Michalakis Averkiou

A new imaging technique based on the nonlinear properties of tissues

Finite amplitude sound propagating in a medium undergoes distortion due to the nonlinear properties of the medium. The nonlinear distortion produces harmonic (and subharmonic) energy in the propagating signal. The amplitudes used by commercial medical scanners during routine diagnostic scanning are in most cases finite and thus within the range that produces nonlinear distortion. Thermoviscous absorption of tissue which is frequency dependent rapidly dissipates this harmonic energy. This has led to the widely held assumption that nonlinear distortion was not a significant factor in medical diagnostic imaging. However, the wide dynamic range, digital architecture, and the signal processing capabilities of modern diagnostic ultrasound systems make it possible to utilize this tissue generated harmonic energy for image formation. These images often demonstrate reduced nearfield artifacts and improved tissue structure visualization. Previously, those images were believed to be the result of transmitted second harmonic energy. It is shown that the nonlinear properties of tissue are the major contribution of harmonic images.

Bioeffects Considerations for Diagnostic Ultrasound Contrast Agents

Diagnostic ultrasound contrast agents have been developed for enhancing the echogenicity of blood and for delineating other structures of the body. Approved agents are suspensions of gas bodies (stabilized microbubbles), which have been designed for persistence in the circulation and strong echo return for imaging. The interaction of ultrasound pulses with these gas bodies is a form of acoustic cavitation, and they also may act as inertial cavitation nuclei. This interaction produces mechanical perturbation and a potential for bioeffects on nearby cells or tissues. In vitro, sonoporation and cell death occur at mechanical index (MI) values less than the inertial cavitation threshold. In vivo, bioeffects reported for MI values greater than 0.4 include microvascular leakage, petechiae, cardiomyocyte death, inflammatory cell infiltration, and premature ventricular contractions and are accompanied by gas body destruction within the capillary bed. Bioeffects for MIs of 1.9 or less have been reported in skeletal muscle, fat, myocardium, kidney, liver, and intestine. Therapeutic applications that rely on these bioeffects include targeted drug delivery to the interstitium and DNA transfer into cells for gene therapy. Bioeffects of contrast‐aided diagnostic ultrasound happen on a microscopic scale, and their importance in the clinical setting remains uncertain.

Tissue harmonic 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 extend these benefits are explained by the properties of nonlinear propagation of the transmitted ultrasonic pulses in the tissue.

Ultrasound contrast imaging research

This article is a review of the research on ultrasound contrast agents in general imaging. While general imaging contrast agent applications are still undergoing investigation and waiting FDA approval in the United States, they are approved for clinical use in Europe and other countries. The contrast microbubble properties are described, including their nonlinear behavior and destruction properties. Imaging techniques like harmonic imaging, pulse inversion, power pulse inversion, agent detection imaging, microvascular imaging, and flash contrast imaging are explained. A connection is made between the aforementioned imaging techniques and the different contrast agents available. The blood flow appearance of different liver tumors in the presence of contrast agents is demonstrated with examples.

Nonlinear distortion of short pulses radiated by plane and focused circular pistons.

Detailed measurements of finite-amplitude pulses radiated by plane and focused circular pistons in water are presented. Comparisons of time waveforms and frequency spectra, both on and off axis, are made with numerical calculations based on the nonlinear parabolic wave equation. Emphasis is on nonlinear distortion of amplitude- and frequency-modulated tone bursts. Use of short pulses enabled resolution of the direct and diffracted waves prior to their coalescence and subsequent shock formation along the axis of the source. Because of its relevance to investigations of cavitation inception, attention is devoted to variation of the peak positive (p+) and negative (p-) pressures along the axis of a focused source. It is shown that with increasing source amplitude, the maximum of each shifts away from the focal plane, toward the source. This effect is more pronounced for p- than for p+.

Modeling of an electrohydraulic lithotripter with the KZK equation

The acoustic pressure field of an electrohydraulic extracorporeal shock wave lithotripter is modeled with a nonlinear parabolic wave equation (the KZK equation). The model accounts for diffraction, nonlinearity, and thermoviscous absorption. A numerical algorithm for solving the KZK equation in the time domain is used to model sound propagation from the mouth of the ellipsoidal reflector of the lithotripter. Propagation within the reflector is modeled with geometrical acoustics. It is shown that nonlinear distortion within the ellipsoidal reflector can play an important role for certain parameters. Calculated waveforms are compared with waveforms measured in a clinical lithotripter and good agreement is found. It is shown that the spatial location of the maximum negative pressure occurs pre-focally which suggests that the strongest cavitation activity will also be in front of the focus. Propagation of shock waves from a lithotripter with a pressure release reflector is considered and because of nonlinear propagation the focal waveform is not the inverse of the rigid reflector. Results from propagation through tissue are presented; waveforms are similar to those predicted in water except that the higher absorption in the tissue decreases the peak amplitude and lengthens the rise time of the shock.

Quantification of Tumor Microvascularity with Respiratory Gated Contrast Enhanced Ultrasound for Monitoring Therapy

The aim of this feasibility study was to evaluate the response to cytotoxic and antiangiogenic treatment of colorectal liver metastasis using respiratory gated contrast enhanced ultrasonography. Seven patients were monitored with contrast enhanced ultrasound. Sulfur hexafluoride filled microbubbles (SonoVue; Bracco S.P.A., Milan, Italy) were used as contrast agent and the scans were performed with a nonlinear imaging technique (power modulation) at low transmit power (MI=0.06). The mean image intensity in the metastatic lesion and in the normal liver parenchyma were measured as a function of time and time-intensity curves from linearized image data were formed. A novel respiratory gating technique was utilized to minimize the effects of respiratory motion on the images. A reference position of the diaphragm (or other echogenic interface) was selected and all frames where the diaphragm deviated from that position were rejected. The wash-in time (start of enhancement to peak) of metastasis and adjacent normal liver parenchyma was measured from time-intensity curves. The ratio of wash-in time of the lesion to that of the normal parenchyma (WITR) was used to compare the perfusion rate. In a reproducibility study (five patients), the average deviation of WITR was found to be 9%. There was an increase in the WITR for patients responding to treatment (mean WITR increase of 17% after first dose of treatment and 75% at the end of the therapy). In four out of five patients (80%) responding to therapy WITR predicted their response from the first treatment. All six patients that responded to therapy by the end of the therapy cycle (6-9 doses) were correctly predicted by using WITR. The WITR may be a new surrogate marker indicative of early tumor response for colorectal cancer patients undergoing cytotoxic and antiangiogenic therapy. (E-mail: maverk@ucy.ac.cy).

Investigation of the relationship of nonlinear backscattered ultrasound intensity with microbubble concentration at low MI.

The aim of this study was to measure the relationship of image intensity with contrast agent concentration. In vitro experiments were performed with a flow phantom and a sulphur hexafluoride filled microbubble contrast agent (SonoVue) at different concentrations (0.004 per thousand to 4 per thousand) covering the range commonly encountered in clinical practice. The concentration of microbubbles in the contrast agent solutions was confirmed optically. Images were collected with a diagnostic ultrasound system (iU22, Phillips Medical Systems, Bothell, WA, USA) and with a nonlinear imaging technique (power modulation) at low mechanical index (MI=0.05) to avoid bubble destruction. The mean intensity within a region of interest was measured to produce time-intensity curves from linearized (absolute scale) data. The relationship of linearized image intensity to contrast agent concentration was found to be linear up to 1 per thousand and reached a plateau at approximately 2 per thousand. To operate in the linear range of the intensity-concentration relationship the contrast agent dose should be adjusted to avoid those high values in vivo and the highest dynamic range of the ultrasound system should be used to avoid unnecessary signal saturation.

American Institute of Ultrasound in Medicine consensus report on potential bioeffects of diagnostic ultrasound: Executive summary

The continued examination of potential biological effects of ultrasound and their relationship to clinical practice is a key element in evaluating the safety of diagnostic ultrasound. Periodically, the American Institute of Ultrasound in Medicine (AIUM) sponsors conferences bringing experts together to examine the literature on ultrasound bioeffects and to develop conclusions and recommendations related to diagnostic ultrasound. The most recent effort included the examination of effects whose origins were thermal or nonthermal, with separate evaluations for potential effects related to fetal ultrasound. In addition, potential effects due to the introduction of ultrasound contrast agents were summarized. This information can be used to assess risks in comparison to the benefits of diagnostic ultrasound. The conclusions and recommendations are organized into 5 broad categories, with a comprehensive background and evaluation of each topic provided in the corresponding articles in this issue. The following summary is not meant as a substitute for the detailed examination of issues presented in each of the articles but rather as a means to facilitate further study of this consensus report and implementation of its recommendations. The conclusions and recommendations are the result of several rounds of deliberations at the consensus conference, subsequent review by the Bioeffects Committee of the AIUM, and approval by the AIUM Board of Governors.

Self‐demodulation of amplitude‐ and frequency‐modulated pulses in a thermoviscous fluid

The self‐demodulation of pulsed sound beams in a thermoviscous fluid is investigated experimentally and theoretically. Experiments were performed in glycerin at megahertz frequencies with amplitude‐ and frequency‐modulated pulses. The theory is based on the Khokhlov–Zabolotskaya–Kuznetsov (KZK) nonlinear parabolic wave equation. Numerical results were obtained from an algorithm that solves the KZK equation in the time domain [Y.‐S. Lee and M. F. Hamilton, Ultrasonics International 91 Conference Proceedings (Butterworth–Heinemann, Oxford, 1991), pp. 177–180]. A quasilinear analytic solution, which describes the main features of the waveform at all axial locations, is developed in the limit of strong absorption. Theory and experiment are in good agreement throughout the near‐ and far fields.