Spatially segmented SVD clutter filtering in cardiac blood flow imaging with diverging waves.

Ultrafast ultrasound imaging enables the visualization of rapidly changing blood flow dynamics in the chambers of the heart. Singular value decomposition (SVD) filters outperform conventional high pass clutter rejection filters for ultrafast blood flow imaging of small and shallow fields of view (e.g., functional imaging of brain activity). However, implementing SVD filters can be challenging in cardiac imaging due to the complex spatially and temporally varying tissue characteristics. To address this challenge, we describe a method that involves excluding the proximal portion of the image (near the chest wall) and divides the reduced field of view into overlapped segments, within which tissue signals are expected to be spatially and temporally coherent. SVD filtering with automatic selection of cut-off singular vector orders to remove tissue and noise signals is implemented for each segment. Auto-thresholding is based on the coherence of spatial singular vectors, delineating tissue, blood, and noise subspaces within a spatial similarity matrix calculated for each segment. Filtered blood flow signals from the segments are reconstructed and then combined and Doppler processing is used to form a set of blood flow images. Preliminary experimental results suggest that the spatially segmented approach improves the separation of the tissue and blood subsets in the spatial similarity matrix so that automatic thresholding is significantly improved, and tissue clutter can then be rejected more effectively in cardiac ultrafast imaging, compared to using the full field of view. In the case studied, spatially segmented SVD improved the rate of correct automatic selection of thresholds from 78% to 98.7% for the investigated cases and improved the post-filter power of blood signals by an average of more than 10 dB during a cardiac cycle.

Lateral Position-Dependent Velocity Estimation Error in Plane-Wave Doppler Ultrasound Systems.

Doppler ultrasound has become a standard method used to diagnose and grade vascular diseases and monitor their progression. Conventional focused-beam color Doppler imaging is routinely used in clinical practice, but suffers from inherent trade-offs between spatial, temporal and velocity resolution. Newer, plane-wave Doppler imaging offers rapid simultaneous acquisition of B-mode, color and spectral Doppler information across large fields of view, making it a potentially useful method for quantitative estimation of blood flow velocities in the clinic. However, plane-wave imaging can lead to a substantial error in velocity estimation, which is dependent on the lateral location within the image. This is seen in both clinical and experimental plane-wave systems. In the work described in this article, we quantified this velocity error under different geometric and beamforming conditions using numerical simulation and experimental phantoms. We found that the lateral-dependent velocity errors are caused by asymmetrical geometric spectral broadening, and outline a correction algorithm that can mitigate these errors.

A novel, hands-free ultrasound patch for continuous monitoring of quantitative Doppler in the carotid artery.

Quantitative Doppler ultrasound of the carotid artery has been proposed as an instantaneous surrogate for monitoring rapid changes in left ventricular output. Tracking immediate changes in the arterial Doppler spectrogram has value in acute care settings such as the emergency department, operating room and critical care units. We report a novel, hands-free, continuous-wave Doppler ultrasound patch that adheres to the neck and tracks Doppler blood flow metrics in the common carotid artery using an automated algorithm. String and blood-mimicking test objects demonstrated that changes in velocity were accurately measured using both manually and automatically traced Doppler velocity waveforms. In a small usability study with 22 volunteer users (17 clinical, 5 lay), all users were able to locate the carotid Doppler signal on a volunteer subject, and, in a subsequent survey, agreed that the device was easy to use. To illustrate potential clinical applications of the device, the Doppler ultrasound patch was used on a healthy volunteer undergoing a passive leg raise (PLR) as well as on a congestive heart failure patient at resting baseline. The wearable carotid Doppler patch holds promise because of its ease-of-use, velocity measurement accuracy, and ability to continuously record Doppler spectrograms over many cardiac and respiratory cycles.

Investigating the Accumulation of Submicron Phase-Change Droplets in Tumors.

Submicron phase-change droplets are an emerging class of ultrasound contrast agent. Compared with microbubbles, their relatively small size and increased stability offer the potential to passively extravasate and accumulate in solid tumors through the enhanced permeability and retention effect. Under exposure to sufficiently powerful ultrasound, these droplets can convert into in situ gas microbubbles and thus be used as an extravascular-specific contrast agent. However, in vivo imaging methods to detect extravasated droplets have yet to be established. Here, we develop an ultrasound imaging pulse sequence within diagnostic safety limits to selectively detect droplet extravasation in tumors. Tumor-bearing mice were injected with submicron perfluorobutane droplets and interrogated with our imaging-vaporization-imaging sequence. By use of a pulse subtraction method, median droplet extravasation signal relative to the total signal within the tumor was estimated to be Etumor=37±5% compared with the kidney Ekidney=-2±8% (p < 0.001). This work contributes toward the advancement of volatile phase-shift droplets as a next-generation ultrasound agent for imaging and therapy.

Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver - Update 2020 - WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS.

The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS), first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB). The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications.The 2012 guideline requires updating as previously the differences of the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including the United States Food and Drug Administration (FDA) approval as well as the extensive Asian experience, to produce a truly international perspective.These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCA) and are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis to improve the management of patients.

Guidelines and Good Clinical Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the Liver-Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS.

The present, updated document describes the fourth iteration of recommendations for the hepatic use of contrast-enhanced ultrasound, first initiated in 2004 by the European Federation of Societies for Ultrasound in Medicine and Biology. The previous updated editions of the guidelines reflected changes in the available contrast agents and updated the guidelines not only for hepatic but also for non-hepatic applications. The 2012 guideline requires updating as, previously, the differences in the contrast agents were not precisely described and the differences in contrast phases as well as handling were not clearly indicated. In addition, more evidence has been published for all contrast agents. The update also reflects the most recent developments in contrast agents, including U.S. Food and Drug Administration approval and the extensive Asian experience, to produce a truly international perspective. These guidelines and recommendations provide general advice on the use of ultrasound contrast agents (UCAs) and are intended to create standard protocols for the use and administration of UCAs in liver applications on an international basis to improve the management of patients.

High-Frequency Nonlinear Doppler Contrast-Enhanced Ultrasound Imaging of Blood Flow.

Current methods for in vivo microvascular imaging (<1 mm) are limited by the tradeoffs between the depth of penetration, resolution, and acquisition time. Ultrasound Doppler approaches combined at elevated frequencies (<7.5 MHz) are able to visualize smaller vasculature and, however, are still limited in the segmentation of lower velocity blood flow from moving tissue. Contrast-enhanced ultrasound (CEUS) has been successful in visualizing changes in microvascular flow at conventional diagnostic ultrasound imaging frequencies (<7.5 MHz). However, conventional CEUS approaches at elevated frequencies have met with limited success, due, in part, to the diminishing microbubble response with frequency. We apply a plane-wave acquisition combined with the non-linear Doppler processing of ultrasound contrast agents at 15 MHz to improve the resolution of microvascular blood flow while compensating for reduced microbubble response. This plane-wave Doppler approach of imaging ultrasound contrast agents also enables simultaneous detection and separation of blood flow in the microcirculation and higher velocity flow in the larger vasculature. We apply singular value decomposition filtering on the nonlinear Doppler signal to orthogonally separate the more stationary lower velocity flow in the microcirculation and higher velocity flow in the larger vasculature. This orthogonal separation was also utilized to improve time-intensity curve analysis of the microcirculation, by removing higher velocity flow corrupting bolus kinetics. We demonstrate the utility of this imaging approach in a rat spinal cord injury model, requiring submillimeter resolution.

Contrast-Enhanced Ultrasound of Focal Liver Masses: A Success Story.

The epidemic of increasing fatty liver disease and liver cancer worldwide, and especially in Western society, has given new importance to non-invasive liver imaging. Contrast-enhanced ultrasound (CEUS) using microbubble contrast agents provides unique advantages over computed tomography (CT) and magnetic resonance imaging (MRI), the currently established methods. CEUS provides determination of malignancy and allows excellent differential diagnosis of a focal liver mass, based on arterial phase enhancement patterns and assessment of the timing and intensity of washout. Today, increased use of CEUS has provided safe and rapid diagnosis of incidentally detected liver masses, improved multidisciplinary management of nodules in a cirrhotic liver, facilitated ablative therapy for liver tumors and allowed diagnosis of hepatocellular carcinoma without biopsy. Benefits of CEUS include the dynamic real-time depiction of tumor perfusion and the fact that it is a purely intravascular agent, accurately reflecting tumoral and inflammatory blood flow. CEUS has many similarities to contrast-enhanced CT and MRI but also unique differences, which are described. The integration of CEUS into a multimodality imaging setting optimizes patient care.

Imaging Methods for Ultrasound Contrast Agents.

Microbubble contrast agents were introduced more than 25 years ago with the objective of enhancing blood echoes and enabling diagnostic ultrasound to image the microcirculation. Cardiology and oncology waited anxiously for the fulfillment of that objective with one clinical application each: myocardial perfusion, tumor perfusion and angiogenesis imaging. What was necessary though at first was the scientific understanding of microbubble behavior in vivo and the development of imaging technology to deliver the original objective. And indeed, for more than 25 years bubble science and imaging technology have evolved methodically to deliver contrast-enhanced ultrasound. Realization of the basic bubbles properties, non-linear response and ultrasound-induced destruction, has led to a plethora of methods; algorithms and techniques for contrast-enhanced ultrasound (CEUS) and imaging modes such as harmonic imaging, harmonic power Doppler, pulse inversion, amplitude modulation, maximum intensity projection and many others were invented, developed and validated. Today, CEUS is used everywhere in the world with clinical indications both in cardiology and in radiology, and it continues to mature and evolve and has become a basic clinical tool that transforms diagnostic ultrasound into a functional imaging modality. In this review article, we present and explain in detail bubble imaging methods and associated artifacts, perfusion quantification approaches, and implementation considerations and regulatory aspects.

Contrast-enhanced ultrasound approach to the diagnosis of focal liver lesions: the importance of washout.

Contrast-enhanced ultrasound (CEUS) is a powerful technique for differentiating focal liver lesions (FLLs) without the risks of potential nephrotoxicity or ionizing radiation. In the diagnostic algorithm for FLLs on CEUS, washout is an important feature, as its presence is highly suggestive of malignancy and its characteristics are useful in distinguishing hepatocellular from nonhepatocellular malignancies. Interpreting washout on CEUS requires an understanding that microbubble contrast agents are strictly intravascular, unlike computed tomography or magnetic resonance imaging contrast agents. This review explains the definition and types of washout on CEUS in accordance with the 2017 version of the CEUS Liver Imaging Reporting and Data System and presents their applications to differential diagnosis with illustrative examples. Additionally, we propose potential mechanisms of rapid washout and describe the washout phenomenon in benign entities.

Ultrasound Imaging of Hepatocellular Adenoma Using the New Histology Classification.

Hepatocellular adenoma is a rare benign liver tumor. Predisposing factors include hepatic storage diseases and some genetic conditions. A new histology-based classification has been proposed but to date, the corresponding ultrasound imaging features have not been reported. Here we review the new classification scheme and discuss the corresponding features on contrast-enhanced ultrasound imaging.

Persistent Enhancement on Contrast-Enhanced Ultrasound Studies of Severe Crohn's Disease: Stuck Bubbles?

A small population of patients with severe Crohn's disease (CD) exhibit atypical lack of intensity decline on intestinal contrast-enhanced ultrasound. From a retrospective CD cohort examined with contrast-enhanced ultrasound, 104 patients were identified. Twenty study patients with severe active disease exhibited high peak enhancement (>23 dB) and minimal decline. From the same cohort, 84 control patients also exhibited high peak enhancement >23dB, but with typical intensity decline. Patient outcomes were assessed. Time-intensity curve analysis revealed a significantly higher (p < 0.0001) area under the curve (44.7 ± 1.5 dB·s), washout time and intensities at 60s and 120s in the study population compared with controls (40.0 ± 1.1 dB·s). Study patients had a worse overall outcome with surgery in 30% versus 10% (p = 0.027) during follow-up. Heightened enhancement with lack of decline on contrast-enhanced ultrasound suggests microbubbles are stuck within the inflamed bowel wall for an extended period. This observation occurs in patients with severe disease and a bad outcome.

3-D Perfusion Imaging Using Principal Curvature Detection Rendering.

Three-dimensional contrast-enhanced ultrasound (CEUS) imaging presents a clear advantage over its 2-D counterpart in detecting and characterizing suspicious lesions as it properly surveys the inherent heterogeneity of tumors. However, 3-D CEUS is also slow compared to 2-D CEUS and tends to undersample the microbubble wash-in. This makes it difficult to resolve the feeding vessels, an important oncogenic marker, from the background perfusion cloud. Contrast-enhanced Doppler is helpful in isolating this conduit flow, but requires too many pulses in conventional line-by-line beamforming design. Recent breakthroughs in plane-wave imaging have greatly accelerated the volumetric imaging frame rate, but volumetric Doppler angiography still remains challenging when considering real-time limitations on the Doppler ensemble length. In this work, we demonstrate the feasibility of volumetric CEUS angiography subjected to real-time imaging constraints. Namely, we show how principal curvature detection can significantly improve 3-D rendering of relatively noisy ultrasound angiograms without degrading the spatial resolution while subjected to a reasonable Doppler ensemble size. Singular value decomposition is also shown to be capable of identifying the quasi-stationary capillary perfusion.

The Role of Microbubble Echo Phase Lag in Multipulse Contrast-Enhanced Ultrasound Imaging.

In this paper, we assess the importance of microbubble shell composition for contrast-enhanced imaging sequences commonly used on clinical scanners. While the gas core dynamics are primarily responsible for the nonlinear harmonic response of microbubbles at diagnostic pressures, it is now understood that the shell rheology plays a dominant role in the nonlinear response of microbubbles subjected to low acoustic pressures. Of particular interest here, acoustic pressures of tens of kilopascal can cause a reversible phase transition of the phospholipid coatings from a stiff elastic organized state to a less stiff disorganized buckled state. Such a transition from elastic to buckled shell induces a steep variation of the shell elasticity, which alters the microbubble acoustic scattering properties. We demonstrate in this paper that this mechanism plays a dominant role in contrast pulse sequences that modulate the amplitude of the insonifying pulse pressure. The contrast-to-tissue ratio (CTR) for amplitude modulation (AM), pulse inversion (PI), and amplitude modulation pulse inversion (AMPI) is measured in vitro for Definity, Sonazoid, both lipid-encapsulted microbubbles, and the albumin-coated Optison. It is found that pulse sequences using AM significantly enhanced the nonlinear response of all studied microbubbles compared to PI (up to 15 dB more) when low insonation pressures under 200 kPa were used. Further investigation reveals that the origin of the hyperechoicity is a small phase lag occurring between the echoes from the full-and half-amplitude driving pulses, and that the effect could be attributed to the shell softening dynamics of lipid and albumin coatings. We assess that this additional phase in microbubble ultrasound scattering can have a dominant role in the CTR achieved in contrast sequences using AM. We also show that the pressure dependent phase lag is a specific marker for microbubbles with no equivalent in tissue, which can be used to segment microbubbles from the tissue harmonics and significantly increase the CTR.

Impact of Encapsulation on in vitro and in vivo Performance of Volatile Nanoscale Phase-Shift Perfluorocarbon Droplets.

Phase-shift droplets can be converted by sound from low-echogenicity, liquid-core agents into highly echogenic microbubbles. Many proposed applications in imaging and therapy take advantage of the high spatiotemporal control over this dynamic transition. Although some studies have reported increased circulation time of the droplets compared with microbubbles, few have directly explored the impact of encapsulation on droplet performance. With the goal of developing nanoscale droplets with increased circulatory persistence, we first evaluate the half-life of several candidate phospholipid encapsulations in vitro at clinical frequencies. To evaluate in vivo circulatory persistence, we develop a technique to periodically measure droplet vaporization from high-frequency B-mode scans of a mouse kidney. Results show that longer acyl chain phospholipids can dramatically reduce droplet degradation, increasing median half-life in vitro to 25.6 min-a 50-fold increase over droplets formed from phospholipids commonly used for clinical microbubbles. In vivo, the best-performing droplet formulations showed a median half-life of 18.4 min, more than a 35-fold increase in circulatory half-life compared with microbubbles with the same encapsulation in vivo. These findings also point to possible refinements that may improve nanoscale phase-shift droplet performance beyond those measured here.

How to perform Contrast-Enhanced Ultrasound (CEUS).

"How to perform contrast-enhanced ultrasound (CEUS)" provides general advice on the use of ultrasound contrast agents (UCAs) for clinical decision-making and reviews technical parameters for optimal CEUS performance. CEUS techniques vary between centers, therefore, experts from EFSUMB, WFUMB and from the CEUS LI-RADS working group created a discussion forum to standardize the CEUS examination technique according to published evidence and best personal experience. The goal is to standardise the use and administration of UCAs to facilitate correct diagnoses and ultimately to improve the management and outcomes of patients.

The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib.

OBJECTIVES: To identify dynamic contrast-enhanced (DCE) imaging parameters from MRI, CT and US that are prognostic and predictive in patients with metastatic renal cell cancer (mRCC) receiving sunitinib. METHODS: Thirty-four patients were monitored by DCE imaging on day 0 and 14 of the first course of sunitinib treatment. Additional scans were performed with DCE-US only (day 7 or 28 and 2 weeks after the treatment break). Perfusion parameters that demonstrated a significant correlation (Spearman p < 0.05) with progression-free survival (PFS) and overall survival (OS) were investigated using Cox proportional hazard models/ratios (HR) and Kaplan-Meier survival analysis. RESULTS: A higher baseline and day 14 value for Ktrans (DCE-MRI) and a lower pre-treatment vascular heterogeneity (DCE-US) were significantly associated with a longer PFS (HR, 0.62, 0.37 and 5.5, respectively). A larger per cent decrease in blood volume on day 14 (DCE-US) predicted a longer OS (HR, 1.45). We did not find significant correlations between any of the DCE-CT parameters and PFS/OS, unless a cut-off analysis was used. CONCLUSIONS: DCE-MRI, -CT and ultrasound produce complementary parameters that reflect the prognosis of patients receiving sunitinib for mRCC. Blood volume measured by DCE-US was the only parameter whose change during early anti-angiogenic therapy predicted for OS and PFS. KEY POINTS: • DCE-CT, -MRI and ultrasound are complementary modalities for monitoring anti-angiogenic therapy. • The change in blood volume measured by DCE-US was predictive of OS/PFS. • Baseline vascular heterogeneity by DCE-US has the strongest prognostic value for PFS.

Improved Contrast-Enhanced Power Doppler Using a Coherence-Based Estimator.

While plane-wave imaging can improve the performance of power Doppler by enabling much longer ensembles than systems using focused beams, the long-ensemble averaging of the zero-lag autocorrelation R(0) estimates does not directly decrease the mean noise level, but only decreases its variance. Spatial variation of the noise due to the time-gain compensation and the received beamforming aperture ultimately limits sensitivity. In this paper, we demonstrate that the performance of power Doppler imaging can be improved by leveraging the higher lags of the autocorrelation [e.g., R(1), R(2),…] instead of the signal power (R(0)). As noise is completely uncorrelated from pulse-to-pulse while the flow signal remains correlated significantly longer, weak signals just above the noise floor can be made visible through the reduction of the noise floor. Finally, as coherence decreases proportionally with respect to velocity, we demonstrate how signal coherence can be targeted to separate flows of different velocities. For instance, we show how long-time-range coherence of microbubble contrast-enhanced flow specifically isolates slow capillary perfusion (as opposed to conduit flow).

Integration of Contrast-enhanced US into a Multimodality Approach to Imaging of Nodules in a Cirrhotic Liver: How I Do It.

Accurate characterization of cirrhotic nodules and early diagnosis of hepatocellular carcinoma (HCC) are of vital importance. Currently, computed tomography (CT) and magnetic resonance (MR) imaging are standard modalities for the investigation of new nodules found at surveillance ultrasonography (US). This article describes the successful integration of contrast material-enhanced US into a multimodality approach for diagnosis of HCC and its benefits in this population. The application of contrast-enhanced US immediately following surveillance US allows for prompt dynamic contrast-enhanced evaluation, removing the need for further imaging of benign lesions. Contrast-enhanced US also provides dynamic real-time assessment of tumor vascularity so that contrast enhancement can be identified regardless of its timing or duration, allowing for detection of arterial hypervascularity and portal venous washout. The purely intravascular nature of US contrast agents is valuable as the rapid washout of nonhepatocyte malignancies is highly contributory to their differentiation from HCC. The authors believe contrast-enhanced US provides complementary information to CT and MR imaging in the characterization of nodules in high-risk patients. © RSNA, 2017 Online supplemental material is available for this article.