Nonlinear intravascular ultrasound contrast imaging

Nonlinear contrast agent imaging with intravascular ultrasound (IVUS) is investigated using a prototype IVUS system and an experimental small bubble contrast agent. The IVUS system employed a mechanically scanned single element transducer and was operated at a 20 MHz transmit frequency (F20) for second harmonic imaging (H40), and at a 40 MHz transmit frequency (F40) for subharmonic imaging (SH20). Characterization experiments were performed with agent and tissue phantom signals acquired during transducer rotation. The suppression of transmit frequency tissue signals was achieved using a combination of pulse-inversion and bandpass filtering. H40 was found to improve the contrast-to-tissue signal ratio (CTR) by up to 22 dB relative to F20, but suffered from tissue propagation harmonics at higher pressures (>0.3 MPa). SH20 was also shown to be possible at a range of pressures (approximately 0.25 to 1.8 MPa), with tissue signals suppressed to near the noise floor. Coronary phantom experiments demonstrated the detection of agent in 1 mm diameter vessels outside a larger 4 mm diameter vessel in which the IVUS catheter was situated. These results suggest the feasibility of harmonic IVUS contrast imaging, which may have applications in coronary lumen boundary detection and vasa vasorum imaging.     

High-frequency subharmonic pulsed-wave Doppler and color flow imaging of microbubble contrast agents

A recent study has shown the feasibility of subharmonic (SH) flow imaging at a transmit frequency of 20 MHz. This paper builds on these results by examining the performance of SH flow imaging as a function of transmit pressure. Further, we also investigate the feasibility of SH pulsed-wave Doppler (PWD) imaging. In vitro flow experiments were performed with a 1-mm-diameter wall-less vessel cryogel phantom using the ultrasound contrast agent Definity and an imaging frequency of 20 MHz. The phantom results show that there is an identifiable pressure range where accurate flow velocity and power estimates can be made with SH imaging at 10 MHz (SH10), above which velocity estimates are biased by radiation force effects and unstable bubble behavior, and below which velocity and power estimates are degraded by poor SNR. In vivo validation of SH PWD was performed in an arteriole of a rabbit ear, and blood velocity estimates compared well with fundamental (F20) mode PWD. The ability to suppress tissue signals using SH signals may enable the use of higher frame rates and improve sensitivity to microvascular flow or slow velocities near large vessel walls by reducing or eliminating the need for clutter filters.     

Harmonic intravascular ultrasound imaging with a dual-frequency catheter

Recent studies have shown the feasibility of tissue and contrast harmonic imaging with a prototype nonlinear intravascular ultrasound (IVUS) system using a conventional single-element rotating IVUS catheter. In this study, a dual-frequency transducer element was mounted in an IVUS catheter and its second harmonic imaging performance was investigated and compared with that of a conventional IVUS catheter. Hydrophone measurements showed a transmit efficiency improvement of >6 dB for the dual-frequency catheter at 20 MHz. In vitro phantom experiments showed a signal-to noise ratio improvement of >5 dB in second harmonic mode at 40 MHz (H40) with the dual-frequency catheter, when using equal transmit voltage for both catheters. Finally, in vivo experiments were conducted and showed image improvement in H40 acquisitions with respect to the conventional IVUS catheter.     

An endoscopic micromanipulator for multiplanar transesophageal imaging

We have developed an esophageal probe with a precision micromanipulator and a transversely oriented 32 element ultrasonic array which operates at 3.5 MHz. The probe allows us to obtain multiple two-dimensional images of the heart with known angular relationships between them over a series of cardiac cycles. Our ultimate purpose is to acquire images for left ventricular volume estimation with a three-dimensional reconstruction method. Technical details of the probe design are given. In vitro tests have shown that the imaging plane can be angulated within 1.5° root mean square error. In vivo results with dogs have demonstrated its ability to obtain multiplanar short axis images of the heart.     

Subharmonic contrast microbubble signals for noninvasive pressure estimation under static and dynamic flow conditions

Our group has proposed the concept of subharmonic aided pressure estimation (SHAPE) utilizing microbubble-based ultrasound contrast agent signals for the noninvasive estimation of hydrostatic blood pressures. An experimental system for in vitro SHAPE was constructed based on two single-element transducers assembled confocally at a 60 degree angle to each other. Changes in the first, second and subharmonic amplitudes of five different ultrasound contrast agents were measured in vitro at static hydrostatic pressures from 0-186 mmHg, acoustic pressures from 0.35-0.60 MPa peak-to-peak and frequencies of 2.5-6.6 MHz. The most sensitive agent and optimal parameters for SHAPE were determined using linear regression analysis and implemented on a Logiq 9 scanner (GE Healthcare, Milwaukee, WI). This implementation of SHAPE was then tested under dynamic-flow conditions and compared to pressure-catheter measurements. Over the pressure range studied, the first and second harmonic amplitudes reduced approximately 2 dB for all contrast agents. Over the same pressure range, the subharmonic amplitudes decreased by 9-14 dB and excellent linear regressions were achieved with the hydrostatic pressure variations (r = 0.98, p < 0.001). Optimal sensitivity was achieved at a transmit frequency of 2.5 MHz and acoustic pressure of 0.35 MPa using Sonazoid (GE Healthcare, Oslo, Norway). A Logiq 9 scanner was modified to implement SHAPE on a convex transducer with a frequency range from 1.5-4.5 MHz and acoustic pressures from 0-3.34 MPa. Results matched the pressure catheter (r2 = 0.87). In conclusion, subharmonic contrast signals are a good indicator of hydrostatic pressure. Out of the five ultrasound contrast agents tested, Sonazoid was the most sensitive for subharmonic pressure estimation. Real-time SHAPE has been implemented on a commercial scanner and offers the possibility of allowing pressures in the heart and elsewhere to be obtained noninvasively.     

High frequency nonlinear scattering from a micrometer to submicrometer sized lipid encapsulated contrast agent

An experimental lipid encapsulated contrast agent comprised substantially of micrometer to submicrometer diameter bubbles was evaluated for its capacity to produce nonlinear scattering in response to high transmit frequencies. Agent characterization experiments were conducted at transmit frequencies of 20 and 30 MHz with bandwidths of 5, 15 and 25% using a broadband focused PVDF transducer. The presence of subharmonic energy was observed for all bandwidths at a wide range of pressures (0.49 to 5.7 MPa and 0.45 to 4.5 MPa for the 20 and 30 MHz cases, respectively). Distinct ultraharmonics were observed only in the 5% bandwidth cases. Second harmonic energy was also present, but this was at least partly due to nonlinear propagation, as indicated by linear scatterer signals. Evidence of destruction was found only at higher peak negative pressures (e.g., >2 MPa for 30 MHz 5% bandwidth pulse). The results suggest that small lipid bubble formulations may be useful for the purposes of high frequency nonlinear contrast imaging.     

血管内超声对粥样硬化冠状动脉成像的研究

研究目的在于评价血管内超声（ＩＶＵＳ）观察粥样硬化冠状动脉（ＣＡ）的安全性和可行性。利用３．５Ｆ，３０ＭＨｚ超声导管对１１例冠心病患者的２０支冠状动脉节段进行了检查，所有病人均顺利接ＩＶＵＳ检查，５例血管造影提示冠脉左主干正常的血管段，ＩＶＵＳ显示有内膜轻度增厚或局灶性斑块，１５支血管造影提示ＣＡ管腔狭窄的血管段，ＩＶＵＳ发现有中至重度的内膜增厚，操作中未发现严重并发症。结论：血管内超声检查是安全可行的，它可提供异常ＣＡ管壁形态学的详细信息。     

Nonlinear Emission from Individual Bound Microbubbles at High Frequencies

Targeted microbubbles detected with high-frequency ultrasound can establish the molecular expression of blood vessels with submillimeter resolution. To improve microbubble-specific imaging at high frequencies, the subharmonic and second harmonic signal from individual microbubbles were measured as a function of size and pressure. Single phospholipid-shell microbubbles (1.1 to 5.0 μm in diameter) bound to gelatin, co-aligned with an optical microscope and transducer, were insonated with 30 MHz Gaussian-enveloped pulses at pressures from 20 kPa to 1 MPa with –6 dB one-way bandwidths of 11%, 20% and 45%. A subharmonic signal (15 MHz) was detected above a pressure threshold of 110 kPa—independent of bandwidth. The signal peaked for microbubbles 1.60 μm in diameter subject to 20% and 11% bandwidth pulses, and 1.80 μm for 45% bandwidth pulses, for pressures up to 400 kPa, agreeing with the notion that microbubbles insonated at twice their resonant frequency preferentially emit a subharmonic component. For pressures between 400 kPa and 1 MPa, a broader range of microbubbles emitted a subharmonic signal, and microbubbles below 1.70 μm in diameter were disrupted. The second harmonic signal measured, within the limited experimental conditions, was consistent with nonlinear propagation. Further, the results shed light on the effect of the shell on the phase of the subharmonic signal with respect to the fundamental signal. (E-mail: michael.sprague@sri.utoronto.ca)     

Doppler colour flow imaging and flow quantification with a novel forward-viewing intravascular ultrasound system

The aim of this work was to investigate the potential of a novel forward-viewing intravascular ultrasound (IVUS) system for flow quantification and colour flow imaging combined with B-mode imaging. A stiff 3.8-mm diameter catheter was used to scan a 72 degrees sector ahead of its tip. Operating at 30 MHz, the catheter was integrated with an IVUS scanner and a radiofrequency (RF) data-acquisition system. RF data were software processed for producing B-mode images and deriving velocity estimates. Steady flow in the range of 45 to 146 mL/min toward the catheter, was used in wall-less tissue-mimicking phantoms simulating healthy lumen (8-mm diameter), 30% diameter symmetrical stenosis and 37% diameter eccentric stenosis. The system provided colour flow images and good estimation of peak velocity and volumetric flows (within 1% to 9% and 16% to 48%, respectively, of calculated values) at 5 to 7 mm distal to the catheter. A sector forward-viewing IVUS imaging/Doppler system is suitable for combined anatomical and functional assessment of stenosed vessels.     

On the IVUS plaque volume error in coronary arteries when neglecting curvature

Plaque volume determined by common linear 3-D IVUS analysis systems will show under- or overestimation in curved vessel segments because these systems approximate the true 3-D transducer pull-back trajectory by a straight line. We developed a mathematical model that showed that the error is primarily dependent on the curvature of the pull-back trajectory and not on vessel tortuosity. Furthermore, we measured this error in vivo in the coronary arteries of 15 patients, comparing the plaque volume using a true 3-D reconstruction method with that of the linear approach. The in vivo plaque volume error ranged from 2.3% to −1.2% for 15 coronary segments with lengths ranging from 38.8 to 89.1 mm (62.2 ± 13 mm). The volume error introduced by linear 3-D IVUS analysis systems is dependent on the curvature of the pull-back trajectory. The error measured in vivo was small and inversely related to segment length.     

Ultrasonic characterization of the nonlinear properties of contrast microbubbles

The nonlinear properties of microbubble contrast agents have been used to create contrast-specific imaging modalities such as harmonic imaging and subharmonic imaging. Thus, a better understanding of the nonlinear performance of contrast microbubbles may enhance the diagnostic capabilities of medical ultrasound (US) imaging. The first and second harmonic, the 1/2 order subharmonic and the 3/2 order ultraharmonic components in spectra of scattered signals from Optison microbubbles insonified at 2 and 4 MHz have been investigated using an in vitro laboratory pulse-echo system. The development of these signal components over time is quite different for 2-MHz insonification compared to 4-MHz insonification. Scattered subharmonic and ultraharmonic signals are much more time-dependent than first and second harmonic echoes. The dependence of the first and second harmonic, subharmonic and ultraharmonic components on acoustic pressure for 2-MHz insonification is similar to that for 4-MHz insonification. The first and second harmonic components increase linearly with acoustic pressure (in double logarithmic scales) and the subharmonic and ultraharmonic amplitudes undergo rapid growths in the intermediate acoustic pressure range and much slower increases at both lower and higher acoustic pressures.     

In vivo kinetics of microbubbles of SH U 508 A (Levovist): comparison with indocyanine green in rabbits

The aim of this study was to evaluate in vivo kinetics of microbubbles of SH U 508 A, in comparison with Indocyanine Green, a dye used as an indicator of blood flow. Microbubble kinetics were evaluated in various vessels (i.e., vena cava, aorta, renal artery, renal vein and portal vein) in rabbits after injection of SH U 508 A by measuring Doppler signals (n = 5). The kinetics of Indocyanine Green were evaluated by measuring absorbance using a photodiode (n = 5). Test substances (SH U 508 A 300 mg/mL and Indocyanine Green 1.25 mg/mL) were injected IV at a dose of 0.1 mL/kg B.W. Peak signal intensity was observed immediately after injection of SH U 508 A, followed by biphasic decay. The rates of biphasic decay were similar in all vessels. A second peak of the signal, which indicated recirculation of the microbubbles, was observed in the vena cava. The circulation and recirculation times of the microbubbles after injection of SH U 508 A were similar to that of Indocyanine Green. These findings suggest that the majority of SH U 508 A microbubbles circulate through the body similarly to blood flow, without retention, in the vasculature.     

A novel method to measure acoustic speed of bone tissue

Acoustic speed is an important parameter that can be used to characterize bone tissue for evaluation of osteoporosis. Traditional approaches for measuring acoustic speed require knowledge of either the specimen thickness, which is sometimes difficult to obtain from biological tissues, or the reference fluid velocity that, moreover, is an unknown parameter for internal tissue in in vivo measurement. In this paper, a new method is proposed to measure acoustic speed from dual reflected ultrasound signals. This technique utilizes two transducers placed on the same side of the test object; one for transmitter and receiver, and the other one for receiver only. The acoustic speed of the test object is based on the information of time-of-flight from the signals received by both transducers and the separation distance between the transducer pair. The technique developed here not only eliminates the requirement of knowledge of specimen thickness, but also shows a feasibility for clinical applications. The results of different porcine and bovine bone samples measured in vitro by this technique are in good agreement with those measured by other published methods. In vivo measurement results of 10 healthy young volunteers' tibias are also reported.     

Non-Invasive Intra-cardiac Pressure Measurements Using Subharmonic-Aided Pressure Estimation: Proof of Concept in Humans

This study evaluated the feasibility of employing non-invasive intra-cardiac pressure estimation using subharmonic signals from ultrasound contrast agents in humans. This institutional review board–approved proof-of-concept study included 15 consenting patients scheduled for left and right heart catheterization. During the catheterization procedure, Definity was infused intra-venously at 4–10 mL/min. Ultrasound scanning was performed with a Sonix RP using pulse inversion, three incident acoustic output levels and 2.5-MHz transmit frequency. Radiofrequency data were processed and subharmonic amplitudes were compared with the pressure catheter data. The correlation coefficient between subharmonic signals and pressure catheter data ranged from ?0.3 to ?0.9. For acquisitions with optimum acoustic output, pressure errors between the subharmonic technique and catheter were as low as 2.6 mmHg. However, automatically determining optimum acoustic output during scanning for each patient remains to be addressed before clinical applicability can be decided.     

A high-frequency continuous-wave Doppler ultrasound system for the detection of blood flow in the microcirculation

Basic ultrasound physics and several clinical and experimental observations suggest that high-frequency Doppler ultrasound (HFD) operating in the frequency range 20–100 MHz holds the promise of detecting blood flow in the microcirculation. This article describes a directional, continuous-wave (CW), 1- to 200-MHz Doppler ultrasound system. The system electronics have a dynamic range of 100 dB, a noise floor of 10 nV and a directional isolation of 50 dB. The development of a 40-MHz Doppler transducer composed of two, 81-μm-thick, lithium niobate crystals that have been air-backed and transmission-line tuned for maximum sensitivity is described. This device is used to test the CW Doppler system using string and capillary phantoms and in vivo tissue. We show that HFD can detect and measure velocities on the order of the blood velocities found in the capillaries (1 mm/s) and arterioles (5 mm/s) with suitable velocity (50–500 μm/s) and temporal (20–250 ms) resolutions. In vivo measurements demonstrate that HFD is sensitive to the detection of blood flow in small vessels.     

A Method for Differentiating Targeted Microbubbles in Real Time Using Subharmonic Micro-Ultrasound and Interframe Filtering

This study introduces a new method for differentiating targeted microbubbles in the presence of flowing microbubbles and tissue using micro-ultrasound. The method relies on subharmonic (SH) imaging for segmenting microbubble signals from tissue signals, and low-pass interframe filtering for segmenting bound targeted microbubbles from flowing microbubbles. The method is evaluated with 30 frames per second SH B-mode imaging in vitro, using a wall-less vessel flow phantom. The SH B-mode cineloops were postprocessed using an interframe moving average filter to segment the regions of bound microbubbles on the inner surface of the vessel phantom. The bound bubbles were then disrupted with sufficiently high ultrasound pressures, so that the dynamic process of targeted microbubble binding under flowing conditions could be observed. These preliminary results show that the proposed method is a feasible solution to the challenge of differentiating targeted microbubbles in the presence of tissue and freely flowing microbubbles at high frequencies, which in turn should improve the specificity of targeted microbubble detection. (E-mail: aneedles@visualsonics.com)     

Subharmonic emission as an indicator of ultrasonically-induced biological damage

This paper describes work in which subharmonic emissions from ultrasonically irradiated biological samples are integrated over time, and the resultant signal (which is believed to be indicative of cavitation activity) is found to correlate well with the extent of cellular damage. Specificially, three studies have been carried out, in which the subharmonic energy emitted from suspension cultures of V79 cells is integrated during exposure to 1 MHz ultrasound. The effect of raised ambient pressure and sample rotation speed on the occurrence of cavitation, and of cavitation related cell death, have been investigated. Use of the subharmonic emission technique has also yielded additional evidence for the occurrence of an ultrasonically induced mechanism for damage that is neither thermal nor cavitational in origin, in experiments where cells are exposed to ultrasound whilst being held at an elevated temperature(43°C). The potential of the use of subharmonic emission monitoring as a quantitative predictor of ultrasonically induced biological damage, both in vitro and in vivo, is discussed.     

Three-dimensional forward-viewing intravascular ultrasound imaging of human arteries in vitro

The aim of this work was to investigate the suitability of a novel forward-viewing intravascular ultrasound (IVUS) technique for three-dimensional imaging of severely stenosed or totally occluded vessels, where the conventional side-viewing IVUS systems are of limited use. A stiff 3.8 mm diameter forward-viewing catheter was manufactured to scan a 72 degrees sector ahead of its tip. Conical volume data were acquired by rotating the catheter over 180 degrees by means of a motorised mechanical system. Operating at 30 MHz, the catheter was integrated with an IVUS scanner and a radiofrequency data acquisition system. Postmortem carotid and femoral arteries were scanned in vitro. Correlation of the reconstructed images with histology demonstrated the ability of this forward-viewing IVUS system to visualise healthy lumens, bifurcations, thickened atherosclerotic walls and, most importantly, severe and complete vessel occlusions. A rotating-sector forward-viewing IVUS system is suitable for anatomical assessment of severely diseased vessels in three dimensions.     

Contrast superharmonic imaging: a feasibility study

Harmonic imaging provided significant improvement in image quality by taking advantage of the scattered second harmonic (2H) component from contrast bubbles. However, differentiation between contrast and tissue (usually termed contrast-to-tissue ratio, CTR) is sometimes cumbersome and this is mainly due to tissue contamination. We have previously demonstrated, using simulations and in vitro measurements, that CTR increases as a function of the order of the harmonic number. A new contrast imaging method based on the detection of the higher harmonics was developed and termed superharmonic (SH). This technique has been shown to be more sensitive to contrast by increasing the signal from contrast and suppressing that from tissue (high CTR). The purpose of this study was to determine the clinical feasibility and usefulness of SH in patients using a commercially available contrast agent (SonoVue(R)) for quantification of myocardial perfusion. A total of 10 patients with various cardiac diseases were assessed. Apical four-chamber views were acquired using SH in triggered mode before and after contrast injection. The superharmonic was performed with a newly developed probe transmitting at 0.8 MHz with a mechanical index of 0.2. Myocardial perfusion was determined visually and analyzed quantitatively using radiofrequency (RF) processing from different regions of interest. The results showed that, before contrast injection, SH was totally blinded to tissue and no superharmonic components were generated in the image view. After administration of SonoVue(R), myocardial opacification was visualized by SH after contrast entered the myocardium. An increase of more than 15 dB in the myocardial bubbles echo compared to tissue echo was measured. In addition, the technique was used to visualize myocardial perfusion after myocardial septal ablation for hypertrophic cardiomyopathy. The clinical results showed the ability of contrast SH imaging in differentiating low and normal perfusion areas, demonstrating the high sensitivity and specificity of the technique.     

Second Harmonic and Subharmonic for Non-Linear Wideband Contrast Imaging Using a Capacitive Micromachined Ultrasonic Transducer Array

When insonified with suitable ultrasound excitation, contrast microbubbles generate various non-linear scattered components, such as the second harmonic (2H) and the subharmonic (SH). In this study, we exploit the wide frequency bandwidth of capacitive micromachined ultrasonic transducers (CMUTs) to enhance the response from ultrasound contrast agents by selective imaging of both the 2H and SH components simultaneously. To this end, contrast images using the pulse inversion method were recorded with a 64-element CMUT linear array connected to an open scanner. In comparison to imaging at 2H alone, the wideband imaging including both the 2H and SH contributions provided up to 130% and 180% increases in the signal-to-noise and contrast-to-tissue ratios, respectively. The wide-frequency band of CMUTs offers new opportunities for improved ultrasound contrast agent imaging.