Motion Artifacts and Correction in Multipulse High-Frame Rate Contrast-Enhanced Ultrasound.

High-frame-rate (HFR) ultrasound (US) imaging and contrast-enhanced US (CEUS) are often implemented using multipulse transmissions, to enhance image quality. Multipulse approaches, however, suffer from degradation in the presence of motion, especially when coherent compounding and CEUS are combined. In this paper, we investigate this effect on the intensity of HFR CEUS in deep tissue imaging using simulations and in vivo contrast echocardiography (CE). The simulation results show that the motion artifact is much higher when the flow is in an axial direction than a lateral direction. Using a pulse repetition frequency suitable for cardiac imaging, a motion of 35 cm/s can cause as much as 28.5 dB decrease in image intensity, where compounding can contribute up to 18.7 dB of intensity decrease (11 angles). These motion effects are also demonstrated for in vivo cardiac HFR CE, where the large velocities of both the myocardium and the blood are present. Intensity reductions of 10.4 dB are readily visible in the chamber. Finally, we demonstrate how performing motion-correction before pulse inversion compounding greatly reduces such motion artifact and improve image signal-to-noise ratio and contrast.

Variability in circulating gas emboli after a same scuba diving exposure.

PURPOSE: A reduction in ambient pressure or decompression from scuba diving can result in ultrasound-detectable venous gas emboli (VGE). These environmental exposures carry a risk of decompression sickness (DCS) which is mitigated by adherence to decompression schedules; however, bubbles are routinely observed for dives well within these limits and significant inter-personal variability in DCS risk exists. Here, we assess the variability and evolution of VGE for 2 h post-dive using echocardiography, following a standardized pool dive in calm warm conditions. METHODS: 14 divers performed either one or two (with a 24 h interval) standardized scuba dives to 33 mfw (400 kPa) for 20 min of immersion time at NEMO 33 in Brussels, Belgium. Measurements were performed at 21, 56, 91 and 126 min post-dive: bubbles were counted for all 68 echocardiography recordings and the average over ten consecutive cardiac cycles taken as the bubble score. RESULTS: Significant inter-personal variability was demonstrated despite all divers following the same protocol in controlled pool conditions: in the detection or not of VGE, in the peak VGE score, as well as time to VGE peak. In addition, intra-personal differences in 2/3 of the consecutive day dives were seen (lower VGE counts or faster clearance). CONCLUSIONS: Since VGE evolution post-dive varies between people, more work is clearly needed to isolate contributing factors. In this respect, going toward a more continuous evaluation, or developing new means to detect decompression stress markers, may offer the ability to better assess dynamic correlations to other physiological parameters.

Acoustic super-resolution with ultrasound and microbubbles.

Ultrasound (US) is a widely used clinical imaging modality that offers penetration depths in tissue of >10 cm. However, the spatial resolution in US imaging is fundamentally limited by diffraction to approximately half the wavelength of the sound wave employed. The spatial resolution of optical microscopy is limited by the same fundamental physics, but in recent years super-resolution imaging techniques have been developed that overcome the diffraction limit through the localization of many spatially separated photo-switchable or photo-activatable fluorophores. In this paper, we apply a related approach to demonstrate super-resolution imaging with US. We imaged dilute suspensions of microbubble contrast agents flowing through narrow tube-based phantoms. By spatially localizing multiple spatially isolated microbubbles, we constructed super-resolved microbubble location density maps that clearly resolve features 5.1-2.2 times smaller than the US system point spread function full width half maximum in the lateral and axial directions respectively. Our initial characterization experiment using a fixed 100 µm diameter brass wire and a US frequency of 2 MHz suggests that for an ideal stationary point scatterer the ultimate resolution of the unmodified clinical US system used could be in the range of 2-4 µm.

A comparison of 31P magnetic resonance spectroscopy and microbubble-enhanced ultrasound for characterizing hepatitis c-related liver disease.

We compared in vivo hepatic (31) P magnetic resonance spectroscopy ((31) P MRS) and hepatic vein transit times (HVTT) using contrast-enhanced ultrasound with a microbubble agent to assess the severity of hepatitis C virus (HCV)-related liver disease. Forty-six patients with biopsy-proven HCV-related liver disease and nine healthy volunteers had (31) P MRS and HVTT performed on the same day. (31) P MR spectra were obtained at 1.5 T. Peak areas were calculated for metabolites, including phosphomonoesters (PME) and phosphodiesters (PDE). Patients also had the microbubble ultrasound contrast agent, Levovist (2 g), injected into an antecubital vein, and time-intensity Doppler ultrasound signals of the right and middle hepatic veins were measured. The HVTT was calculated as the time from injection to a sustained rise in Doppler signal 10% greater than baseline. The shortest times were used for analysis. Based on Ishak histological scoring, there were 15 patients with mild hepatitis, 20 with moderate/severe hepatitis and 11 with cirrhosis. With increasing severity of disease, the PME/PDE ratio was steadily elevated, while the HVTT showed a monotonic decrease. Both imaging modalities could separate patients with cirrhosis from the mild and moderate/severe hepatitis groups. No statistical difference was observed in the accuracy of each test to denote mild, moderate/severe hepatitis and cirrhosis (Fisher's exact test P =1.00). (31) P MRS and HVTT show much promise as noninvasive imaging tests for assessing the severity of chronic liver disease. Both are equally effective and highly sensitive in detecting cirrhosis.

Quantitative contrast-enhanced ultrasound imaging: a review of sources of variability.

Ultrasound provides a valuable tool for medical diagnosis offering real-time imaging with excellent spatial resolution and low cost. The advent of microbubble contrast agents has provided the additional ability to obtain essential quantitative information relating to tissue vascularity, tissue perfusion and even endothelial wall function. This technique has shown great promise for diagnosis and monitoring in a wide range of clinical conditions such as cardiovascular diseases and cancer, with considerable potential benefits in terms of patient care. A key challenge of this technique, however, is the existence of significant variations in the imaging results, and the lack of understanding regarding their origin. The aim of this paper is to review the potential sources of variability in the quantification of tissue perfusion based on microbubble contrast-enhanced ultrasound images. These are divided into the following three categories: (i) factors relating to the scanner setting, which include transmission power, transmission focal depth, dynamic range, signal gain and transmission frequency, (ii) factors relating to the patient, which include body physical differences, physiological interaction of body with bubbles, propagation and attenuation through tissue, and tissue motion, and (iii) factors relating to the microbubbles, which include the type of bubbles and their stability, preparation and injection and dosage. It has been shown that the factors in all the three categories can significantly affect the imaging results and contribute to the variations observed. How these factors influence quantitative imaging is explained and possible methods for reducing such variations are discussed.

Photoacoustics, thermoacoustics, and acousto-optics for biomedical imaging.

Recently there have been significant advances in developing hybrid techniques combining electromagnetic waves with ultrasound for biomedical imaging, namely photoacoustic, thermoacoustic, and acousto-optic (or ultrasound modulated optical) tomography. All three techniques take advantage of tissue contrast offered by electromagnetic (EM) waves, while achieving good spatial resolution in deeper tissue facilitated by ultrasound. In this review the principles of the three techniques are introduced. A description of existing experimental and image reconstruction techniques is provided. Some recent key developments are highlighted and current issues in each of the areas are discussed.

Hepatic vein transit times of a microbubble agent in assessing response to antiviral treatment in patients with chronic hepatitis C.

Microbubble measurement of hepatic vein transit times (HVTT) may have the potential to assess severity of hepatitis C virus (HCV)-related liver disease, where there is a shorter HVTT with more severe disease. We investigated the utility of this test as a marker of response to antiviral treatment. Thirty-seven patients with biopsy-proven HCV-related disease undergoing antiviral treatment were studied. All had baseline scans and then repeat scans 6 months after the end of treatment. HVTT using Levovist were obtained from the right and middle hepatic veins, and the shorter time was used for analysis. The aspartate aminotransferase to platelet ratio index (APRI) scores were calculated retrospectively. There were seven patients with mild hepatitis, 23 with moderate/severe hepatitis and seven with cirrhosis. The mean baseline HVTT in responders ± SE increased from 27.3 ± 2.29 s to 33.5 ± 2.8 s posttreatment (P = 0.01). In the 10 nonresponders, the HVTT remained the same; 43.3 ± 9 s baseline compared to 44 ± 7.8 s posttreatment (P = 0.84). This trend was also seen with the APRI score where in responders, the mean score decreased from 1.1 ± 0.2 to 0.74 ± 1 (P = 0.03) and in nonresponders, the score remained unchanged; 0.88 ± 0.2 compared to 0.84 ± 0.2 (P = 0.31). HVTT measurement lengthened, while APRI scores decreased in patients who responded to antiviral treatment while both remained the same, shortened (HVTT) or increased (APRI), respectively, in patients who were nonresponders. These results are encouraging and indicate that these tests could be potentially used as markers of response to treatment and could obviate the need for serial biopsies in antiviral future treatment studies.

Hepatic vein transit times using a microbubble agent can predict disease severity non-invasively in patients with hepatitis C.

BACKGROUND AND AIMS: A reliable non-invasive assessment of the severity of diffuse liver disease is much needed. We investigated the utility of hepatic vein transit times (HVTT) for grading and staging diffuse liver disease in a cohort of patients with hepatitis C virus (HCV) infection using an ultrasound microbubble contrast agent as a tracer. MATERIALS AND METHODS: Eighty five untreated patients with biopsy proven HCV induced liver disease were studied prospectively. All were HCV RNA positive on polymerase chain reaction testing. Based on their histological fibrosis (F) and necroinflammatory (NI) scores, untreated patients were divided into mild hepatitis (F < or =2/6, NI < or =3/18), moderate/severe hepatitis (3 < or =F <6 or NI > or =4), and cirrhosis (F=6/6) groups. In addition, 20 age matched healthy volunteers were studied. After an overnight fast, a bolus of contrast agent (Levovist) was injected into an antecubital vein and spectral Doppler signals were recorded from both the right and middle hepatic veins for analysis. HVTTs were calculated as the time from injection to a sustained rise in Doppler signal >10% above baseline. The Doppler signals from the carotid artery were also measured in 60 patients and carotid delay times (CDT) calculated as the difference between carotid and hepatic vein arrival times. The earliest HVTT in each patient was used for analysis. RESULTS: Mean (SEM) HVTT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis groups showed a monotonic decrease of 38.1 (2.8), 38.8 (2.4), 26.0 (2.4), and 15.8 (0.8) seconds, respectively. Mean (SEM) CDT for the control, mild hepatitis, moderate/severe hepatitis, and cirrhosis patients again showed progressive shortening of 30.3 (2.6), 25.9 (2.6), 14.8 (2.1), and 5.6 (1.2) seconds, respectively. There were significant differences between the groups for HVTT (ANOVA, p<0.001) and CDT (ANOVA, p<0.001). There was 100% sensitivity and 80% specificity for diagnosing cirrhosis and 95% sensitivity and 86% specificity for differentiating mild hepatitis from more severe liver disease. CONCLUSION: We have shown, for the first time, that HVTT using an ultrasound microbubble contrast agent can assess HCV related liver disease with clear differentiation between mild hepatitis and cirrhosis. There were significant differences between these two groups and the moderate/severe hepatitis group. CDT offers no additional benefit or greater differentiation than HVTT and can be omitted, thus simplifying this technique. HVTT may complement liver biopsy and may also be a useful alternative for assessment of liver disease in patients who have contraindications to biopsy.

Liver microbubble transit time compared with histology and Child-Pugh score in diffuse liver disease: a cross sectional study.

BACKGROUND: A previous pilot study showed that early arrival time of a microbubble in a hepatic vein is a sensitive indicator of cirrhosis. AIM: To see if this index can also grade diffuse liver disease. PATIENTS: Thirty nine fasted patients with histologically characterised disease were studied prospectively. Nine patients had no evidence of liver fibrosis, 10 had fibrosis without cirrhosis, and 20 had cirrhosis (five Child's A, seven Child's B, and eight Child's C). METHODS: Bolus injections of a microbubble (Levovist; Schering, Berlin) were given intravenously, followed by a saline flush. Time intensity curves of hepatic vein and carotid artery spectral Doppler signals were analysed. Hepatic vein transit time (HVTT) was calculated as the time after injection at which a sustained signal increase >10% of baseline was seen. Carotid delay time (CDT) was calculated as the difference between carotid and hepatic vein enhancement. RESULTS: Diagnostic studies were achieved in 38/39 subjects. Both HVTT and CDT became consistently shorter with worsening disease, as follows (means (SD)): HVTT: no fibrosis 44 (25) s, fibrosis 26 (8) s, Child's A 21 (1) s, Child's B 16 (3) s, and Child's C 16 (2) s; CDT: no fibrosis 31 (29) s, fibrosis 14 (6) s, Child's A 8 (1) s, Child's B 4 (4) s, and Child's C 3 (3) s. These differences were highly significant (p<0.001, ANOVA comparison). A HVTT <24 s and a CDT <10 s were 100% sensitive for cirrhosis (20/20 and 18/18, respectively) but not completely specific: 2/8 subjects with fibrosis had CDT values <10 s and 3/9 had HVTT <24 s. CONCLUSION: This minimally invasive test shows promise not only in diagnosing cirrhosis but also in assessing disease severity.

Functional ultrasound methods in oncological imaging.

The real time nature of ultrasound and functional methods such as Doppler ultrasound mean that ultrasound can claim to have always been a functional imaging method, but recent developments in quantitation, dramatic improvement in Doppler performance and now microbubbles have created many exciting new applications. These include methods for assessing the neovascularity of tumours, for following the effects of therapy and for predicting the likelihood of development of metastatic disease at the staging of primary tumours.

Do different types of liver lesions differ in their uptake of the microbubble contrast agent SH U 508A in the late liver phase? Early experience.

PURPOSE: To compare the uptake of SH U 508A in different types of liver lesions by using stimulated acoustic emission. MATERIALS AND METHODS: Thirty-seven patients with characterized lesions (metastasis, n = 17; hepatocellular carcinoma, n = 4; hemangioma, n = 9; focal nodular hyperplasia, n = 7) received 2.5 g SH U 508A. After 5 minutes, stimulated acoustic emission was elicited by using a previously described method. Liver and/or lesional differences were assessed with videodensitometry (objective conspicuity score), and two observers assessed each lesion by using a six-point scale (subjective conspicuity score). RESULTS: Metastases and hepatocellular carcinoma had low stimulated acoustic emission; median objective conspicuity scores were 70% and 68% (all scores were > or =43%), respectively, and subjective conspicuity scores were 2 or higher for both observers. Hemangiomas had reduced stimulated acoustic emission, with more variability; the median objective conspicuity score was 41% (range, 9%-72%), and the median subjective conspicuity scores were 2 (range, 1-4) and 3.5 (range, 1-5) for observers 1 and 2, respectively. Focal nodular hyperplasia had stimulated acoustic emission comparable to that of the liver in all cases; the median objective conspicuity score was -4.7% (all scores were <6%), and the subjective conspicuity score was 1 or lower for both observers. This finding completely separated focal nodular hyperplasia and malignancies. Significant differences were seen between focal nodular hyperplasia and all other lesion types (P < .05). CONCLUSION: Strong late-phase lesional uptake of SH U 508A is characteristic of focal nodular hyperplasia, is seen in some hemangiomas, and was not observed in malignancies.

Developments in ultrasound contrast media.

Ultrasound microbubble contrast agents are effective and safe echo enhancers. An ingenious array of methods are employed to achieve stability and provide a clinically useful enhancement period. Microbubbles enhance ultrasound signals by up to 25 dB (greater than 300-fold increase) due to resonant behaviour. This is used to rescue failed Doppler studies and may be extended to image the microcirculation of tumours and the myocardium using non-linear modes. Functional studies open up a whole range of applications by using a variety of active and passive quantitation techniques to derive indices from the transit of contrast through a tissue of interest. This has been especially successful in the detection of liver metastases and cirrhosis and shows great promise as a clinical tool. It also has great potential in measuring microcirculatory flow velocity. The demonstration that some microbubbles are not just pure blood pool agents but have a hepatosplenic specific phase has extended the versatility of ultrasound. Imaging of this stationary phase with non-linear modes such as phase inversion and stimulated acoustic emission, has improved the sensitivity and specificity of ultrasound in the detection and characterisation of focal liver lesions to rival that of CT and MR.

Liver lesions: intermittent second-harmonic gray-scale US can increase conspicuity with microbubble contrast material-early experience.

The authors investigated the effect of intermittent second-harmonic gray-scale (ISHGS) ultrasonography (US) with SH U 508A microbubbles on the conspicuity of focal liver lesions. Twenty-three patients were included in the study. Images were analyzed subjectively and quantitatively. Objective lesion conspicuity was increased. In 12 of the 15 patients with liver malignancy, gray-scale defects were seen in previously unsuspected areas. ISHGS US may improve the sensitivity of US for liver lesions.

Hepatic malignancies: improved detection with pulse-inversion US in late phase of enhancement with SH U 508A-early experience.

Twenty consecutive patients with known liver malignancies underwent ultrasonography (US) in conventional B mode and in pulse-inversion mode in the late hepatic-specific parenchymal phase after intravenous administration of SH U 508A, a microbubble US contrast agent. Two experienced readers assessed subjective and objective conspicuity, number of lesions, and smallest lesion diameter in each mode. Subjective and objective conspicuity were improved with pulse-inversion mode, and smaller lesions were depicted with pulse-inversion mode than with conventional B mode, improving the detection of metastases less than 1 cm in size.

Pulse-inversion mode imaging of liver specific microbubbles: improved detection of subcentimetre metastases.

Pulse-inversion mode (a new ultrasound mode) can be used to image the late liver-specific parenchymal phase of the microbubble contrast-agent Levovist. Scanning in pulse-inversion mode after Levovist improves the detection of liver metastases and reveals more lesions of smaller size than conventional ultrasonography and computed tomography.

[Stimulated acoustic emissions with the ultrasound contrast medium levovist: a clinically useful contrast effect with liver-specific properties]. / Stimulierte akustische Emission mit dem Ultraschall-Kontrastmittel Levovist: Ein klinisch nutzbarer Kontrasteffekt mit leberspezifischen Eigenschaften.

PURPOSE: The purpose of this study was systematically to investigate stimulated acoustic emission (SAE) with the microbubble contrast agent Levovist (Schering AG, Berlin) in vivo with regards to reproducibility, distribution in various organs over time, dependence on technical factors, and influence on the delineation of focal liver lesions. PATIENTS AND METHODS: 2 intravenous injections of 1 g of Levovist were given to 2 dogs and 1-6 injections of 2.5 g Levovist to 5 healthy volunteers and 37 patients. The liver, spleen, large abdominal vessels, and kidney were intermittently scanned for up to 30 min. Studies were evaluated for the presence of SAE signals by 2 observers. In 20 patients with focal liver lesions (15 with metastases, 4 haemangiomata, 1 hepatocellular carcinoma, and 1 cyst) the influence on lesion visualization was also assessed. RESULTS: SAE effects, lasting up to 30 minutes, were seen in all subjects in the liver and spleen. Vascular and renal SAE signals were noted shortly after injection, lasting up to 6 minutes. SAE was absent or markedly reduced in focal liver lesions, which were seen as colour voids. This increased the conspicuity of focal lesions, and in 5 patients additional metastases were detected that could not be delineated on B-mode alone. CONCLUSION: A liver- and spleen-specific late phase of Levovist can be consistently demonstrated using SAE and the effect increases the conspicuity of focal liver lesions.

Improved imaging of liver metastases with stimulated acoustic emission in the late phase of enhancement with the US contrast agent SH U 508A: early experience.

PURPOSE: To see whether stimulated acoustic emission (SAE) in the liver parenchyma in the late phase of enhancement with SH U 508A increases the conspicuity of occult metastases at ultrasonography (US). MATERIALS AND METHODS: Eighteen patients with known hypo- or hypervascular hepatic metastases underwent US after SH U 508A administration, after a delay of at least 5 minutes, to ensure decay of blood pool enhancement. In 16 patients with visible metastases, conspicuity was compared on registered SAE and gray-scale scans by two blinded readers and by using computerized analysis of relative gray-scale and color Doppler conspicuity scores inside and outside the lesion. In nine patients, areas suspected of being involved but without definite gray-scale masses were imaged in the same way. Paired sections were analyzed by two blinded readers looking for parenchymal color defects without corresponding gray-scale masses; nine control images from three healthy volunteers were also included. RESULTS: Intense, transient parenchymal SAE was seen in all subjects. All metastases appeared as areas of reduced or absent signal. The conspicuity score was 80% for SAE versus 9% for gray-scale US (P < .001, Wilcoxon signed rank test). SAE-specific defects were seen in all patients but in none of the volunteers. Metastases seen on SAE but undetectable on gray-scale images were proved in three patients. CONCLUSION: SAE with SH U 508A improves the conspicuity of metastases. SAE-specific defects may reveal isoechoic or subtle metastases.

Stimulated acoustic emission to image a late liver and spleen-specific phase of Levovist in normal volunteers and patients with and without liver disease.

Quantitative studies were performed to investigate liver- specific uptake of the microbubble Levovist, using stimulated acoustic emission (SAE), which can detect microbubbles even when stationary or slow-moving. These comprised studies of biodistribution comparing the liver and kidney in five normal volunteers, reproducibility in 34 patients, comparison between cirrhotics and controls (n = 9 each) and maximal depth of effect at different frequencies (180 measurements in 31 patients). Stimulated acoustic emission lasted beyond 30 min, with strongly liver-specific properties in each volunteer and was highly reproducible. No difference in the amount of SAE in the superficial liver was seen between cirrhotic and normal livers, but attenuation was higher in cirrhotics. This demonstrates a frequency-dependent effect on liver SAE penetration. We conclude that the liver uptake of Levovist lasts over 30 min, is reproducible, occurs even where diffuse liver disease is present and can be used to assess tissue attenuation in a novel fashion.