinal direction. Particular emphasis is placed on solutions with rotational symmetry. For these solutions, the wave concentrates strongly near the axis at a given time. We provide closed-form expressions for some of these fields, and show that their wavefronts are approximately spherical. Solutions carrying orbital and spin angular momenta are also considered.

Crawling wave optical coherence elastography.

Elastography is a technique that measures and maps the local elastic property of biological tissues. Aiming for detection of micron-scale inclusions, various optical elastography, especially optical coherence elastography (OCE), techniques have been investigated over the past decade. The challenges of current optical elastography methods include the decrease in elastographic resolution as compared with its parent imaging resolution, the detection sensitivity and accuracy, and the cost of the overall system. Here we report for the first time, we believe, on an elastography technique-crawling wave optical coherence elastography (CRW-OCE)-which significantly lowers the requirements on the imaging speed and opens the path to high-resolution and high-sensitivity OCE at relatively low cost. Methods of crawling wave excitation, data acquisition, and crawling wave tracking are presented.

Temporal artifact minimization in sonoelastography through optimal selection of imaging parameters.

Sonoelastography is an ultrasonic technique that uses Kasai's autocorrelation algorithms to generate qualitative images of tissue elasticity using external mechanical vibrations. In the absence of synchronization between the mechanical vibration device and the ultrasound system, the random initial phase and finite ensemble length of the data packets result in temporal artifacts in the sonoelastography frames and, consequently, in degraded image quality. In this work, the analytic derivation of an optimal selection of acquisition parameters (i.e., pulse repetition frequency, vibration frequency, and ensemble length) is developed in order to minimize these artifacts, thereby eliminating the need for complex device synchronization. The proposed rule was verified through experiments with heterogeneous phantoms, where the use of optimally selected parameters increased the average contrast-to-noise ratio (CNR) by more than 200% and reduced the CNR standard deviation by 400% when compared to the use of arbitrarily selected imaging parameters. Therefore, the results suggest that the rule for specific selection of acquisition parameters becomes an important tool for producing high quality sonoelastography images.

Shear wave dispersion in lean versus steatotic rat livers.

OBJECTIVES: The precise measurement of fat accumulation in the liver, or steatosis, is an important clinical goal. Our previous studies in phantoms and mouse livers support the hypothesis that, starting with a normal liver, increasing accumulations of microsteatosis and macrosteatosis will increase the lossy viscoelastic properties of shear waves in a medium. This increase results in an increased dispersion (or slope) of the shear wave speed in the steatotic livers. METHODS: In this study, we moved to a larger animal model, lean versus obese rat livers ex vivo, and a higher-frequency imaging system to estimate the shear wave speed from crawling waves. RESULTS: The results showed elevated dispersion in the obese rats and a separation of the lean versus obese liver parameters in a 2-dimensional parameter space of the dispersion (slope) and shear wave speed at a reference frequency of 150 Hz. CONCLUSIONS: We have confirmed in 3 separate studies the validity of our dispersion hypothesis in animal models.

Oestreicher and elastography.

A sphere moving back and forth in tissue generates the kinds of complex displacement fields that are used in elastography. The analytical solution of Hans Oestreicher for this phenomenon [(1951). J. Acoust. Soc. Am. 23, 704-714] gives an understanding of the transverse and longitudinal, fast and slow waves that are generated. The results suggest several ways to determine the absorption coefficients of tissues, which together with phase velocity permit the computation of both the real shear modulus and the shear viscosity as functions of frequency.

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.

Real and causal hysteresis elements.

Hysteresis is a phenomenon that has been observed across many different materials and situations. Under small-amplitude cyclical motion, classical hysteresis designates a constant loss per cycle over a wide range of frequencies. This is also consistent with an increase in losses or attenuation with frequency that is strictly proportional to the first power of frequency. Unfortunately, the classical (and simple) frequency domain description of hysteresis does not result in a real and causal impulse response, and therefore is not useful for predicting laboratory results. This problem has led to many errors as well as other more fruitful approaches over the years. The frequency domain requirements for hysteresis are re-examined and it is demonstrated that there is a family of solutions that provide real and causal impulse responses over some extended frequency range. The family is conveniently divided into highpass, lowpass, and bandpass causal systems. These are populated by closed form analytical solutions which can be applied to the prediction of motion and waves in hysteretic materials and systems.

Shear wave speed and dispersion measurements using crawling wave chirps.

This article demonstrates the measurement of shear wave speed and shear speed dispersion of biomaterials using a chirp signal that launches waves over a range of frequencies. A biomaterial is vibrated by two vibration sources that generate shear waves inside the medium, which is scanned by an ultrasound imaging system. Doppler processing of the acquired signal produces an image of the square of vibration amplitude that shows repetitive constructive and destructive interference patterns called "crawling waves." With a chirp vibration signal, successive Doppler frames are generated from different source frequencies. Collected frames generate a distinctive pattern which is used to calculate the shear speed and shear speed dispersion. A special reciprocal chirp is designed such that the equi-phase lines of a motion slice image are straight lines. Detailed analysis is provided to generate a closed-form solution for calculating the shear wave speed and the dispersion. Also several phantoms and an ex vivo human liver sample are scanned and the estimation results are presented.

H-Scan Discrimination for Tumor Microenvironmental Heterogeneity in Melanoma.

OBJECTIVE: Melanoma is a form of malignant skin cancer that exhibits significant inter-tumoral differences in the tumor microenvironment (TME) secondary to genetic mutations. The heterogeneity may be subtle but can complicate the treatment of metastatic melanoma, contributing to a high mortality rate. Therefore, developing an accurate and non-invasive procedure to discriminate microenvironmental heterogeneity to facilitate therapy selection is an important goal. METHODS: In vivo murine melanoma models that recapitulate human disease using synchronous implanted YUMM 1.7 (Yale University Mouse Melanoma) and YUMMER 1.7 (Yale University Mouse Melanoma Exposed to Radiation) murine melanoma lines were investigated. Mice were treated with antibodies to modulate the immune response and longitudinally scanned with ultrasound (US). US radiofrequency data were processed using the H-scan analysis, attenuation estimation and B-mode processing to extract five US features. The measures were used to compare different TMEs (YUMMER vs. YUMM) and responses to immunomodulatory therapies with CD8 depletion or programmed cell death protein 1 (PD-1) inhibition. RESULTS: Multiparametric analysis produced a combined H-scan parameter, resolving significant differences (i) between untreated YUMMER and YUMM and (ii) between untreated, PD-1-treated and CD8-treated YUMMER. However, more importantly, the B-mode and attenuation measures failed to differentiate YUMMER and YUMM and to monitor treatment responses, indicating that H-scan is required to differentiate subtle differences within the TME. CONCLUSION: We anticipate that the H-scan analysis could discriminate heterogeneous melanoma metastases and guide diagnosis and treatment selection, potentially reducing the need for invasive biopsies or immunologic procedures.

Multiparametric ultrasound imaging for early-stage steatosis: Comparison with magnetic resonance imaging-based proton density fat fraction.

BACKGROUND: The prevalence of liver diseases, especially steatosis, requires a more convenient and noninvasive tool for liver diagnosis, which can be a surrogate for the gold standard biopsy. Magnetic resonance (MR) measurement offers potential, however ultrasound (US) has better accessibility than MR. PURPOSE: This study aims to suggest a multiparametric US approach which demonstrates better quantification and imaging performance than MR imaging-based proton density fat fraction (MRI-PDFF) for hepatic steatosis assessment. METHODS: We investigated early-stage steatosis to evaluate our approach. An in vivo (within the living) animal study was performed. Fat inclusions were accumulated in the animal livers by feeding a methionine and choline deficient (MCD) diet for 2 weeks. The animals (n = 19) underwent US and MR imaging, and then their livers were excised for histological staining. From the US, MR, and histology images, fat accumulation levels were measured and compared: multiple US parameters; MRI-PDFF; histology fat percentages. Seven individual US parameters were extracted using B-mode measurement, Burr distribution estimation, attenuation estimation, H-scan analysis, and shear wave elastography. Feature selection was performed, and the selected US features were combined, providing quantification of fat accumulation. The combined parameter was used for visualizing the localized probability of fat accumulation level in the liver; This procedure is known as disease-specific imaging (DSI). RESULTS: The combined US parameter can sensitively assess fat accumulation levels, which is highly correlated with histology fat percentage (R = 0.93, p-value < 0.05) and outperforms the correlation between MRI-PDFF and histology (R = 0.89, p-value < 0.05). Although the seven individual US parameters showed lower correlation with histology compared to MRI-PDFF, the multiparametric analysis enabled US to outperform MR. Furthermore, this approach allowed DSI to detect and display gradual increases in fat accumulation. From the imaging output, we measured the color-highlighted area representing fatty tissues, and the fat fraction obtained from DSI and histology showed strong agreement (R = 0.93, p-value < 0.05). CONCLUSIONS: We demonstrated that fat quantification utilizing a combination of multiple US parameters achieved higher performance than MRI-PDFF; therefore, our multiparametric analysis successfully combined selected features for hepatic steatosis characterization. We anticipate clinical use of our proposed multiparametric US analysis, which could be beneficial in assessing steatosis in humans.

WATUNet: a deep neural network for segmentation of volumetric sweep imaging ultrasound.

Limited access to breast cancer diagnosis globally leads to delayed treatment. Ultrasound, an effective yet underutilized method, requires specialized training for sonographers, which hinders its widespread use. Volume sweep imaging (VSI) is an innovative approach that enables untrained operators to capture high-quality ultrasound images. Combined with deep learning, like convolutional neural networks, it can potentially transform breast cancer diagnosis, enhancing accuracy, saving time and costs, and improving patient outcomes. The widely used UNet architecture, known for medical image segmentation, has limitations, such as vanishing gradients and a lack of multi-scale feature extraction and selective region attention. In this study, we present a novel segmentation model known as Wavelet_Attention_UNet (WATUNet). In this model, we incorporate wavelet gates and attention gates between the encoder and decoder instead of a simple connection to overcome the limitations mentioned, thereby improving model performance. Two datasets are utilized for the analysis: the public 'Breast Ultrasound Images' dataset of 780 images and a private VSI dataset of 3818 images, captured at the University of Rochester by the authors. Both datasets contained segmented lesions categorized into three types: no mass, benign mass, and malignant mass. Our segmentation results show superior performance compared to other deep networks. The proposed algorithm attained a Dice coefficient of 0.94 and an F1 score of 0.94 on the VSI dataset and scored 0.93 and 0.94 on the public dataset, respectively. Moreover, our model significantly outperformed other models in McNemar's test with false discovery rate correction on a 381-image VSI set. The experimental findings demonstrate that the proposed WATUNet model achieves precise segmentation of breast lesions in both standard-of-care and VSI images, surpassing state-of-the-art models. Hence, the model holds considerable promise for assisting in lesion identification, an essential step in the clinical diagnosis of breast lesions.

Brain elastography in aging relates to fluid/solid trendlines.

The relatively new tools of brain elastography have established a general trendline for healthy, aging adult humans, whereby the brain's viscoelastic properties 'soften' over many decades. Earlier studies of the aging brain have demonstrated a wide spectrum of changes in morphology and composition towards the later decades of lifespan. This leads to a major question of causal mechanisms: of the many changes documented in structure and composition of the aging brain, which ones drive the long term trendline for viscoelastic properties of grey matter and white matter? The issue is important for illuminating which factors brain elastography is sensitive to, defining its unique role for study of the brain and clinical diagnoses of neurological disease and injury. We address these issues by examining trendlines in aging from our elastography data, also utilizing data from an earlier landmark study of brain composition, and from a biophysics model that captures the multiscale biphasic (fluid/solid) structure of the brain. Taken together, these imply that long term changes in extracellular water in the glymphatic system of the brain along with a decline in the extracellular matrix have a profound effect on the measured viscoelastic properties. Specifically, the trendlines indicate that water tends to replace solid fraction as a function of age, then grey matter stiffness decreases inversely as water fraction squared, whereas white matter stiffness declines inversely as water fraction to the 2/3 power, a behavior consistent with the cylindrical shape of the axons. These unique behaviors point to elastography of the brain as an important macroscopic measure of underlying microscopic structural change, with direct implications for clinical studies of aging, disease, and injury.