Pulse inversion Doppler: a new method for detecting nonlinear echoes from microbubble contrast agents

A novel technique for the selective detection of ultrasound contrast agents, called pulse inversion Doppler, has been developed. In this technique, a conventional Doppler or color Doppler pulse sequence is modified by inverting every second transmit pulse. Either conventional or harmonic Doppler processing is then performed on the received echoes. In the resulting Doppler spectra, Doppler shifts from linear and nonlinear scattering are separated into two distinct regions that can be analyzed separately or combined to estimate the ratio of nonlinear to linear scattering from a region of tissue. The maximum Doppler shift that can be detected is 1/2 the normal Nyquist limit. This has the advantage over conventional harmonic Doppler that it can function over the entire bandwidth of the echo signal, thus achieving superior spatial resolution in the Doppler image. In vitro measurements comparing flowing agent and cellulose particles suggest that pulse inversion Doppler can provide 3 to 10 dB more agent to tissue contrast than harmonic imaging with similar pulses. Similar measurements suggest that broadband pulse inversion Doppler can provide up to 16 dB more contrast than broadband conventional Doppler. Nonlinear propagation effects limit the maximum contrast obtainable with both harmonic and pulse inversion Doppler techniques.     

Fast B-flow imaging: a method for improving frame rate in Golay coded B-flow imaging

A technique for Golay coded B-flow imaging, called fast B-flow imaging, has been developed. This technique improves the frame rate of Golay coded B-flow imaging. In this technique, three instead of four input pulses are used to produce each scan line. A standard Golay pulse-pair is used as two of the three inputs, and pulse compression is performed upon receive returning the echoes from stationary (tissue) objects in the image. The third input is a repetition of one of the first two inputs. Upon receive, this pulse is cross correlated with an inverted copy of its input pulse. Addition of the cross-correlated signals produced from the identical input pulses results in the cancellation of the strong tissue echoes, and enables visualization of the weaker/moving blood echoes. Combining a small fraction of the tissue echoes with the weaker blood echoes allows both to be visualized in the same gray scale image. By using three instead of four input pulses, this technique can achieve a frame rate improvement of 33% compared with standard Golay coded B-flow imaging, with some loss in signal-to-noise ratio. The impact of axial and lateral motion on these techniques is examined. A quantitative comparison of both techniques is presented.     

A new ultrasound contrast imaging approach based on the combination of multiple imaging pulses and a separate release burst

A new ultrasound contrast imaging technique is described that optimally employs the rupture of the contrast agent. It is based on a combination of multiple high frequency, broadband, imaging pulses and a separate release burst. The imaging pulses are used to survey the target before and after the rupture and release of free gas bubbles. In this way, both processes (imaging and release) can be optimized separately. The presence of the contrast agent is simply detected by correlating or subtracting the signal responses of the imaging pulses. Because the time delay between the imaging pulses can be very short, the subtraction is less affected by tissue motion and can be done in real time. In vitro measurements showed that by using a release burst, the detection sensitivity increased 12 to 43 dB for different types of contrast agents. In the presence of a moving phantom, the increase in sensitivity was 22 dB. This new method is very sensitive for contrast agent detection in fundamental imaging mode and, therefore, non-linear propagation effects do not limit the maximum obtainable agent-to-tissue ratio. However, because of the inherent destruction of the contrast agent, it has to operate in an intermittent way. Through experiments, we have demonstrated the potential of the method to achieve simultaneous high sensitivity for contrast detection, i.e., high agent-to-tissue ratio, and high spatial resolution performance for different types of contrast agents     

Techniques for perfusion imaging with microbubble contrast agents

The acoustic properties of ultrasound contrast agents vary widely with agent composition and insonation conditions. For contrast imaging, methods are required to match RF and Doppler processing to each combination of transmission parameters and agent and tissue properties. We propose a method that uses the measured or modeled echoes from agent and tissue to specify directly the characteristics of RF and Doppler filters for contrast imaging. The proposed method is sufficiently general to cover most common imaging techniques including harmonic greyscale, Doppler, and pulse inversion imaging. Using this method, sample filters were designed to detect myocardial perfusion with the contrast agent Optison^TM (Mallinckrodt Medical, St. Louis, MO) under selected imaging conditions. Simplified power Doppler filtering, using a weighted sum of the Doppler samples, matched the performance of more complicated matrix filters. By coordinating the selection of RF and Doppler filters rather than designing these filters sequentially, agent-to-tissue contrast was increased by up to 3.9 dB. Under some conditions, fundamental RF filtering outperformed harmonic filtering for intermittent Doppler imaging     

Changes in the echoes from ultrasonic contrast agents with imaging parameters

Current harmonic imaging scanners transmit a narrowband signal that limits spatial resolution in order to differentiate the echoes from tissue from the echoes from microbubbles. Because spatial resolution is particularly important in applications, including mapping vessel density in tumors, we explore the use of wideband signals in contrast imaging. It is first demonstrated that microspheres can be destroyed using one or two pulses of ultrasound. Thus, temporal signal processing strategies that use the change in the echo over time can be used to differentiate echoes from bubbles and echoes from tissue. Echo parameters, including intensity and spectral shape for narrowband and wideband transmission, are then evaluated. Through these experiments, the echo intensity received from bubbles after wideband transmission is shown to be at least as large as that for narrowband transmission, and can be larger. In each case, the echo intensity increases in a nonlinear fashion in comparison with the transmitted signal intensity. Although the echo intensity at harmonic multiples of the transmitted wave center frequency can be larger for narrowband insonation, echoes received after wideband insonation demonstrate a broadband spectrum with significant amplitude over a very wide range of frequencies.     

Pulse inversion sequences for mechanically scanned transducers

Mechanically scanned transducers are currently used for tissue harmonic imaging (THI) and nonlinear microbubble imaging at high frequencies. The pulse inversion (PI) technique is widely used for suppressing the fundamental signal, but its effectiveness is reduced by relative tissue/ transducer motion. In this paper, we investigate multipulse inversion (MPI) sequences that achieve a significant improvement on the fundamental suppression for mechanically scanned single-element transducers. MPI was subsequently applied on simulated and measured RF-data and relative fundamental suppression was compared with the 2-pulse PI technique. Simulations showed, for example, an increased fundamental suppression of 6 and 10 dB for MPI-sequences that combined 3 and 7 pulses, respectively, for a rotating intravascular ultrasound transducer with an interpulse angle of 0.15deg. Initial application of MPI sequences on RF-data from in vivo acquisitions resulted in similar fundamental suppression levels. The investigated MPI technique will help to reduce relative tissue/transducer motion effects and might lead to improved sensitivity and spatial resolution in nonlinear tissue imaging and improved microbubble detection in contrast imaging for mechanically scanned transducers.     

Contrast imaging with chirped excitation

Coded excitation has been successfully used in imaging to increase the signal-to-noise ratio (SNR) and penetration depth. With a contrast agent, wideband signals have been hypothesized to increase the contrast-to-tissue ratio (CTR). However, nonlinear properties of contrast agents make decoding difficult when applying coded excitation to contrast imaging. We propose two chirped excitation methods to image contrast agents, with a mechanical index (MI) ranging from 0.05 to 0.34. In the single chirp method, one chirp is transmitted, followed by a clutter filter to reject tissue echoes, then a matched filter is used to recover range resolution. In the chirp sequence method, an increasing and decreasing chirp sequence is transmitted followed by subtraction of the compressed echoes to reject tissue echoes (assuming tissue is a linear scatterer at low MI). Ten independent acoustic experiments were performed to evaluate the CTR for chirp and tone burst insonation, with the same spatial peak temporal averaged intensity (I(SPTA)). A significant increase in CTR, ranging from 4 dB to 8 dB, is observed for chirped excitation as compared with tone burst insonation, at an I(SPTA) of 0.1 and 0.3 mW/cm2 (P < or = 5e-3). To achieve the same CTR of 15 dB, the spatial peak pulse averaged intensity (I(SPPA)) can be decreased by 6 dB for chirp insonation as compared with tone burst insonation (P < 1e-5). Additionally, an increase of more than 10 dB in tissue rejection ratio (TRR) is observed for a chirp sequence insonation compared to tone burst phase inversion for this set of parameters (P < or = 1e-9). Deconvolution of the linear microbubble response from the received echoes is proposed as a method to recover spatial resolution. The difference in the axial resolution resulting from chirp and three-cycle tone burst insonation is approximately 220 microm. The difference in the mainlobe width between experimental and predicted compressed echoes is less than 20%. The side-lobe amplitude is 9 dB to 16 dB below the mainlobe with a transmitted I(SPTA) from 0.1 to 6.6 mW/cm2.     

Nonlinear propagation of ultrasound through microbubble contrast agents and implications for imaging

Microbubble contrast agents produce nonlinear echoes under ultrasound insonation, and current imaging techniques detect these nonlinear echoes to generate contrast agent images accordingly. For these techniques, there is a potential problem in that bubbles along the ultrasound transmission path between transducer and target can alter the ultrasound transmission nonlinearly and contribute to the nonlinear echoes. This can lead to imaging artefacts, especially in regions at depth. In this paper we provide insight, through both simulation and experimental measurement, into the nonlinear propagation caused by microbubbles and the implications for current imaging techniques. A series of investigations at frequencies below, at, and above the resonance frequency of microbubbles were performed. Three specific effects on the pulse propagation (i.e., amplitude attenuation, phase changes, and harmonic generation) were studied. It was found that all these effects are dependent on the initial pulse amplitude, and their dependence on the initial phase of the pulse is shown to be insignificant. Two types of imaging errors are shown to result from this nonlinear propagation: first, that tissue can be misclassified as microbubbles; second, the concentration of microbubbles in the image can be misrepresented. It is found that these imaging errors are significant for all three pulse frequencies when the pulses transmit through a microbubble suspension of 6 cm in path length. It also is found that the first type of error is larger at the bubble resonance frequency.     

Harmonic chirp imaging method for ultrasound contrast agent

Coded excitation is currently used in medical ultrasound to increase signal-to-noise ratio (SNR) and penetration depth. We propose a chirp excitation method for contrast agents using the second harmonic component of the response. This method is based on a compression filter that selectively compresses and extracts the second harmonic component from the received echo signal. Simulations have shown a clear increase in response for chirp excitation over pulse excitation with the same peak amplitude. This was confirmed by two-dimensional (2-D) optical observations of bubble response with a fast framing camera. To evaluate the harmonic compression method, we applied it to simulated bubble echoes, to measured propagation harmonics, and to B-mode scans of a flow phantom and compared it to regular pulse excitation imaging. An increase of approximately 10 dB in SNR was found for chirp excitation. The compression method was found to perform well in terms of resolution. Axial resolution was in all cases within 10% of the axial resolution from pulse excitation. Range side-lobe levels were 30 dB below the main lobe for the simulated bubble echoes and measured propagation harmonics. However, side-lobes were visible in the B-mode contrast images.     

Motion artifacts of pulse inversion-based tissue harmonic imaging

Motion artifacts of the pulse inversion technique were studied for finite amplitude distortion-based harmonic imaging. Motion in both the axial and the lateral directions was considered. Two performance issues were investigated. One is the harmonic signal intensity relative to the fundamental intensity and the other is the potential image quality degradation resulting from spectral leakage. A one-dimensional (1-D) correlation-based correction scheme also was used to compensate for motion artifacts. Results indicated that the tissue harmonic signal is significantly affected by tissue motion. For axial motion, the tissue harmonic intensity decreases much more rapidly than with lateral motion. The fundamental signal increases for both axial and lateral motion. Thus, filtering is still required to remove the fundamental signal, even if the pulse inversion technique is applied. The motion also potentially decreases contrast resolution because of the uncancelled spectral leakage. Also, it was indicated that 1-D motion correction is not adequate if nonaxial motion is present.     

Harmonic leakage and image quality degradation in tissue harmonic imaging

Image quality degradation caused by harmonic leakage was studied for finite amplitude distortion-based harmonic imaging. Various sources of harmonic leakage, including transmit waveform, signal bandwidth, and system nonlinearity, were investigated using both simulations and hydrophone measurements. Effects of harmonic leakage in the presence of sound velocity inhomogeneities were also considered. Results indicated that sidelobe levels of the harmonic beam pattern were directly affected by harmonic leakage when the harmonic signal was obtained by filtering out the fundamental signal. Because sidelobe levels also increase with the bandwidth of the transmitted signal, a trade-off exists between axial resolution and contrast resolution. It is concluded that accurate control of the frequency content of the waveform prior to propagation is necessary to optimize imaging performance of tissue harmonic imaging. The filtering technique was also compared with the pulse inversion technique. It was shown that the pulse inversion technique effectively suppresses harmonic leakage at the cost of imaging frame rate and potential motion artifacts     

Third harmonic transmit phasing for tissue harmonic generation

Generation of tissue harmonic signals during acoustic propagation is based on the combined effect of two different spectral interactions of the transmit signal. One produces harmonic whose frequency is the sum of transmit frequencies. The other results in harmonic at difference frequency of the transmit signals. Both the frequency-sum component and the frequency-difference component are sensitive to the phase of their constitutive spectral signals. In this study, a novel approach for modifying the amplitude of tissue harmonic signal is proposed based on phasing these two components to achieve either harmonic enhancement or suppression. Both experiments and simulations were performed to investigate the effects of 3f0 transmit phasing on tissue harmonic generation. Results indicate that the relative phasing between the frequency-sum component and the frequency-difference component markedly changes the amplitude of the second harmonic signal. For harmonic enhancement, approximate 6 dB increase of second harmonic amplitude can be achieved while the lateral harmonic beam pattern also is improved as compared to conventional situations in which only the frequency-sum component is considered. For harmonic suppression, the second harmonic signal also could be significantly reduced by about 11 dB when the frequency-difference component is out of phase with the frequency-sum component. Hence, the method of 3f0 transmit phasing has potentials for both improving signal-to-noise ratio in tissue harmonic imaging and enhancing image contrast in contrast-agent imaging by suppression of tissue harmonic background.     

Design of chirp excitation waveform for dual-frequency harmonic contrast detection

Tissue background suppression is essential for harmonic detection of ultrasonic contrast microbubbles. To reduce the tissue harmonic amplitude for improvement of contrast-to-tissue ratio (CTR), the method of third harmonic (3f₀) transmit phasing uses an additional 3f₀ transmit signal to provide mutual cancellation between the frequency-sum component and the frequency-difference component of tissue harmonic signal. Chirp excitation can further improve the SNR in harmonic imaging without requiring an excessive transmit pressure and thus reduce potential bubble destruction. However, for effective suppression of tissue harmonic background in 3f₀ transmit phasing, the 3f₀ chirp waveform has to be carefully designed for the generation of spectrally matched cancellation pairs over the entire second harmonic band. In this study, we proposed a chirp waveform suitable for the method of 3f₀ transmit phasing, the different-bandwidth chirp signal (DBCS). With the DBCS waveform, the frequency-difference component of tissue harmonic signal becomes a chirp signal similar to its frequency-sum counterpart. Thus, the combination of the DBCS waveform with the 3f₀ transmit phasing can markedly suppress the tissue harmonic amplitude for CTR improvement together with effective SNR increase of contrast harmonic signal. Our results indicate that, as compared with the conventional Gaussian pulse, the DBCS waveform can provide 6-dB improvement of SNR in 3f₀ transmit phasing with a CTR increase of 3 dB. Nevertheless, the limitation of available transmit bandwidth and the frequency-dependent attenuation can degrade the performance of the DBCS waveform in tissue suppression. The design of the DBCS waveform is also applicable to other dual-frequency imaging techniques that rely on the harmonic generation at the difference frequency.     

Suppression of propagating second harmonic in ultrasound contrast imaging

Contrast agents, such as bubbles, are used in ultrasound to enhance backscatter from blood. To increase contrast between these agents and tissue, nonlinear methods such as harmonic imaging can be used. Contrast is limited, however, by tissue second harmonic signals. We show that a major source of this signal is nonlinear propagation through tissue. In addition, we present methods to suppress this second harmonic generation. One simple approach is to decrease the f/number of the imaging system. Simulations show that doubling the size of the array, while keeping total power output constant, decreases propagating second harmonic generation. A second approach uses active noise cancellation to suppress second harmonic generation. A specific method, the harmonic cancellation system (HCS), is developed and presented as an example. In simulations, HCS decreased second harmonic generation by over 30 dB. Using such methods, contrast can be improved between tissue and bubbles in harmonic imaging.     

Comparison of pulse subtraction Doppler and pulse inversion Doppler

In this paper, a new Doppler technique based on pulse subtraction imaging (PSD) is described and compared with pulse inversion Doppler (PID). Combining a nonlinear contrast agent imaging technique with a Doppler process provides a tool for detecting motion of both contrast agents and tissues. This has potential in targeted imaging in which attached microbubbles need to be separated from moving ones and surrounding tissues. The results from both simulation and experiment show that PSD is able to differentiate bubble motion from tissue motion. For Doppler processing conducted at the fundamental frequency, the contrast-to-tissue ratio (CTR) in PSD was 3.3 (±0.4) times higher on average than PID at a mechanical index (MI) of 0.1. At the harmonic frequency, PID was shown to have a 3.1 (±0.4) times higher CTR than PSD. Overall, taken in their optimum processing conditions, PID has a CTR up to 1.9 (±0.4) times higher than PSD. The CTRs for both techniques have also been shown to increase with increasing MI. However, for the same axial Doppler resolution. PSD also allows less energy to be transmitted into the medium, which makes it less disruptive. The relative performances of PSD and PID in terms of the bandwidth of the imaging system are also discussed.     

Radial modulation of microbubbles for ultrasound contrast imaging

Over the past few years, extensive research has been carried out in the field of ultrasound contrast imaging. In addition to the development of new types of ultrasound contrast agents, various imaging methods dedicated to contrast agents have been introduced, and some of them are now commercially available. In this study, we present results of an imaging technique that is capable of detecting echoes from microbubbles and eliminating those emanating from nonoscillating structures (tissue), thereby enhancing contrast imaging. The method is based on mixing a low frequency (LF) modulator signal and a high frequency (HF) imaging signal to effectively modulate the size of the contrast microbubble through its volumetric oscillations using the LF signal and to probe the radial motion using the HF imaging signal. To evaluate the performances and limitations of the method, high-speed optical observations and acoustic measurements were carried out on soft-shelled microbubbles. The results showed that, by incorporating the modulator signal, the bubbles respond differently compared to the HF excitation alone. The decorrelation between the signals obtained at the compression and expansion phase of the modulator signal is significantly high to be used as a parameter to detect contrast microbubbles and discriminate them from tissue. The echo received from a solid reflector shows identical responses during the compression and rarefaction phase of the LF signal. In conclusion, these results demonstrate the feasibility of this fully linear approach for improving the contrast detection.     

Golay pulse encoding for microbubble contrast imaging in ultrasound

We present a technique that uses Golay phase encoding, pulse inversion, and amplitude modulation (GPIAM) for microbubble contrast agent imaging with ultrasound. This technique improves the contrast-to-tissue ratio (CTR) by increasing the time-bandwidth product of the insonating waveforms. A nonlinear pulse compression algorithm is used to compress the signal energy upon receive. A 6.5-dB improvement in CTR was observed using an 8-chip GPIAM sequence compared to a conventional pulse-inversion amplitude-modulation sequence. The CTR improvement comes at the cost of a reduction in frame rate: GPIAM coding uses four input pulses whereas most contrast imaging sequences require two or three pulses. Our results showed that the microbubble response can be phase encoded and subsequently compressed using a nonlinear matched-filtering algorithm, in order to enhance the signal from the contrast agent, while maintaining resolution and suppressing the tissue signal.     

Pulse subtraction time delay imaging method for ultrasound contrast agent detection

Detection of contrast agent in perfused tissues has been an important research topic for many years. Currently available methods are mostly based on the strong nonlinear scattering of contrast agent microbubbles. These methods selectively extract those parts of the spectrum that show the largest difference in nonlinearity between contrast agent and tissue. The method introduced in this paper expands this extraction approach in that it additionally exploits differences in system behavior between tissue and contrast bubbles. The resonant nature of contrast bubbles implies that the response of a contrast bubble is stateful, i.e., the response not only depends on the current input, but also on all previous inputs. Tissue does not show this dependence on previous inputs. Our method is based on a 3 pulse design in which the echoes from 2 nonoverlapping pulses are subtracted from a third pulse. With this method we aim to separate and suppress those parts in an echo signal that originate from tissue while leaving the part originating from contrast bubbles relatively undisturbed. Simulation results show increases up to 30 dB in contrast-to-tissue ratio (CTR) with this method relative to single pulse echoes. This was confirmed in an in vitro experiment that showed an increase of approximately 12 dB in CTR.     

Pulse-inversion-based fundamental imaging for contrast detection

Pulse-inversion-based fundamental imaging was experimentally investigated for the enhancement of contrast detection. The pulse-inversion technique involves two firings with inverted waveforms. When the returning echoes from the two firings are summed, the residue signal is limited to even-order harmonics for tissue. However, when the returning echoes are from microbubbles, the fundamental signal is not completely cancelled because the reaction of the bubbles under compression is different from that under rarefaction. Thus, with the application of pulse-inversion technique, the fundamental signal can be used to enhance the contrast-to-tissue ratio. In this paper, B-mode, pulse-inversion-based fundamental images were constructed with various transmit waveforms. Motion artifacts also were studied. The results indicate that the contrast-to-tissue ratio was significantly enhanced compared to that obtained using either conventional, fundamental imaging or second-harmonic imaging. Longer transmit pulses resulted in a better signal-to-noise ratio, but did not noticeably affect the nonlinear response of the bubbles. In addition, the optimal ratio of the magnitude of the positive pulse to that of the negative pulse was unity, in terms of avoiding the uncancelled, third-order response in the fundamental frequency range. It also was found that the pulse-inversion fundamental technique is highly sensitive to tissue motion because the fundamental tissue signal is not cancelled when motion is present.     

Detection of tissue harmonic motion induced by ultrasonic radiation force using pulse-echo ultrasound and Kalman filter

A method using pulse echo ultrasound and the Kalman filter is developed for detecting submicron harmonic motion induced by ultrasonic radiation force. The method estimates the amplitude and phase of the motion at desired locations within a tissue region with high sensitivity. The harmonic motion generated by the ultrasound radiation force is expressed as extremely small oscillatory Doppler frequency shifts in the fast time (A-line) of ultrasound echoes, which are difficult to estimate. In slow time (repetitive ultrasound echoes) of the echoes, the motion also is presented as oscillatory phase shifts, from which the amplitude and phase of the harmonic motion can be estimated with the least mean squared error by Kalman filter. This technique can be used to estimate the traveling speed of a harmonic shear wave by tracking its phase changes during propagation. The shear wave propagation speed can be used to solve for the elasticity and viscosity of tissue as reported in our earlier study. Validation and in vitro experiments indicate that the method provides excellent estimations for very small (submicron) harmonic vibrations and has potential for noninvasive and quantitative stiffness measurements of tissues such as artery.