Comparison of fundamental, second harmonic, and superharmonic imaging: a simulation study

In medical ultrasound, fundamental imaging (FI) uses the reflected echoes from the same spectral band as that of the emitted pulse. The transmission frequency determines the trade-off between penetration depth and spatial resolution. Tissue harmonic imaging (THI) employs the second harmonic of the emitted frequency band to construct images. Recently, superharmonic imaging (SHI) has been introduced, which uses the third to the fifth (super) harmonics. The harmonic level is determined by two competing phenomena: nonlinear propagation and frequency dependent attenuation. Thus, the transmission frequency yielding the optimal trade-off between the spatial resolution and the penetration depth differs for THI and SHI. This paper quantitatively compares the concepts of fundamental, second harmonic, and superharmonic echocardiography at their optimal transmission frequencies. Forward propagation is modeled using a 3D-KZK implementation and the iterative nonlinear contrast source (INCS) method. Backpropagation is assumed to be linear. Results show that the fundamental lateral beamwidth is the narrowest at focus, while the superharmonic one is narrower outside the focus. The lateral superharmonic roll-off exceeds the fundamental and second harmonic roll-off. Also, the axial resolution of SHI exceeds that of FI and THI. The far-field pulse-echo superharmonic pressure is lower than that of the fundamental and second harmonic. SHI appears suited for echocardiography and is expected to improve its image quality at the cost of a slight reduction in depth-of-field.     

Investigation of linear and nonlinear frequency modulated excitation effects on tissue harmonic imaging

The generation of tissue harmonics is due to nonlinear nature of ultrasound wave propagation in biological tissues.The tissue harmonics for imaging i.e.tissue harmonic imaging (THI)uses higher frequency components for imaging in which the resolution improves significantly but signal-to-noise ratio(SNR)and penetration depth remains low as compared to both fundamental and second harmonic imaging.The coded excitations have potential to improve the SNR which ultimately leads to improved penetration depth.In the present work,the linear frequency modulated(chirp/LFM)and nonlinear frequency modulated(NLFM)signals have been used to investigate the nonlinear ultrasound wave propagation and harmonic generation in biological tissues.The SNR has been found to be substantially improved for coded tissue harmonic imaging(CTHI)as well as for coded superharmonic imaging(CSHI).     

Generation of ultraharmonics in surfactant based ultrasound contrast agents: use and advantages.

A unique distinction between surfactant stabilized ultrasound contrast agent ST68 and water (or tissue), is the enhanced ability of the agent to generate non-linear frequencies such as sub-harmonics (f0/2), higher harmonics (2fo, 3fo, 4fo,...), and ultraharmonics (3f0/2, Sf0/2, 7f0/2,...), when insonated with fundamental frequency f0. Currently, second harmonics (2f0) have been predominantly researched, to exploit the diagnostic benefits of the contrast-specific non-linear imaging. However, we found that at normal imaging pressures (100 kPa-1 MPa), ST68 agent-generated second harmonic enhancements dropped to approximately 8 dB at 100 kPa and approximately 2 dB at 1 MPa. Moreover, at these pressures water (or tissue) produced strong second harmonics due to non-linear propagation. Ultraharmonics and sub-harmonics on the other hand, were generated only by the agent, and were not produced due to the non-linear propagation of ultrasound in either water or tissue. Additionally, ultraharmonic (3f0/2) enhancements of approximately 23 dB at 100 kPa, approximately 35 dB at 0.5 MPa and approximately 41dB at 1.1 MPa for ST68-PFC, offer much greater signal to noise ratio than higher harmonics.     

Tissue harmonic ultrasonic imaging

Harmonic imaging was originally developed for microbubble contrast agents in the early 90s under the assumption that tissue is linear and all harmonic echoes are generated by the bubbles. In fact, tissue, like bubbles, is a nonlinear medium. Whereas the harmonic echoes from bubbles have their origins in nonlinear scattering, those from tissue are a result of nonlinear propagation. The clinical benefits of tissue harmonic imaging are reduced reverberation noise and overall clutter level, improved border delineation, increased contrast resolution, and reduced phase aberration artifacts. To a large extent these benefits are explained by the properties of nonlinear propagation of the transmitted ultrasonic pulses in the tissue.     

Contrast harmonic imaging

The behavior of ultrasound contrast agents depends highly on the acoustic pressure of the insonified ultrasound wave. For low pressure the expansion and compression is linear to the pressure, for medium acoustic pressure nonlinear behavior starts to occur and for high pressures, but still in the diagnostic range transient scattering can be noticed, resulting in an enhanced scattering followed by a disappearance of the bubble. The nonlinear and transient regime can be utilized for imaging of the contrast agent in or nearby tissue. The magnitude of the nonlinear signal from the contrast has to compete with the nonlinear component of the ultrasound wave, which is generated during propagation. It is shown that contrast is superior to tissue when using low frequencies and imaging the third or fourth harmonic of the transmitted frequency.     

Nonlinear pulsed ultrasound beams radiated by rectangular focused diagnostic transducers

A numerical model for simulating nonlinear pulsed beams radiated by rectangular focused transducers, which are typical of diagnostic ultrasound systems, is presented. The model is based on a KZK-type nonlinear evolution equation generalized to an arbitrary frequency-dependent absorption. The method of fractional steps with an operator-splitting procedure is employed in the combined frequency-time domain algorithm. The diffraction is described using the implicit backward finite-difference scheme and the alternate direction implicit method. An analytic solution in the time domain is employed for the nonlinearity operator. The absorption and dispersion of the sound speed are also described using an analytic solution but in the frequency domain. Numerical solutions are obtained for the nonlinear acoustic field in a homogeneous tissue-like medium obeying a linear frequency law of absorption and in a thermoviscous fluid with a quadratic frequency law of absorption. The model is applied to study the spatial distributions of the fundamental and second harmonics for a typical diagnostic ultrasound source. The nonlinear distortion of pulses and their spectra due to the propagation in tissues are presented. A better understanding of nonlinear propagation in tissue may lead to improvements in nonlinear imaging and in specific tissue harmonic imaging. Published in Russian in Akusticheskiĭ Zhurnal, 2006, Vol. 52, No. 4, pp. 560–570. This article was translated by the authors.     

Subharmonic imaging of contrast agents

Ultrasound contrast agents promise to improve the sensitivity and specificity of diagnostic ultrasound imaging. It is of great importance to adapt ultrasound equipment for optimal use with contrast agents e.g., by exploiting the nonlinear properties of the contrast microbubbles. Harmonic imaging is one technique that has been extensively studied and is commercially available. However, harmonic imaging is associated with problems, due to second harmonic generation and accumulation within the tissue itself. Given the lack of subharmonic generation in tissue, one alternative is the creation of subharmonic images by transmitting at the fundamental frequency (fo) and receiving at the subharmonic (fo/2). Subharmonic imaging should have a much better lateral resolution and may be suitable for scanning deep-lying structures owing to the higher transmit frequency and the much smaller attenuation of scattered subharmonic signals. In this paper, we will review different aspects of subharmonic imaging including implementation, in-vitro gray-scale imaging and subharmonic aided pressure estimation.     

Difference frequency and its harmonic emitted by microbubbles under dual frequency excitation

Vibro-acoustography is an elasticity imaging method that uses two ultrasound beams of slightly different frequency to excite an object and detects the resulting acoustic emission (AE) at the difference frequency. This method is especially sensitive to bubbles due to their nonlinearity. This study explores the harmonic acoustic emission (HAE) at twice the difference frequency emitted from bubbles. A perturbation method based on the dynamic bubble equation is used to derive the AE and HAE from a single bubble excited by dual frequency waves. Simulation shows that HAE is generated only by microbubbles whose resonant frequencies match the incident ultrasound frequencies. In contrast, AE is more sensitive to resonance at the difference frequency, which is relevant to sub-millimeter bubbles. This finding was confirmed by experiments where HAE was produced from Optison microbubbles, but not from larger air bubbles which are off resonance at the incident ultrasound frequency. In conclusion, harmonic acoustic emission is present for microbubbles. It is very sensitive to the size of the bubble and may be used for selective detection of microbubbles.     

Modelling of nonlinear effects and the response of ultrasound contrast micro bubbles: simulation and experiment

The propagation of diagnostic ultrasonic imaging pulses in tissue and their interaction with contrast micro bubbles is a very complex physical process, which we assumed to be separable into three stages: pulse propagation in tissue, the interaction of the pulse with the contrast bubble, and the propagation of the scattered echo. The model driven approach is used to gain better knowledge of the complex processes involved. A simplified way of field simulation is chosen due to the complexity of the task and the necessity to estimate comparative contributions of each component of the process. Simulations are targeted at myocardial perfusion estimation. A modified method for spatial superposition of attenuated waves enables simulations of low intensity pulse pressure fields from weakly focused transducers in a nonlinear, attenuating, and liquid-like biological medium. These assumptions enable the use of quasi-linear calculations of the acoustic field. The simulations of acoustic bubble response are carried out with the Rayleigh-Plesset equation with the addition of radiation damping. Theoretical simulations with synthesised and experimentally sampled pulses show that the interaction of the excitation pulses with the contrast bubbles is the main cause of nonlinear scattering, and a 2-3 dB increase of second harmonic amplitude depends on nonlinear distortions of the incident pulse.     

Weakly nonlinear focused ultrasound in viscoelastic media containing multiple bubbles

To facilitate practical medical applications such as cancer treatment utilizing focused ultrasound and bubbles, a mathematical model that can describe the soft viscoelasticity of human body, the nonlinear propagation of focused ultrasound, and the nonlinear oscillations of multiple bubbles is theoretically derived and numerically solved. The Zener viscoelastic model and Keller–Miksis bubble equation, which have been used for analyses of single or few bubbles in viscoelastic liquid, are used to model the liquid containing multiple bubbles. From the theoretical analysis based on the perturbation expansion with the multiple-scales method, the Khokhlov–Zabolotskaya–Kuznetsov (KZK) equation, which has been used as a mathematical model of weakly nonlinear propagation in single phase liquid, is extended to viscoelastic liquid containing multiple bubbles. The results show that liquid elasticity decreases the magnitudes of the nonlinearity, dissipation, and dispersion of ultrasound and increases the phase velocity of the ultrasound and linear natural frequency of the bubble oscillation. From the numerical calculation of resultant KZK equation, the spatial distribution of the liquid pressure fluctuation for the focused ultrasound is obtained for cases in which the liquid is water or liver tissue. In addition, frequency analysis is carried out using the fast Fourier transform, and the generation of higher harmonic components is compared for water and liver tissue. The elasticity suppresses the generation of higher harmonic components and promotes the remnant of the fundamental frequency components. This indicates that the elasticity of liquid suppresses shock wave formation in practical applications.     

Time domain simulation of nonlinear acoustic beams generated by rectangular pistons with application to harmonic imaging

A time-domain numerical code (the so-called Texas code) that solves the Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation has been extended from an axis-symmetric coordinate system to a three-dimensional (3D) Cartesian coordinate system. The code accounts for diffraction (in the parabolic approximation), nonlinearity and absorption and dispersion associated with thermoviscous and relaxation processes. The 3D time domain code was shown to be in agreement with benchmark solutions for circular and rectangular sources, focused and unfocused beams, and linear and nonlinear propagation. The 3D code was used to model the nonlinear propagation of diagnostic ultrasound pulses through tissue. The prediction of the second-harmonic field was sensitive to the choice of frequency-dependent absorption: a frequency squared f2 dependence produced a second-harmonic field which peaked closer to the transducer and had a lower amplitude than that computed for an f1.1 dependence. In comparing spatial maps of the harmonics we found that the second harmonic had dramatically reduced amplitude in the near field and also lower amplitude side lobes in the focal region than the fundamental. These findings were consistent for both uniform and apodized sources and could be contributing factors in the improved imaging reported with clinical scanners using tissue harmonic imaging.     

Experimental investigation of the pulse inversion technique for imaging ultrasound contrast agents

The application of ultrasound contrast agents aims to detect low velocity blood flow in the microcirculation. To enhance discrimination between tissue and blood containing the contrast agent, harmonic imaging is used. Harmonic imaging requires the application of narrow-band signals and is obscured by high levels of native harmonics generated in an intervening medium. To improve discrimination between contrast agent and native harmonics, a pulse inversion technique has been proposed. Pulse inversion allows wide-band signals, thus preserving the axial resolution. The present study examines the interference of native harmonics and discusses the practical difficulties of wide-band pulse inversion measurements of harmonics by a single transducer. Native harmonics are not eliminated by pulse inversion. Furthermore, only even harmonics remain and are amplified by 6 dB, alleviating the requirement for selective filtering. Finally, it is shown that the contaminating third harmonic contained in the square wave activation signal leaks through in the emitted signal. The spectral location of the contaminating third harmonic is governed by the transducer spectral characteristics while the location of the native and contrast agent second harmonics is not. Thus the contaminating third harmonic and the native and contrast agent second harmonics may overlap and interfere. Optimal discrimination requires a balance between maximal sensitivity for the second harmonic at reception and minimal interference from the contaminating third harmonic.     

Fundamental study on subharmonic imaging by irradiation of amplitude-modulated ultrasound waves

The second harmonic and subharmonic components, the frequencies of which are twice and one half the fundamental frequency, are included in echoes from contrast agents. An imaging method, which employs a second harmonic (second harmonic imaging), is widely used in medical diagnoses. On the other hand, subharmonic is expected to provide a higher contrast between biological tissues and blood flow because echo signals are generated only from blood containing the contrast agents. However, the subharmonic component echo signal power from contrast agents is relatively low. This has resulted in little progress in the field of subharmonic imaging. In this study, a new imaging method is proposed using amplitude-modulated waves as transmitted waves combined with the pulse inversion method to enhance subharmonic echo signals. Two optimal frequencies are set, including the modulated waves, F(1) and F(2), so that the subharmonic frequency of F(1) and the second harmonic frequency of F(2) may result in the same value. This allows a more powerful signal at the frequency band because the second harmonic and subharmonic components are integrated. Furthermore, a B-mode ultrasound image of an agar phantom that imitated biological tissue and showed the effectiveness of our method was reconstructed. As a result, the echo power of the subharmonic component was enhanced by approximately 11.8 dB more than the conventional method and the signal to noise ratio showed an improvement of 7.6 dB.     

Nonlinear propagation delay and pulse distortion resulting from dual frequency band transmit pulse complexes

A method of acoustic imaging is discussed that potentially can improve the diagnostic capabilities of medical ultrasound. The method, given the name second order ultrasound field imaging, is achieved by the processing of the received signals from transmitted dual frequency band pulse complexes with at least partly overlapping high frequency (HF) and low frequency (LF) pulses. The transmitted HF pulses are used for image reconstruction whereas the transmitted LF pulses are used to manipulate the elastic properties of the medium observed by the HF imaging pulses. In the present paper, nonlinear propagation effects observed by a HF imaging pulse due to the presence of a LF manipulation pulse is discussed. When using dual frequency band transmit pulse complexes with a large separation in center frequency (e.g., 1:10), these nonlinear propagation effects are manifested as a nonlinear HF propagation delay and a HF pulse distortion different from conventional harmonic distortion. In addition, with different transmit foci for the HF and LF pulses, nonlinear aberration will occur.     

突变截面驻波管和极高纯净驻波场的实验研究

突变截面驻波管属于失谐驻波管,即其高阶共振频率不是一阶共振频率的整数倍。通过对STAS的优化设计,利用STAS的失谐性质在一阶和二阶共振频率下激励分别获得了180 dB和177 dB的极高纯净驻波声场。尽管声压级已经很高,但在接下来的对一阶和二阶共振频率激励下的声波波形畸变和谐波饱和情况进行的实验研究中仍然没有观察到谐波饱和现象。与此同时,对三阶共振频率激励下的声场进行了实验研究,由于三阶共振频率激励下的大振幅非线性声场的二次谐波频率接近六阶共振频率,在声压级达到170 dB时观测到了三阶共振频率激励下的声波波形畸变和谐波饱和现象。      

Resonance frequency of microbubbles: effect of viscosity

The transmitted frequency at which a gas bubble of millimeter or submillimeter size oscillates resonantly in a low-viscosity liquid is approximately equal to the undamped natural frequency (referred to as the Minnaert frequency if surface tension effects are disregarded). Based on a theoretical analysis of bubble oscillation, this paper shows that such an approximation cannot be validated for microbubbles used in contrast-enhanced ultrasound imaging. The contrast-agent microbubbles represent either encapsulated bubbles of size less than 10 microm or free (nonencapsulated) bubbles of submicron size. The resonance frequency of the microbubbles deviates significantly from the undamped natural frequency over the whole range of microbubble sizes due to the increased viscous damping coefficient. The difference between these two frequencies is shown to have a tremendous impact on the resonant backscatter by the microbubbles. In particular, the first and second harmonics of the backscattered signal from the microbubbles are characterized by their own resonance frequencies, equal to neither the microbubble resonance frequency nor the undamped natural frequency.     

Optimization of acoustic scattering from dual-frequency driven microbubbles at the difference frequency

The second harmonic radiation of acoustically driven bubbles is a useful discriminant for their presence in clinical ultrasound applications. It is useful because the scatter from a bubble at a frequency different from the driving can have a contrast-to-tissue ratio better than at the drive frequency. In this work a technique is developed to optimize the scattering from a microbubble at a frequency different from the driving. This is accomplished by adjusting the relative phase and amplitudes of the components of a dual-frequency incident ultrasound wave form. The investigation is focused primarily on the example of dual-mode driving at frequencies of 1 MHz and 3 MHz, with the scattering optimized at 2 MHz. Bubble radii of primary interest are 0.5 to 2 microm and driving amplitudes to 0.5 atm. Bubbles in this size range are sensitive to modulation of driving. It is shown that an optimal forcing scheme can increase the target response eightfold or more. This suggests new applications in imaging and in bubble detection.     

Automated quantitative analysis of the shift of frequency spectra generated by attenuated signals from contrast microbubbles

The ultrasound-induced harmonic microbubble response spectrum is known to shift to lower frequencies with increasing tissue attenuation. We hypothesized that this shift could be reproducibly detected in received broadband radiofrequency spectra. We used an automatic Gaussian curve-fitting technique to measure the mean harmonic response generated by three different contrast agents at six incremental levels of attenuation. Analytical curve fitting identified a consistent, reproducible, and statistically significant shift in mean harmonic frequency with increasing attenuation. The presented method could be a step toward attenuation estimation by contrast harmonic imaging; optimization of harmonic signal reception by ultrasound systems; and, ultimately, automatic detection of contrast agents in tissue.     

Theoretical prediction of the scattering of spherical bubble clusters under ultrasonic excitation

Due to the nonlinear vibration of ultrasound contrast agent bubbles, a nonlinear scattered sound field will be generated when bubbles are driven by ultrasound. A bubble cluster consists of numerous bubbles gathering in a spherical space. It has been noted that the forward scattering of a bubble cluster is larger than its backscattering, and some studies have experimentally found the angular dependence of a bubble cluster’s scattering signal. In this paper, a theory is proposed to explain the difference of acoustic scattering at different directions of a bubble cluster when it is driven by ultrasound, and predicts the angular distribution of scattered acoustic pressure under different parameters. The theory is proved to be correct under circumstances of small clusters and weak interactions by comparing theoretical results with numerical simulations. This theory not only sheds light on the physics of bubble cluster scattering, but also may contribute to the improvement of ultrasound imaging technology, including ultrasonic harmonic imaging and contrast-enhanced ultrasonography.