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.     

超声造影剂微泡尺寸分布及浓度测量方法

通过计算机采集光学显微图片,以Image-ProPlus和Photoshop两种图像分析软件实现了微泡的浓度及尺寸分析进行定性测定。结果表明,本文采用的方法快速、简便、重现性良好,可作为超声造影剂微泡的定性测定。     

High-frequency dynamics of ultrasound contrast agents

Ultrasound contrast agents enhance echoes from the microvasculature and enable the visualization of flow in smaller vessels. Here, we optically and acoustically investigate microbubble oscillation and echoes following insonation with a 10 MHz center frequency pulse. A high-speed camera system with a temporal resolution of 10 ns, which provides two-dimensional (2-D) frame images and streak images, is used in optical experiments. Two confocally aligned transducers, transmitting at 10 MHz and receiving at 5 MHz, are used in acoustical experiments in order to detect subharmonic components. Results of a numerical evaluation of the modified Rayleigh-Plesset equation are used to predict the dynamics of a microbubble and are compared to results of in vitro experiments. From the optical observations of a single microbubble, nonlinear oscillation, destruction, and radiation force are observed. The maximum bubble expansion, resulting from insonation with a 20-cycle, 10-MHz linear chirp with a peak negative pressure of 3.5 MPa, has been evaluated. For an initial diameter ranging from 1.5 to 5 microm, a maximum diameter less than 8 microm is produced during insonation. Optical and acoustical experiments provide insight into the mechanisms of destruction, including fragmentation and active diffusion. High-frequency pulse transmission may provide the opportunity to detect contrast echoes resulting from a single pulse, may be robust in the presence of tissue motion, and may provide the opportunity to incorporate high-frequency ultrasound into destruction-replenishment techniques.     

Piezoelectric contrast materials for ultrasound imaging

Piezoelectric ceramics and polymers can be used as a type of marker and contrast material for medical ultrasound imaging systems. High-frequency electrical signals are detected from surface electrodes when these materials are introduced into conducting media such as tissue and scanned by ultrasound imaging systems. Detected signals are applied to the imaging circuits of a modified ultrasound system such that they display a unique type of electrical image that shows the piezomaterial's polarization, shape, and position at arbitrarily high contrast compared to the conventional ultrasound acoustic image. The resulting piezoelectric image can be merged in real-time with conventional ultrasound acoustic imaging to form a composite image. This approach is of interest in the development of improved techniques for imaging medical devices that are implanted or otherwise introduced into the body.     

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     

Asymmetric oscillation of adherent targeted ultrasound contrast agents

With a lipid shell containing biotin, micron-sized bubbles bound to avidin on a porous and flexible cellulose boundary were insonified by ultrasound. The oscillation of these targeted microbubbles was observed by high-speed photography and compared to the oscillation of free-floating microbubbles. Adherent microbubbles were observed to oscillate asymmetrically in the plane normal to the boundary, and nearly symmetrically in the plane parallel to the boundary, with a significantly smaller maximum expansion in each dimension for bound than free bubbles. With sufficient transmitted pressure, a jet was produced traveling toward the boundary.     

A new formalism for the quantification of tissue perfusion by the destruction-replenishment method in contrast ultrasound imaging

A new formalism is presented for the destruction-replenishment perfusion quantification approach at low mechanical index. On the basis of physical considerations, best-fit methods should be applied using perfusion functions with S-shape characteristics. These functions are first described for the case of a geometry with a single flow velocity, then extended to the case of vascular beds with blood vessels having multiple flow velocity values and directions. The principles guiding the analysis are, on one hand, a linearization of video echo signals to overcome the log-compression of the imaging instrument, and, on the other hand, the spatial distribution of the transmit-receive ultrasound beam in the elevation direction. An in vitro model also is described; it was used to confirm experimentally the validity of the approach using a commercial contrast agent. The approach was implemented in the form of a computer program, taking as input a sequence of contrast-specific images, as well as parameters related to the ultrasound imaging equipment used. The generated output is either flow-parameter values computed in regions-of-interest, or parametric flow-images (e.g., mean velocity, mean transit time, mean flow, flow variance, or skewness). This approach thus establishes a base for extracting information about the morphology of vascular beds in vivo, and could allow absolute quantification provided that appropriate instrument calibration is implemented.     

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.     

Predicting backscatter characteristics from micron- and submicron-scale ultrasound contrast agents using a size-integration technique

In this paper, a computationally, inexpensive, size-integration method based on a modified Rayleigh-Plesset model is developed to predict backscatter spectra from groups of bubbles with various size distributions, incident acoustic amplitudes, and driving frequencies. The method was validated using experimentally measured spectra from contrast bubbles of various sizes: Optison, Levovist, ST68 microbubbles, and submicron bubbles. This method provides a computationally inexpensive means of examining backscatter spectrum from multiple bubbles, especially in predicting occurrence and relative amplitude of subharmonics and second harmonics.     

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.     

Shell waves and acoustic scattering from ultrasound contrast agents

Ultrasound contrast agents are encapsulated microbubbles, filled either with air or a higher weight molecular gas, ranging in size from 1 to 10 μm in diameter. The agents are modeled as air-filled spherical elastic shells of variable thickness and material properties. The scattered acoustic field is computed from a modal series solution, and reflectivity and angular scattering are then determined from the computed fields for agents of various properties. We show that contrast agents also support shell resonance responses in addition to the monopole response, which has been the focus of previous contrast agent studies. Lamb waves appear to be the source of these additional responses. A shell or curvature Lamb wave generates dipole peaks in the 1- to 40-MHz range for 2.5 to 3.5 μm radius agents with elastic properties approximating those of albumin protein. The inclusion of damping affects the lower frequency dipole peaks but is less important for responses occurring above approximately 30 MHz. Moreover, these responses hold untapped potential for clinical ultrasound applications such as tissue perfusion studies and high frequency contrast agent imaging     

Doppler spectra from contrast agents crossing an ultrasound field

When contrast agents are injected in a fluid, it is implicitly assumed that they move at the same velocity as the fluid itself. However, a series of in vitro tests performed by using air-filled microbubbles suspended in distilled water, have shown that the Doppler spectrum generated in this case may be notably different from that obtained from non-resonating scatterers. In this paper, we show, through a simple simulation model, that the actual movement of microbubbles may be predicted as the result of the complex balance between two forces: the ultrasound radiation force, which tends to move the particles along the sound beam direction, and the fluid drag force, which tends to move the particles along the fluid stream. The contrast agents turn out to be displaced only during the passage of the ultrasound burst; during the remaining time, they are maintained at the fluid velocity by the drag force. Based on the total particle displacement estimated between consecutive pulses, a series of Doppler spectra corresponding to different intensity levels was computed. This series was shown to be in excellent agreement with the experimental spectra obtained in vitro using Levovist(R) (Schering AG, Berlin, Germany) particles suspended in distilled water flowing at a steady rate.     

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.     

High frequency nonlinear B-scan imaging of microbubble contrast agents

It was previously shown that it is possible to produce nonlinear scattering from microbubble contrast agents using transmit frequencies in the 14-32 MHz range, suggesting the possibility of performing high-frequency, nonlinear microbubble imaging. In this study, we describe the development of nonlinear microbubble B-scan imaging instrumentation capable of operating at transmit center frequencies between 10 and 50 MHz. The system underwent validation experiments using transmit frequencies of 20 and 30 MHz. Agent characterization experiments demonstrate the presence of nonlinear scattering for the conditions used in this study. Using wall-less vessel phantoms, nonlinear B-scan imaging is performed using energy in one of the subharmonic, ultraharmonic, and second harmonic frequency regions for transmit frequencies of 20 and 30 MHz. Both subharmonic and ultraharmonic imaging modes achieved suppression of tissue signals to below the noise floor while achieving contrast to noise ratios of up to 26 and 17 dB, respectively. The performance of second harmonic imaging was compromised by nonlinear propagation and offered no significant contrast improvement over fundamental mode imaging. In vivo experiments using the subharmonic of a 20 MHz transmit pulse show the successful detection of microvessels in the rabbit ear and in the mouse heart. The results of this study demonstrate the feasibility of nonlinear microbubble imaging at high frequencies     

High-frequency, nonlinear flow imaging of microbubble contrast agents

It has been shown that nonlinear scattering can be stimulated from microbubble contrast agents at high-transmit frequencies (14-32 MHz). This work was extended to demonstrate the feasibility of nonlinear contrast imaging through modifications of existing ultrasound biomicroscopy linear B-scan imaging instrumentation. In this study, we describe the development and evaluation of prototype coherent flow imaging instrumentation for nonlinear microbubble imaging using transmit frequencies from 10 to 50 MHz. Phantom validation experiments were conducted to demonstrate color and power flow imaging using nonlinear 10 MHz (subharmonic) scattering induced by a 20 MHz transmit frequency. In vivo flow imaging of a rabbit ear microvessel was successfully performed. This work indicates the feasibility of performing flow imaging at high frequencies using nonlinear scattering from microbubbles.     

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.     

Contrast response analysis for medical ultrasound imaging

Traditional measures of spatial resolution are helpful but incomplete for characterizing the imaging performance of medical ultrasound systems because the challenge is not so much resolving strong point reflectors as limiting the impact of stronger scattering regions on weaker regions. This paper discusses the use of an alternative measure which is based on the ability of a system to accurately image an anechoic region surrounded by a uniform scattering medium. This measure, called contrast response, includes effects of both mainlobe width and sidelobe level. Since the impulse response of a linear system to a target is the convolution of the system spatial impulse response (beam pattern) and the target scattering function, the system output can be described by a three dimensional integral. The contrast response is defined as the ratio of this system output when the anechoic target is not present to the output when it is present, evaluated over a range of target sizes. Contrast response analysis is useful for both system design and performance comparison. Examples are presented which compare the performance of systems with different apodization functions and aperture sizes. This analysis approach suggests why the strong window functions popular in signal processing have not been used for apodization in medical ultrasound and why 256 channel systems have not demonstrated a dramatic performance improvement over 128 channel systems     

气泡尺寸分布对造影剂散射特性的影响

1引言 由于在B超成像中使用超声造影剂能提高图像的清晰度和对比度,有关超声造影剂的研究近年来受到了越来越多的关注.目前主流造影剂主要是一些含包膜气泡的流体,如Albunex 等.因此,包膜气泡的声散射特性的研究对于造影剂的研制具有非常重要的价值.对于造影剂的包膜气泡线性散射特性的研究,从单个气泡散射到多个气泡散射,从弹性包膜气泡模型到粘弹性包膜气泡模型,目前已有不少成果[1-3].但是对于含有一定尺寸分布的多个粘弹包膜气泡散射特性的研究,目前还未涉及.本文就是在文献[2]的造影剂中单个粘弹包膜和多个等大的粘弹包膜气泡散射特性计算结果的基础上,用WT多泡散射法[4]计算并讨论了气泡尺寸分布对于造影剂散射特性的影响.     

Optical and acoustical observations of the effects of ultrasound on contrast agents

Optimal use of encapsulated microbubbles for ultrasound contrast agents and drug delivery requires an understanding of the complex set of phenomena that affect the contrast agent echo and persistence. With the use of a video microscopy system coupled to either an ultrasound flow phantom or a chamber for insonifying stationary bubbles, we show that ultrasound has significant effects on encapsulated microbubbles. In vitro studies show that a train of ultrasound pulses can alter the structure of an albumin-shelled bubble, initiate various mechanisms of bubble destruction or produce aggregation that changes the echo spectrum. In this analysis, changes observed optically are compared with those observed acoustically for both albumin and lipid-shelled agents. We show that, when insonified with a narrowband pulse at an acoustic pressure of several hundred kPa, a phospholipid-shelled bubble can undergo net radius fluctuations of at least 15%; and an albumin-shelled bubble initially demonstrates constrained expansion and contraction. If the albumin shell contains air, the shell may not initially experience surface tension; therefore, the echo changes more significantly with repeated pulsing. A set of observations of contrast agent destruction is presented, which includes the slow diffusion of gas through the shell and formation of a shell defect followed by rapid diffusion of gas into the surrounding liquid. These observations demonstrate that the low-solubility gas used in these agents can persist for several hundred milliseconds in solution. With the transmission of a high-pulse repetition rate and a low pressure, the echoes from, contrast agents can be affected by secondary radiation force. Secondary radiation force is an attractive force for these experimental conditions, creating aggregates with distinct echo characteristics and extended persistence. The scattered echo from an aggregate is several times stronger and more narrowband than echoes from individual bubbles.