Initial investigation of acoustic droplet vaporization for occlusion in canine kidney.

Acoustic droplet vaporization (ADV) shows promise for spatially and temporally targeted tissue occlusion. In this study, substantial tissue occlusion was achieved in operatively exposed and transcutaneous canine kidneys by generating ADV gas bubbles in the renal arteries or segmental arteries. Fifteen canines were anesthetized, among which 10 underwent laparotomy to externalize the left kidney and five were undisturbed for transcutaneous ADV. The microbubbles were generated by phase conversion of perfluoropentane droplets encapsulated in albumin or lipid shells in the blood. A 3.5-MHz single-element therapy transducer was aligned with an imaging array in a water tank with direct access to the renal artery or a segmental artery. In vivo color flow and spectral Doppler imaging were used to identify the target arteries. Tone bursts of 1 kHz pulse repetition frequency with 0.25% duty cycle vaporized the droplets during bolus passage. Both intracardiac (IC) and intravenous (IV) injections repeatedly produced ADV in chosen arteries in externalized kidneys, as seen by B-mode imaging. Concurrent with this in two cases was the detection by pulse-wave Doppler of blood flow reversal, along with a narrowing of the waveform. Localized cortex occlusion was achieved with 87% regional flow reduction in one case using IC injections. Vaporization from IV injections resulted in a substantial echogenicity increase with an average half-life of 8 min per droplet dose. Gas bubbles sufficient to produce some shadowing were generated by transcutaneous vaporization of intrarenal artery or IV-administered droplets, with a tissue path up to 5.5 cm.

Rapid 3-D imaging of contrast flow: application in a perfused kidney phantom.

Previous studies indicate imaging of ultrasound contrast in 3-D is potentially superior to 2-D imaging for vascular characterization. A dual-beam, dynamic refill technique, which relies on volumetric contrast clearance and sequential imaging, was used to image a preserved porcine kidney perfused with contrast. A model was developed for the contrast profile across the renal artery to estimate fractional blood volume. This model was used along with refill curve information to measure absolute perfusion within renal cortex for a 100-cm(3) volume. Perfusion measurements from a slice within the volume were also made using a modified interval imaging technique. The measured perfusion using the dual-beam technique was consistent with the perfusion measured using the interval imaging technique (dual-beam values were 1.06 +/- 0.04 x corresponding interval imaging values). These experiments suggest that ultrasound contrast perfusion measurements are independent of the volume of contrast eliminated before refill.

Analysis of refill curve shape in ultrasound contrast agent studies.

Contrast destruction and replenishment by Flash Echo Imaging (FEI) (also referred to as interval or intermittent imaging) has been qualitatively and quantitatively used for tissue blood refill measurements. Many features and capabilities of contrast refill in tissue blood flow and perfusion remain to be elucidated. To aid the development and full reliable utilization of the technique in medical practice, in this paper we undertake physical and mathematical modeling to evaluate different measures derivable from FEI and to provide a basis for the further study of sensitivity and stability of such measures for the detection and measurement of various flow properties and abnormalities. A phantom was developed and used to conduct a dynamic contrast study. Refill curves were investigated as a means of calculating the mean transit time (MTT) and investigating other information that can be determined from their shape. Exponential and error function fits and the area above these curves were used to estimate MTT. The bubble disruption zone was visually measured and theoretically modeled. Computer simulated refill curves based on the flow phantom for different velocity ranges were then computed and compared to the experimental refill curves. The simulated refill curves closely matched the experimental curves in both shape and MTT. The simulated refill curves matched the shape of the experimental results for different velocity ranges. Another simulation examined how a real circulatory system might influence refill. Different refill curve shapes were obtained for different vascular models. Models including the large arteries and veins showed a much faster initial slope than models where the large vessels were not included. Likewise, simulated "shunting" displayed a different slope than models without "shunting" and specific portions of the refill curve that could maximally distinguish shunting. This computer simulation could lead to some experimental hypotheses about differences between normal and cancerous blood flow.

Doppler quantitative measures by region to discriminate prostate cancer.

This study was conducted to assess if sonographic discrimination between healthy and cancerous prostate tissue might be improved using regional analysis of ultrasound (US) Doppler measures. A total of 39 subjects underwent 3-D Doppler sonography before radical prostatectomy. Cancer locations were identified from hematoxylin and eosin (H&E)-stained slides. Three prostate data volumes consisting of a frequency shift and power-mode Doppler US and whole mount histology images were spatially registered for each prostate, then divided into entirely 1 mL-sized regions of cancerous or noncancerous tissue. Each prostate was visually divided into a peripheral and a periurethral region within which US Doppler measures were calculated. Receiver operating characteristic (ROC) and simulated biopsy analyses within each prostate were performed. Mean speed in colored pixels (V), and speed-weighted pixel density (SWD) are good discriminators for prostate cancer in the periurethral and the peripheral regions, respectively. Using SWD in a simulated biopsy yields increased cancer detection in the peripheral region.

Analysis of three-dimensional Doppler ultrasonographic quantitative measures for the discrimination of prostate cancer.

OBJECTIVE: The purpose of this study was to determine whether several quantitative ultrasonographic measures have potential to discriminate prostate cancer from normal prostate and to determine the best combination of these measures. The true spatial distributions of cancer within the prostates studied were obtained histologically after radical prostatectomy. The relationship between Doppler ultrasonography and microvessel count was also investigated. METHODS: Three-dimensional Doppler ultrasonographic data were acquired from 39 patients before radical prostatectomy. The removed prostate was sectioned, and whole-mount hematoxylineosin-stained slides were used to identify all regions of cancer within each prostate. These histologic and ultrasonographic data were spatially registered. Doppler ultrasonographic measures were calculated within uniformly sized three-dimensional regions that were either entirely cancerous or noncancerous, and receiver operating characteristic analysis was performed on the results. Microvessel counts were made within each contiguous cancerous region and correlated with ultrasonographic measures. RESULTS: Color pixel density was the best simple measure for discriminating prostate cancer (accuracy, 80%). The mean power mode value (normalized mean power in color pixels) was inversely related to cancer with an accuracy of 1--normalized mean power in color pixels = 65% (low mean power is more cancerous). When color pixel density was combined with the normalized mean power in color pixels, its accuracy improved slightly to 84%. The peak microvessel count had a negative correlation with color pixel density as well as with cancer stage. CONCLUSION: Doppler ultrasonography does provide discriminatory information for prostate cancer, with color pixel density being the most promising measure.

Analysis of three-dimensional ultrasound Doppler for the detection of prostate cancer.

OBJECTIVES: To investigate the relative effectiveness of Doppler ultrasound quantitative measures in discriminating prostate cancer from normal prostate tissue. The true locations of prostate cancer within these prostates were determined by histologic examination after radical prostatectomy. METHODS: Three-dimensional Doppler ultrasound data were acquired from 39 men before radical prostatectomy. The removed prostates were sectioned and all cancerous regions in each prostate were identified on whole-mount hematoxylin-eosin-stained slides. The ultrasound and histologic data were then spatially registered. Biopsy results were simulated on a grid of potential sites within each prostate. Along each simulated biopsy site, the amount of cancer was computed from the hematoxylin-eosin-identified cancerous regions and the peak speed-weighted pixel density (SWD) was compared. RESULTS: By selecting the biopsy sites with higher associated SWDs within each sextant, the probability of having at least one positive biopsy within a prostate increased from 75% if the SWD was ignored to 85% if only the top 15% of potential biopsy sites in each sextant were selected. This trend was seen within each sextant individually as well. CONCLUSIONS: Doppler ultrasound provides discriminatory information for prostate cancer using the SWD. Translating this into a practical strategy that might improve the yield of prostate biopsy remains under development. The results of our study indicate that biopsying regions of high Doppler color could potentially increase the cancer yield to a small degree and improve the accuracy of the biopsy results. These results also objectively verify previous visual studies suggesting a modest improvement with the use of color Doppler.

Discrimination of sonographically detected breast masses using frequency shift color Doppler imaging in combination with age and gray scale criteria.

Frequency shift color Doppler imaging was assessed in conjunction with patient age and gray scale (GS) features for discriminating benign from malignant breast masses. Thirty-eight women with sonographically detected masses scheduled for biopsy were evaluated using a 6- to 13-MHz scan head, and the masses were delineated in ultrasonographic image volumes. Vascularity in and around each mass was quantified using speed-weighted pixel density (SWD). Gray scale features were ranked visually on a linear scale. Combinations of indices were compared with histologic findings (18 benign and 20 malignant). Receiver operating characteristic analysis ranked performance in decreasing order from the SWD-Age-GS index, to SWD-GS, SWD-Age, Age-GS, GS criteria, SWD, and Age. At 100% sensitivity, SWD-Age-GS, SWD-GS, and SWD-Age discriminated benign from malignant masses with specificities of 94%, 89%, and 72%, respectively. These results indicate significant improvement in ultrasonographic discrimination of sonographically detected breast masses by combining the vascularity measure SWD with age and GS criteria.

Acoustic droplet vaporization for therapeutic and diagnostic applications.

A phase shift droplet emulsion is introduced as an aid to unusual ultrasound (US) applications. The transpulmonary droplet emulsion (90% < 6 microm diameter) is made by mixing saline, bovine albumin and dodecafluoropentane. It has been observed that an acoustic pressure threshold exists, above which the droplets vaporize into bubbles approximately 25 times the original diameter. For frequencies between 1.5 and 8 MHz, the threshold decreases from 4.5 to 0.75 MPa peak rarefactional pressure. This paper presents preliminary results for droplet preparation and their evaporation as a function of applied acoustic pressure and frequency, as well as simulations of the lifetime of these gas bubbles based on gas diffusion. In vivo experiments were simulated by the evaporation of droplets in blood flowing under attenuating material. We propose that this agent might be useful for tissue occlusion in cancer treatment, as well as for phase aberration corrections in acoustic imaging.

Cavitation nucleation agents for nonthermal ultrasound therapy.

The use of a nucleation-promoting agent can greatly enhance therapeutically useful nonthermal bioeffects. A blank agent (saline), Optison ultrasound contrast agent, a stabilized perfluoropentane droplet suspension (SDS), and retained air space were compared as nucleation agents in whole blood. Fresh canine whole blood with added agent was exposed in 1.3-ml disposable pipette bulbs to lithotripter shock waves (2-Hz rate; +24.4, -5.2 MPa peak pressure amplitudes). Cavitation activity was assessed by measuring hemolysis. The droplet suspension performed nearly as well as retained air when added at a concentration sufficient to provide a roughly equal volume of gas after vaporization. Optison also yielded nucleation, but a concentration of 10%-20% was needed for large enhancement of hemolysis comparable to 5% SDS. Exposure at room temperature, which was less than the 29 degrees C boiling point of perfluoropentane, eliminated the enhancement of the hemolysis effect relative to the blank. Application of 100-kPa excess pressure during exposure reduced but did not eliminate the nucleation ability of Optison, SDS, or retained air. However, this small pressure (relative to the peak positive pressure of the shock waves) eliminated the hemolysis induced with the blank agent. The stabilized perfluoropentane droplet suspension appears to be a good nucleation agent for nonthermal ultrasound therapy applications.

3D spatial compounding of ultrasound images using image-based nonrigid registration.

Medical ultrasound images are often distorted enough to significantly limit resolution during compounding (i.e., summation of images from multiple views). A new, volumetric image registration technique has been used successfully to enable high spatial resolution in three-dimensional (3D) spatial compounding of ultrasound images. Volumetric ultrasound data were acquired by scanning a linear matrix array probe in the elevational direction in a focal lesion phantom and in a breast in vivo. To obtain partly uncorrelated views, the volume of interest was scanned at five different transducer tilt angles separated by 4 degrees to 6 degrees. Pairs of separate views were registered by an automatic procedure based on a mutual information metric, using global full affine and thin-plate spline warping transformations. Registration accuracy was analyzed automatically in the phantom data, and manually in vivo, yielding average registration errors of 0.31 mm and 0.65 mm, respectively. In the vicinity of the warping control points, registrations obtained with warping transformations were significantly more accurate than full affine registrations. Compounded images displayed the expected reduction in speckle noise and increase in contrast-to-noise ratio (CNR), as well as better delineation of connective tissues and reduced shadowing. Compounding also revealed some apparent low contrast lobulations that were not visible in the single-sweep images. Given expected algorithmic and hardware enhancements, nonrigid, image-based registration shows great promise for reducing tissue motion and refraction artifacts in 3D spatial compounding.

Speckle decorrelation flow measurement with B-mode US of contrast agent flow in a phantom and in rabbit kidney.

PURPOSE: To use speckle decorrelation in the presence of ultrasonographic (US) contrast agent as an alternative flow measurement technique to Doppler US. MATERIALS AND METHODS: In vivo and in vitro studies were performed. A tube with flowing saline solution containing contrast agent was positioned horizontally across a US image. The amount of decorrelation between a series of images was recorded. The flow profile across the tube was generated by averaging the decorrelation values and was compared with a Doppler frequency shift image. In addition, B-mode images of six rabbit kidneys were obtained during and after intravenous injection of contrast agent. Images were analyzed to compute the correlation between successive points in time. RESULTS: The velocity profiles across the tube were parabolic, with the fastest flow rates measured in the center of the tube. In the rabbit kidneys, measurements indicated the largest decorrelation rates occurred in the larger vessels. The cortical decorrelation rates were significantly slower than those for the hilar vessels (P < .05) and were relatively angle independent. CONCLUSIONS: Decorrelation flow measurements can be used to estimate flow in vitro and in vivo similar to measurements obtained with Doppler US but with less angle dependence. These measurements could lead to a US perfusion technique.

Semiautomatic registration of volumetric ultrasound scans.

We demonstrate the ability to register easily and accurately volumetric ultrasound scans without significant data preprocessing or user intervention. Two volumetric ultrasound breast scan data sets were acquired from two different patients with breast cancer. Volumetric scan data were acquired by manually sweeping a linear array transducer mounted on a linear slider with a position encoder. The volumetric data set pairs consisted of color flow and/or power mode Doppler data sets acquired serially on the same patients. A previously described semiautomatic registration method based on maximizing mutual information was used to determine the transform between data sets. The results suggest that, even for the deformable breast, three-dimensional full affine transforms can be sufficient to obtain clinically useful registrations; warping may be necessary for increased registration accuracy. In conclusion, mutual information-based automatic registration as implemented on modern workstations is capable of yielding clinically useful registrations in times <35 min.

Transcutaneous interruption of ultrasound contrast agents for blood flow evaluation.

RATIONALE AND OBJECTIVES: The ability to create short boluses in targeted arteries with rapid rise times is limited by the transport of bubbles from the venous to arterial portion of the circulation. Acoustic interruption of contrast agent in arteries may create the short boluses necessary for simple wash-in/wash-out measures of blood flow. METHODS: An ultrasound contrast agent was used with spectral Doppler ultrasound to observe contrast interruption in femoral arteries and VX2 carcinoma in a rabbit model. At an upstream location in the femoral artery, single, sinusoidal ultrasound tone bursts at 1.8 MHz with durations of 0.25 to 1 seconds were applied to interrupt the flow of contrast agent injected intravenously. RESULTS: In VX2 carcinoma, bursts as short as 40 cycles produced contrast interruption lasting only one cardiac cycle within the tumor periphery and I(SPPA) <3 W/cm2 produced measurable interruptions. CONCLUSIONS: Acoustic fields applied transcutaneously interrupted flow of contrast agents to form temporally short negative boluses.

3-D color Doppler image quantification of breast masses.

In this article, new measures obtained from color Doppler images are introduced and a pilot study is described, in which these and previously published indices are evaluated for use in future work. Twenty women with breast masses observed on mammography and going to surgical biopsy were studied. Of the masses, 11 proved to be benign and 9 were malignant. Both 3-D mean frequency shift (f-CDI) and power mode Doppler (p-CDI) imaging were performed. To identify the mass and other regions of interest, vessels were displayed as rotatable 3-D color volumes, superimposed on selectable grey-scale/color flow slices. Doppler signals were recorded in each of 6 ellipsoidal regions of interest in and around the mass and 2 in normal tissues. Seven measures were computed in each region, three from power mode, two from mean frequency and two from combinations of both. Radiologists rated the grey-scale appearances of the masses on a scale of 1 to 5 (5=most suspicious) for each of 6 conventional grey-scale criteria. Of the individual vascularity measures in individual ROIs, the log speed-weighted pixel density and log power-weighted pixel density in the lesion internal periphery showed the greatest discrimination of malignancy, although neither was statistically significant nor as good as the peak variables described below. The mean visual grey-scale rating was the best discriminator overall, but two peak vascularity measures each made promising scatterplots in conjunction with the average visual grey-scale rating. These two vascularity measures were the log peak normalized power-weighted pixel density (peak NPD) and log of peak mean Doppler frequency times the peak NPD (vM x NPD(M)). Each of these two values was the maximum in any one of the five chosen ROIs closely associated with the mass. A possible rationale for the relative success of these peak values is the blood signal's normalization and the inhomogeneity of most breast cancers and the expectation that the highest velocities (shunting) and largest collections of blood are not necessarily in the same region in and around the tumor. Peak NPD of cancers varied with age, decreasing by a factor of 45 from 33 to 77 y.

Automated three-dimensional US frame positioning computed from elevational speckle decorrelation.

For ultrasonographic B-scan images collected by means of a handheld transducer moving in the elevational direction, frame spacings are computed with a speckle-decorrelation algorithm, without additional positioning hardware. Fully developed speckle volumes are automatically segmented and spacing computed from the decorrelation curves. Position accuracy is within 10% for phantoms and 15% for breast studies. The algorithm provides image-based registration, which allows accurate three-dimensional volume rendering.

Determination of sample time for T1 measurement.

In spin-lattice relaxation time measurements, the relaxation time T1 is estimated from measuring the longitudinal magnetization during its return to thermal equilibrium from an initial (nonequilibrium) state. T1 estimation error depends on a number of factors, including the sample spacing, number of sample points, target T1 range, etc. We describe here a sample-time determination method based on the principles of optimal experimental design. A two-parameter model and a more general three-parameter model of the general T1 measurement experiment are used in this study. Both linear and power-law sample spacing strategies are evaluated. The proposed method formulates the sample-time determination problem in closed form expressions that allow for easy calculation of optimum sample times, if a prior T1 estimate or a probable T1 distribution over the target range is given. Valuable insights can be gained from evaluation of these expressions concerning the relationship of T1 estimation error and the sample spacing, number of sample points, target T1 range, etc.

Variables controlling contrast generation in a urinary bladder model.

An ultrasound system has been developed to generate microbubbles in vivo for use as ultrasound contrast agent. Possible application include diagnosis of reflux in the urinary tract. In experiments designed to elucidate the contrast microbubble generation process, acoustic bursts (at 1.8 MHz, 125 ms) were propagated through a latex rubber balloon, modeled after a rabbit urinary bladder, containing fluids of various air and carbon dioxide saturations and concentrations of cavitation nuclei (0.198-micron-diam polystyrene particles). The peak rarefactional pressure threshold for contrast microbubble generation, as visualized with a diagnostic ultrasound system, decreased approximately a factor of 2 for increasing particle concentration from 10(8) to 10(10) particles/cc, with the lowest threshold of 5.24 MPa. For samples with gas saturations below 50% and 10(10) particles/cc, the average thresholds were at least twice as high as those of more saturated fluids (with mean threshold for saturated fluids of 6.45 MPa), and samples containing CO2 had considerably lower thresholds than respective under-saturations in air. At a fixed pressure amplitude, echogenicity tended to increase with both increasing particle concentration and gas saturation; this was more favorable for samples containing CO2. Even in a restricted-nuclei environment such as the urinary bladder, generation of vaporous cavitation should be possible; however, subsequently, abundant gas is needed to grow vaporous bubbles to persistent and imageable sizes, to assist in the diagnosis of urinary reflux.