Scott Dianis

Simultaneous grayscale and subharmonic ultrasound imaging on a modified commercial scanner

OBJECTIVE To demonstrate the feasibility of simultaneous dual fundamental grayscale and subharmonic imaging on a modified commercial scanner. MOTIVATION The ability to generate signals at half the insonation frequency is exclusive to ultrasound contrast agents (UCA). Thus, subharmonic imaging (SHI; transmitting at f(0) and receiving at f(0)/2) provides improved visualization of UCA within the vasculature via suppression of the surrounding tissue echoes. While this capability has proven useful in a variety of clinical applications, the SHI suppression of surrounding tissue landmarks (which are needed for sonographic navigation) also limits it use as a primary imaging modality. In this paper we present results using a commercial ultrasound scanner modified to allow imaging in both grayscale (f(0)=4.0 MHz) and SHI (f(0)=2.5 MHz, f(0)/2=1.25 MHz) modes in real time. METHODS A Logiq 9 ultrasound scanner (GE Healthcare, Milwaukee, WI) with a 4C curvilinear probe was modified to provide this capability. Four commercially available UCA (Definity, Lantheus Medical Imaging, North Billerica, MA; Optison, GE Healthcare, Princeton, NJ; SonoVue, Bracco Imaging, Milan, Italy; and Sonazoid, GE Healthcare, Oslo, Norway) were all investigated in vitro over an acoustic output range of 3.34 MPa. In vivo the subharmonic response of Sonazoid was investigated in the portal veins of four canines (open abdominal cavity) and four patients with suspected portal hypertension. RESULTS In vitro, the four UCA showed an average maximum subharmonic amplitude of 44.1±5.4 dB above the noise floor with a maximum subharmonic amplitude of 48.6±1.6 dB provided by Sonazoid. The average in vivo maximum signal above the noise floor from Sonazoid was 20.8±2.3 dB in canines and 33.9±5.2 dB in humans. Subharmonic amplitude as a function of acoustic output in both groups matched the S-curve behavior of the agent observed in vitro. The dual grayscale imaging provided easier sonographic navigation, while the degree of tissue suppression in SHI mode varied greatly on a case by case basis. CONCLUSIONS These results demonstrate the feasibility of dual grayscale and SHI on a modified commercial scanner. The ability to simultaneously visualize both imaging modes in real time should improve the applicability of SHI as a future primary clinical imaging modality.

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.

Chronic Liver Disease: Noninvasive Subharmonic Aided Pressure Estimation of Hepatic Venous Pressure Gradient

PURPOSE To compare subharmonic aided pressure estimation (SHAPE) with pressure catheter-based measurements in human patients with chronic liver disease undergoing transjugular liver biopsy. MATERIALS AND METHODS This HIPAA-compliant study had U.S. Food and Drug Administration and institutional review board approval, and written informed consent was obtained from all participants. Forty-five patients completed this study between December 2010 and December 2011. A clinical ultrasonography (US) scanner was modified to obtain SHAPE data. After transjugular liver biopsy with pressure measurements as part of the standard of care, 45 patients received an infusion of a microbubble US contrast agent and saline. During infusion, SHAPE data were collected from a portal and hepatic vein and were compared with invasive measurements. Correlations between data sets were determined by using the Pearson correlation coefficient, and statistical significance between groups was determined by using the Student t test. RESULTS The 45 study patients included 27 men and 18 women (age range, 19-71 years; average age, 55.8 years). The SHAPE gradient between the portal and hepatic veins was in good overall agreement with the hepatic venous pressure gradient (HVPG) (R = 0.82). Patients at increased risk for variceal hemorrhage (HVPG ≥ 12 mm Hg) had a significantly higher mean subharmonic gradient than patients with lower HVPGs (1.93 dB ± 0.61 [standard deviation] vs -1.47 dB ± 0.29, P < .001), with a sensitivity of 100% and a specificity of 81%, indicating that SHAPE may be a useful tool for the diagnosis of clinically important portal hypertension. CONCLUSION Preliminary results show SHAPE to be an accurate noninvasive technique for estimating portal hypertension.

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.

Investigating the Efficacy of Subharmonic Aided Pressure Estimation for Portal Vein Pressures and Portal Hypertension Monitoring

The efficacy of using subharmonic emissions from Sonazoid microbubbles (GE Healthcare, Oslo, Norway) to track portal vein pressures and pressure changes was investigated in 14 canines using either slow- or high-flow models of portal hypertension (PH). A modified Logiq 9 scanner (GE Healthcare, Milwaukee, WI, USA) operating in subharmonic mode (f(transmit): 2.5 MHz, f(receive): 1.25 MHz) was used to collect radiofrequency data at 10-40% incident acoustic power levels with 2-4 transmit cycles (in triplicate) before and after inducing PH. A pressure catheter (Millar Instruments, Inc., Houston, TX, USA) provided reference portal vein pressures. At optimum insonification, subharmonic signal amplitude changes correlated with portal vein pressure changes; r ranged from -0.82 to -0.94 and from -0.70 to -0.73 for PH models considered separately or together, respectively. The subharmonic signal amplitudes correlated with absolute portal vein pressures (r: -0.71 to -0.79). Statistically significant differences between subharmonic amplitudes, before and after inducing PH, were noted (p ≤ 0.01). Portal vein pressures estimated using subharmonic aided pressure estimation did not reveal significant differences (p > 0.05) with respect to the pressures obtained using the Millar pressure catheter. Subharmonic-aided pressure estimation may be useful clinically for portal vein pressure monitoring.

On the implementation of an automated acoustic output optimization algorithm for subharmonic aided pressure estimation

Incident acoustic output (IAO) dependent subharmonic signal amplitudes from ultrasound contrast agents can be categorized into occurrence, growth or saturation stages. Subharmonic aided pressure estimation (SHAPE) is a technique that utilizes growth stage subharmonic signal amplitudes for hydrostatic pressure estimation. In this study, we developed an automated IAO optimization algorithm to identify the IAO level eliciting growth stage subharmonic signals and also studied the effect of pulse length on SHAPE. This approach may help eliminate the problems of acquiring and analyzing the data offline at all IAO levels as was done in previous studies and thus, pave the way for real-time clinical pressure monitoring applications. The IAO optimization algorithm was implemented on a Logiq 9 (GE Healthcare, Milwaukee, WI) scanner interfaced with a computer. The optimization algorithm stepped the ultrasound scanner from 0% to 100% IAO. A logistic equation fitting function was applied with the criterion of minimum least squared error between the fitted subharmonic amplitudes and the measured subharmonic amplitudes as a function of the IAO levels and the optimum IAO level was chosen corresponding to the inflection point calculated from the fitted data. The efficacy of the optimum IAO level was investigated for in vivo SHAPE to monitor portal vein (PV) pressures in 5 canines and was compared with the performance of IAO levels, below and above the optimum IAO level, for 4, 8 and 16 transmit cycles. The canines received a continuous infusion of Sonazoid microbubbles (1.5 μl/kg/min; GE Healthcare, Oslo, Norway). PV pressures were obtained using a surgically introduced pressure catheter (Millar Instruments, Inc., Houston, TX) and were recorded before and after increasing PV pressures. The experiments showed that optimum IAO levels for SHAPE in the canines ranged from 6% to 40%. The best correlation between changes in PV pressures and in subharmonic amplitudes (r=-0.76; p=0.24), and between the absolute PV pressures and the subharmonic amplitudes (r=-0.89; p<0.01) were obtained for the optimized IAO and 4 transmit cycles. Only for the optimized IAO and 4 transmit cycles did the subharmonic amplitudes differ significantly (p<0.01) before and after increasing PV pressures. A new algorithm to identify optimum IAO levels for SHAPE has been developed and validated with the best results being obtained for 4 transmit cycles. The work presented in this study may pave the way for real-time clinical applications of estimating pressures using the subharmonic signals from ultrasound contrast agents.

Quantitative analysis of subharmonic imaging using microbubbles in contrast imaging

Second-harmonic imaging (SecHI) has been widely used to improve the contrast of microbubbles with respect to tissue since microbubbles have a large second-harmonic response. Unlike tissue, microbubbles can also have a response at subharmonic frequency. In order to take advantage of subharmonics in contrast imaging, the image quality of subharmonic imaging (SubHI) and SecHI are analyzed through quantitative comparisons. Nonlinear tissue and bubble responses are simulated for numerical analysis. SubHI and SecHI modes are implemented on a Logiq 9 scanner (GE Healthcare, Milwaukee, WI, USA). Images of a flow phantom (ATS laboratories, CT, USA) with Sonazoid (GE Healthcare, Oslo, Norway) microbubbles are presented. The contrast-to-tissue ratio (CTR) and signal-to-noise ratio (SNR) are calculated with variations of the bubble concentration and the depth of the vessel tube. The experimental results agree well with the simulations. The CTR at the subharmonic frequency can be higher than the value in second-harmonics. For deep-lying bubbles, the CTR for SubHI is 15 dB higher than for SecHI. Although the SNR at the subharmonic frequency can be lower than that at the second-harmonic frequency, it is suggested that SubHI with high blood-to-tissue contrast may be useful when the sensitivity is a major concern.

Ring array PSF synthesis by delay dithering

In this paper we examine synthetic aperture acoustic imaging for a forward-looking ring array. To investigate how the well-known Bessel sum approach using pulsed insonification in the nearfield works, we introduce an extension of the sum coarray. This coarray accounts for the dithering, or shot-to-shot variation in the transmit and receive delays that are added to any beamsteering and focusing delays to effect the synthesis. We observe that an arbitrary configuration of the extended coarray can always be implemented using N-squared data, but that the reconstruction algorithm from such data requires the addition of multiple, shifted versions of each transmit/receive element pair data record, which is an extension of the standard reconstruction approach. In order to produce a design that can be implemented as a small number of whole-array transmissions, we structure the array dither in a way that mimics the dither applied to produce Bessel beams, but with greater freedom in the configuration. This approach, with peak PSF sidelobes minimized by simulated annealing, is shown to produce lower sidelobe PSFs than Bessel synthesis designed by existing methods.

Perfusion estimation using 3D subharmonic imaging: An in vivo study

Under sufficient acoustic excitation microbubble-based ultrasound contrast agents (UCA) produce a marked subharmonic (f0/2) frequency component. By selectively receiving at the subharmonic, it is possible to perform UCA specific subharmonic imaging (SHI). We investigated the ability to quantify tissue perfusion (in ml/min/g) in 5 canines using 3D SHI. A 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 3D SHI (ftransmit=5.8 MHz and freceive=2.9 MHz). Imaging was performed in the lower renal pole of open-abdomen canines after injection of Definity (Lantheus Medical Imaging, N Billerica, MA). The canines received a 5 μl/kg bolus injection of Definity for HI and a 20 μl/kg for SHI in triplicate for each kidney. A microvascular staining technique based on isotope-labeled microspheres was used to quantify the degree of perfusion in each kidney. Ligation of a surgically exposed branch of the renal arteries induced low perfusion. Time-intensity curves were generated from regions-of-interest (ROIs) corresponding to the tissue samples used for microvascular staining. Perfusion was estimated from the initial slope of the fractional blood volume uptake and compared to the reference standard using linear regression analysis. Microsphere perfusion data showed an average perfusion of 9.30±6.60 and 5.15±3.42 ml/min/g pre and post ligation, respectively. The reference standard showed significant correlation with 3D HI perfusion estimates (r=0.38; p=0.007), but correlated better with 3D SHI (r=0.62; p<;0.001). Additionally, these results showed an improvement 2D SHI perfusion estimates previously reported by our group (r=0.57; Forsberg et al JUM 2006). In conclusion, 3D SHI perfusion estimates were in better overall agreement with the reference standard than 3D HI and were superior to previously reported 2D SHI results.

4D subharmonic imaging in vivo

Subharmonic imaging (SHI) improves the isolation of ultrasound contrast agent signals from the surrounding tissue signals by transmitting at f0 and receiving at f0/2. In this study we investigated the feasibility of generating real-time 3D (i.e., 4D) SHI volumes. Four-dimensional SHI (f0 = 5.8 MHz, transmitting 4 cycle pulses) was implemented on a Logiq 9 ultrasound scanner with a mechanically controlled 4D10L probe (GE Healthcare, Milwaukee, WI). Experimental software provided access to both individual slice data and rendered images. This software also allowed imaging in B-mode (at 10 MHz) and harmonic imaging (HI; f0 = 5 MHz, freceive= 10 MHz). Two canines received 5 μl/kg bolus injections of Definity (Lantheus Medical Imaging, N Billerica, MA) for HI and 20 μl/kg bolus for SHI of the lower renal pole. The contrast-to-tissue ratio was then calculated for three injections in each canine and compared between modes. Patients scheduled for biopsy of a mammographically identified breast lesion provided informed consent. Baseline scanning was performed in both B-mode and power Doppler. Patients then received a 0.25 ml bolus of Definity for HI followed by a bolus injection of 20 μl/kg for SHI. Baseline 2D cine loops, 3D slice data and rendered volumes were saved for off-line comparison. While scan volumes varied, a volume of 2.5 cm x 2.5 cm × 2.5 cm acquired at a 19° volume angle resulted in 45-50 slices per volume at an acquisition rate of 1.8 to 2.2 Hz depending on depth. In the canine model, SHI resulted in significant improvement in contrast visualization and rendered SHI images demonstrated superior tissue suppression and a greater overall view of renal vasculature. In breast lesions, enhancement varied greatly on a case by case basis. However, SHI resulted in improved tissue suppression and detection of contrast in almost all cases. Future work will explore the ability of 4D SHI to classify breast lesions.