Kirk Wallace

Three-Dimensional Subharmonic Ultrasound Imaging In Vitro and In Vivo

RATIONALE AND OBJECTIVES Although contrast-enhanced ultrasound imaging techniques such as harmonic imaging (HI) have evolved to reduce tissue signals using the nonlinear properties of the contrast agent, levels of background suppression have been mixed. Subharmonic imaging (SHI) offers near complete tissue suppression by centering the receive bandwidth at half the transmitting frequency. The aims of this study were to demonstrate the feasibility of three-dimensional (3D) SHI and to compare it to 3D HI. MATERIALS AND METHODS Three-dimensional HI and SHI were implemented on a Logiq 9 ultrasound scanner with a 4D10L probe. Four-cycle SHI was implemented to transmit at 5.8 MHz and receive at 2.9 MHz, while two-cycle HI was implemented to transmit at 5 MHz and receive at 10 MHz. The ultrasound contrast agent Definity was imaged within a flow phantom and the lower pole of two canine kidneys in both HI and SHI modes. Contrast-to-tissue ratios and rendered images were compared offline. RESULTS SHI resulted in significant improvement in contrast-to-tissue ratios relative to HI both in vitro (12.11 ± 0.52 vs 2.67 ± 0.77, P< .001) and in vivo (5.74 ± 1.92 vs 2.40 ± 0.48, P = .04). Rendered 3D subharmonic images provided better tissue suppression and a greater overall view of vessels in a flow phantom and canine renal vasculature. CONCLUSIONS The successful implementation of SHI in 3D allows imaging of vascular networks over a heterogeneous sample volume and should improve future diagnostic accuracy. Additionally, 3D SHI provides improved contrast-to-tissue ratios relative to 3D HI.

4-D spatiotemporal analysis of ultrasound contrast agent dispersion for prostate cancer localization: a feasibility study

Currently, nonradical treatment for prostate cancer is hampered by the lack of reliable diagnostics. Contrastultrasound dispersion imaging (CUDI) has recently shown great potential as a prostate cancer imaging technique. CUDI estimates the local dispersion of intravenously injected contrast agents, imaged by transrectal dynamic contrast-enhanced ultrasound (DCE-US), to detect angiogenic processes related to tumor growth. The best CUDI results have so far been obtained by similarity analysis of the contrast kinetics in neighboring pixels. To date, CUDI has been investigated in 2-D only. In this paper, an implementation of 3-D CUDI based on spatiotemporal similarity analysis of 4-D DCE-US is described. Different from 2-D methods, 3-D CUDI permits analysis of the entire prostate using a single injection of contrast agent. To perform 3-D CUDI, a new strategy was designed to estimate the similarity in the contrast kinetics at each voxel, and data processing steps were adjusted to the characteristics of 4-D DCE-US images. The technical feasibility of 4-D DCE-US in 3-D CUDI was assessed and confirmed. Additionally, in a preliminary validation in two patients, dispersion maps by 3-D CUDI were quantitatively compared with those by 2-D CUDI and with 12-core systematic biopsies with promising results.

Perfusion estimation using contrast-enhanced 3-dimensional subharmonic ultrasound imaging: an in vivo study.

ObjectivesThe ability to estimate tissue perfusion (in milliliter per minute per gram) in vivo using contrast-enhanced 3-dimensional (3D) harmonic and subharmonic ultrasound imaging was investigated. Materials and MethodsA LOGIQ™ 9 scanner (GE Healthcare, Milwaukee, WI) equipped with a 4D10L probe was modified to perform 3D harmonic imaging (HI; ftransmit, 5 MHz and freceive, 10 MHz) and subharmonic imaging (SHI; ftransmit, 5.8 MHz and freceive, 2.9 MHz). In vivo imaging was performed in the lower pole of both kidneys in 5 open-abdomen canines after injection of the ultrasound contrast agent (UCA) Definity (Lantheus Medical Imaging, N Billerica, MA). The canines received a 5-&mgr;L/kg bolus injection of Definity for HI and a 20-&mgr;L/kg bolus for SHI in triplicate for each kidney. Ultrasound data acquisition was started just before the injection of UCA (to capture the wash-in) and continued until washout. A microvascular staining technique based on stable (nonradioactive) isotope-labeled microspheres (Biophysics Assay Laboratory, Inc, Worcester, MA) was used to quantify the degree of perfusion in each kidney (the reference standard). Ligating a surgically exposed branch of the renal arteries induced lower perfusion rates. This was followed by additional contrast-enhanced imaging and microsphere injections to measure post-ligation perfusion. Slice data were extracted from the 3D ultrasound volumes and used to generate time-intensity curves offline in the regions corresponding to the tissue samples used for microvascular staining. The midline plane was also selected from the 3D volume (as a quasi–2-dimensional [2D] image) and compared with the 3D imaging modes. Perfusion was estimated from the initial slope of the fractional blood volume uptake (for both HI and SHI) and compared with the reference standard using linear regression analysis. ResultsBoth 3D HI and SHI were able to provide visualization of flow and, thus, perfusion in the kidneys. However, SHI provided near-complete tissue suppression and improved visualization of the UCA flow. Microsphere perfusion data were available for 4 canines (1 was excluded because of an error with the reference blood sample) and showed a mean (SD) perfusion of 9.30 (6.60) and 5.15 (3.42) mL/min per gram before and after the ligation, respectively. The reference standard showed significant correlation with the overall 3D HI perfusion estimates (r = 0.38; P = 0.007), but it correlated more strongly with 3D SHI (r = 0.62; P < 0.001). In addition, these results showed an improvement over the quasi-2D HI and SHI perfusion estimates (r = −0.05 and r = 0.14) and 2D SHI perfusion estimates previously reported by our group (r = 0.57). ConclusionsIn this preliminary study, 3D contrast-enhanced nonlinear ultrasound was able to quantify perfusion in vivo. Three-dimensional SHI resulted in better overall agreement with the reference standard than 3D HI did and was superior to previously reported 2D SHI results. Three-dimensional SHI outperforms the other methods for estimating blood perfusion because of the improved visualization of the complete perfused vascular networks.

Quantitative analysis of vascular heterogeneity in breast lesions using contrast-enhanced 3-D harmonic and subharmonic ultrasound imaging

Ability to visualize breast lesion vascularity and quantify the vascular heterogeneity using contrast-enhanced 3-D harmonic (HI) and subharmonic (SHI) ultrasound imaging was investigated in a clinical population. Patients (n = 134) identified with breast lesions on mammography were scanned using power Doppler imaging, contrast-enhanced 3-D HI, and 3-D SHI on a modified Logiq 9 scanner (GE Healthcare). A region of interest corresponding to ultrasound contrast agent flow was identified in 4D View (GE Medical Systems) and mapped to raw slice data to generate a map of time-intensity curves for the lesion volume. Time points corresponding to baseline, peak intensity, and washout of ultrasound contrast agent were identified and used to generate and compare vascular heterogeneity plots for malignant and benign lesions. Vascularity was observed with power Doppler imaging in 84 lesions (63 benign and 21 malignant). The 3-D HI showed flow in 8 lesions (5 benign and 3 malignant), whereas 3-D SHI visualized flow in 68 lesions (49 benign and 19 malignant). Analysis of vascular heterogeneity in the 3-D SHI volumes found benign lesions having a significant difference in vascularity between central and peripheral sections (1.71 ± 0.96 vs. 1.13 ± 0.79 dB, p <; 0.001, respectively), whereas malignant lesions showed no difference (1.66 ± 1.39 vs. 1.24 ± 1.14 dB, p = 0.24), indicative of more vascular coverage. These preliminary results suggest quantitative evaluation of vascular heterogeneity in breast lesions using contrast-enhanced 3-D SHI is feasible and able to detect variations in vascularity between central and peripheral sections for benign and malignant lesions.

Toward 3-D Echocardiographic Determination of Regional Myofiber Structure

As a step toward the goal of relating changes in underlying myocardial structure to observed altered cardiac function in the hearts of individual patients, this study addresses the feasibility of creating echocardiography-derived maps of regional myocardial fiber structure for entire, intact, excised sheep hearts. Backscatter data were obtained from apical echocardiographic images acquired with a clinical ultrasonic imaging system and used to determine local fiber orientations in each of seven hearts. Systematic acquisition across the entire heart volume provided information sufficient to give a complete map for each heart. Results from the echocardiography-derived fiber maps compare favorably with corresponding results derived from diffusion tensor magnetic resonance imaging. The results of this study provide evidence of the feasibility of using echocardiographic methods to generate individualized whole heart fiber maps for patients.

Effect of Pulse Shaping on Subharmonic Aided Pressure Estimation In Vitro and In Vivo.

Subharmonic imaging (SHI) is a technique that uses the nonlinear oscillations of microbubbles when exposed to ultrasound at high pressures transmitting at the fundamental frequency ie, fo and receiving at half the transmit frequency (ie, fo/2). Subharmonic aided pressure estimation (SHAPE) is based on the inverse relationship between the subharmonic amplitude of the microbubbles and the ambient pressure change.

On factors impacting subharmonic aided pressure estimation (SHAPE)

Subharmonic aided pressure estimation (SHAPE) uses ultrasound contrast agents (UCAs) to estimate hydrostatic pressure by transmitting at one frequency, receiving at its subharmonic frequency and then monitoring the subharmonic amplitude variations. The subharmonic response of the UCAs has an inverse linear relationship with the ambient pressure. In order to optimize SHAPE, we studied the impact of varying input acoustic output (IAO), UCA concentration and hematocrit concentrations. The current IAO selection algorithm is prone to noise, due to motion. A modified Logiq 9 ultrasound scanner with a 4C curvi-linear probe (GE, Milwaukee, WI) was used to acquire SHAPE data from Sonazoid (GE Healthcare, Oslo, Norway) transmitting at 2.5 MHz and receiving subharmonic signals at 1.25 MHz. The new selection algorithm provided improved or similar correlation between the SHAPE signal and hydrostatic pressure for all setups (r ranging from −0.85 to −0.95 vs −0.39 to −0.98). Also, it is important to study the effect of hematocrit, since the clinical population presents with a wide range of values. Additionally, the effect on SHAPE of varying UCA concentration was studied in vitro. The reduction in subharmonic amplitude as the pressure increased from 10 to 40 mmHg remained almost the same (Δ0.00–0.01 dB, p=0.18) with no significant change as the hematocrit concentration was tripled (from 1.8 to 4.5 ml/l). Likewise, the SHAPE gradient changed only slightly (Δ 0.02–0.05 dB, p=0.75) as the UCA concentration was increased from 0.2 to 1.2 ml/l. In conclusion the relative change in the subharmonic signal is independent of hematocrit and UCA concentration. An improved algorithm for identifying optimum IAO levels correctly should make SHAPE more sensitive and accurate.

Improved selection of optimal acoustic output power for subharmonic aided pressure estimation of portal hypertension

Subharmonic aided pressure estimation (SHAPE) is based on the inverse relationship between the subharmonic amplitude of contrast microbubbles and the ambient pressure. A noninvasive ultrasound based pressure estimation procedure would be a major development in the diagnosis of portal hypertension and less invasive than the current hepatic venous pressure gradient (HVPG) measurement. The hypothesis of this study was that portal vein pressures could be monitored and quantified noninvasively in humans using SHAPE. For maximum SHAPE sensitivity, the optimum acoustic power is currently selected using an algorithm, which collects subharmonic data at power levels increasing from 0 % to 100 % in 8 cine clips. The ROI is selected on a common Maximum Intensity Projection (MIP) for all these 8 clips, data is plotted against the power levels and the point of maximum inflection gives the optimum power. However, this algorithm is prone to motion due to breathing and can greatly affect the results, hence was improved to minimize the error.

Contrast-enhanced nonlinear 3D ultrasound imaging of breast lesions in a clinical population

The ability to visualize breast lesion vascularity and quantify the vascular heterogeneity using contrast-enhanced 3-D nonlinear ultrasound imaging was investigated in a clinical population. Patients (n = 236) identified with breast lesions on mammography were scanned using power Doppler imaging, contrast-enhanced 3D HI, and 3D SHI on a modified Logiq 9 scanner (GE Healthcare). Time-intensity curve volumes were developed corresponding to ultrasound contrast agent flow in the lesions after being identified in 4D View (GE Medical Systems). Time points corresponding to, wash-in, baseline, peak intensity, and washout of ultrasound contrast agent were identified and used to generate and compare vascular heterogeneity plots for malignant and benign lesions. Vascularity was observed with power Doppler imaging in 93 lesions (69 benign and 24 malignant). The 3D HI showed flow in 8 lesions (5 benign and 3 malignant), whereas 3D SHI visualized flow in 83 lesions (58 benign and 25 malignant). Analysis of vascular heterogeneity in the 3D SHI volumes found benign lesions having a significant difference in vascularity between central and peripheral sections (1.8 ± 0.16 vs. 1.2 ± 0.09 dB, p = 0.0003, respectively), whereas malignant lesions showed no difference (1.7 ± 0.33 vs. 1.3 ± 0.21 dB, p = 0.23), indicative of more vascular coverage. Parametric volumes, that contained a single parametric value for every voxel within the 3D volume in order to visualize localized variations, were generated based on perfusion (PER) and area under the curve (AUC). These maps highlighted the variations in the vascularity for individual voxels in the lesion volume. Finally, a preliminary measure for lesion characterization, based on vascular heterogeneity, achieved an area under the ROC of 0.72. These preliminary results suggest quantitative evaluation of vascular heterogeneity in breast lesions using contrast-enhanced 3D SHI is feasible and able to detect variations in vascularity between central and peripheral sections for benign and malignant lesions to aid in characterization.

Robust lumen segmentation in 3D contrast enhanced ultrasound images

The detection and quantification of carotid artery stenosis guides the decision of the need for surgical intervention such as endarterectomy or stenting of a patient. Contrast enhanced ultrasound highlights detailed information on hemodynam-ics and even on pathophysiology, and 3D scans yield full in-situ information of the complete anatomy. We introduce 3D image analysis algorithms that enable quantification and visualization of the carotid lumen in these scans. Our method enhances the lumen intensity contrast, extracts lumen centerlines using a gradient concentration calculation, and then uses a graph search method to obtain a coarse lumen segmentation, which is refined through a level set method applied on an intensity-corrected image. We processed 35 images acquired from 7 patients, and demonstrated quantitative comparisons with MR/CT lumen segmentations. We obtained a segmentation correlation score of R2 = 0.94 and a coefficient of 0.99 for US versus MR/CT through a linear regression on effective diameters extracted from slices in the XY-plane.