T. Douglas Mast

Ultrasound-enhanced thrombolysis using Definity® as a cavitation nucleation agent

Ultrasound has been shown previously to act synergistically with a thrombolytic agent, such as recombinant tissue plasminogen activator (rt-PA) to accelerate thrombolysis. In this in vitro study, a commercial contrast agent, Definity, was used to promote and sustain the nucleation of cavitation during pulsed ultrasound exposure at 120 kHz. Ultraharmonic signals, broadband emissions and harmonics of the fundamental were measured acoustically by using a focused hydrophone as a passive cavitation detector and used to quantify the level of cavitation activity. Human whole blood clots suspended in human plasma were exposed to a combination of rt-PA, Definity and ultrasound at a range of ultrasound peak-to-peak pressure amplitudes, which were selected to expose clots to various degrees of cavitation activity. Thrombolytic efficacy was determined by measuring clot mass loss before and after the treatment and correlated with the degree of cavitation activity. The penetration depth of rt-PA and plasminogen was also evaluated in the presence of cavitating microbubbles using a dual-antibody fluorescence imaging technique. The largest mass loss (26.2%) was observed for clots treated with 120-kHz ultrasound (0.32-MPa peak-to-peak pressure amplitude), rt-PA and stable cavitation nucleated by Definity. A significant correlation was observed between mass loss and ultraharmonic signals (r = 0.85, p < 0.0001, n = 24). The largest mean penetration depth of rt-PA (222 microm) and plasminogen (241 microm) was observed in the presence of stable cavitation activity. Stable cavitation activity plays an important role in enhancement of thrombolysis and can be monitored to evaluate the efficacy of thrombolytic treatment.

Empirical relationships between acoustic parameters in human soft tissues

Previously published summaries of sound speed, density, attenuation coefficient, and nonlinearity parameter, B/A, in human soft tissues are quantitatively analyzed. A highly significant empirical linear relationship is found to hold between sound speed and density for a wide range of soft tissues, including adipose, parenchymal, muscular, and connective tissues as well as body fluids. Even higher correlations occur between nondimensional parameters describing density variations and compressibility variations. Values for the nonlinearity parameter correlate significantly with sound speed and density, while the attenuation coefficient is found not to correlate significantly with any of the other parameters considered. Implications for tissue modeling and quantitative ultrasonic imaging are discussed.

Simulation of ultrasonic pulse propagation through the abdominal wall

Ultrasonic pulse propagation through the abdominal wall has been simulated using a model for two-dimensional propagation through anatomically realistic tissue cross sections. The time-domain equations for wave propagation in a medium of variable sound speed and density were discretized to obtain a set of coupled finite-difference equations. These difference equations were solved numerically using a two-step MacCormack scheme that is fourth-order accurate in space and second-order accurate in time. The inhomogeneous tissue of the abdominal wall was represented by two-dimensional matrices of sound speed and density values. These values were determined by processing scanned images of abdominal wall cross sections stained to identify connective tissue, muscle, and fat, each of which was assumed to have a constant sound speed and density. The computational configuration was chosen to simulate that of wavefront distortion measurements performed on the same specimens. Qualitative agreement was found between those measurements and the results of the present computations, indicating that the computational model correctly depicts the salient characteristics of ultrasonic wavefront distortion in vivo. However, quantitative agreement was limited by the two-dimensionality of the computation and the absence of detailed tissue microstructure. Calculations performed using an asymptotic straight-ray approximation showed good agreement with time-shift aberrations predicted by the full-wave method, but did not explain the amplitude fluctuations and waveform distortion found in the experiments and the full-wave calculations. Visualization of computed wave propagation within tissue cross sections suggests that amplitude fluctuations and waveform distortion observed in ultrasonic propagation through the abdominal wall are associated with scattering from internal inhomogeneities such as septa within the subcutaneous fat. These observations, as well as statistical analysis of computed and observed amplitude fluctuations, suggest that weak fluctuation models do not fully describe ultrasonic wavefront distortion caused by the abdominal wall.

Focusing and imaging using eigenfunctions of the scattering operator

An inverse scattering method that uses eigenfunctions of the scattering operator is presented. This approach provides a unified framework that encompasses eigenfunction methods of focusing and quantitative image reconstruction in arbitrary media. Scattered acoustic fields are described using a compact, normal operator. The eigenfunctions of this operator are shown to correspond to the far-field patterns of source distributions that are directly proportional to the position-dependent contrast of a scattering object. Conversely, the eigenfunctions of the scattering operator specify incident-wave patterns that focus on these effective source distributions. These focusing properties are employed in a new inverse scattering method that represents unknown scattering media using products of numerically calculated fields of eigenfunctions. A regularized solution to the nonlinear inverse scattering problem is shown to result from combinations of these products, so that the products comprise a natural basis for efficient and accurate reconstructions of unknown inhomogeneities. The corresponding linearized problem is solved analytically, resulting in a simple formula for the low-pass-filtered scattering potential. The linear formula is analytically equivalent to known filtered-backpropagation formulas for Born inversion, and, at least in the case of small scattering objects, has advantages of computational simplicity and efficiency. A similarly efficient and simple formula is derived for the nonlinear problem in which the total acoustic pressure can be determined based on an estimate of the medium. Computational results illustrate focusing of eigenfunctions on discrete and distributed scattering media, quantitative imaging of inhomogeneous media using products of retransmitted eigenfunctions, inverse scattering in an inhomogeneous background medium, and reconstructions for data corrupted by noise.

Passive cavitation imaging with ultrasound arrays

A method is presented for passive imaging of cavitational acoustic emissions using an ultrasound array, with potential application in real-time monitoring of ultrasound ablation. To create such images, microbubble emissions were passively sensed by an imaging array and dynamically focused at multiple depths. In this paper, an analytic expression for a passive image is obtained by solving the Rayleigh-Sommerfield integral, under the Fresnel approximation, and passive images were simulated. A 192-element array was used to create passive images, in real time, from 520-kHz ultrasound scattered by a 1-mm steel wire. Azimuthal positions of this target were accurately estimated from the passive images. Next, stable and inertial cavitation was passively imaged in saline solution sonicated at 520 kHz. Bubble clusters formed in the saline samples were consistently located on both passive images and B-scans. Passive images were also created using broadband emissions from bovine liver sonicated at 2.2 MHz. Agreement was found between the images and source beam shape, indicating an ability to map therapeutic ultrasound beams in situ. The relation between these broadband emissions, sonication amplitude, and exposure conditions are discussed.

Bulk ablation of soft tissue with intense ultrasound: Modeling and experiments

Methods for the bulk ablation of soft tissue using intense ultrasound, with potential applications in the thermal treatment of focal tumors, are presented. An approximate analytic model for bulk ablation predicts the progress of ablation based on tissue properties, spatially averaged ultrasonic heat deposition, and perfusion. The approximate model allows the prediction of threshold acoustic powers required for ablation in vivo as well as the comparison of cases with different starting temperatures and perfusion characteristics, such as typical in vivo and ex vivo experiments. In a full three-dimensional numerical model, heat deposition from array transducers is computed using the Fresnel approximation and heat transfer in tissue is computed by finite differences, accounting for heating changes caused by boiling and thermal dose-dependent absorption. Similar ablation trends due to perfusion effects are predicted by both the simple analytic model and the full numerical model. Comparisons with experimental results show the efficacy of both models in predicting tissue ablation effects. Phenomena illustrated by the simulations and experiments include power thresholds for in vivo ablation, differences between in vivo and ex vivo lesioning for comparable source conditions, the effect of tissue boiling and absorption changes on ablation depth, and the performance of a continuous rotational scanning method suitable for interstitial bulk ablation of soft tissue.

The effect of abdominal wall morphology on ultrasonic pulse distortion. Part I. Measurements

The relative importance of the fat and muscle layers of the human abdominal wall in producing ultrasonic wavefront distortion was assessed by means of direct measurements. Specimens employed included six whole abdominal wall specimens and twelve partial specimens obtained by dividing each whole specimen into a fat and a muscle layer. In the measurement technique employed, a hemispheric transducer transmitted a 3.75-MHz ultrasonic pulse through a tissue section. The received wavefront was measured by a linear array translated in the elevation direction to synthesize a two-dimensional aperture. Insertion loss was also measured at various locations on each specimen. Differences in arrival time and energy level between the measured waveforms and computed references that account for geometric delay and spreading were calculated. After correction for the effects of geometry, the received waveforms were synthetically focused. The characteristics of the distortion produced by each specimen and the quality of the resulting focus were analyzed and compared. The measurements show that muscle produces greater arrival time distortion than fat while fat produces greater energy level distortion than muscle, but that the distortion produced by the entire abdominal wall is not equivalent to a simple combination of distortion effects produced by the layers. The results also indicate that both fat and muscle layers contribute significantly to the distortion of ultrasonic beams by the abdominal wall. However, the spatial characteristics of the distortion produced by fat and muscle layers differ substantially. Distortion produced by muscle layers, as well as focal images aberrated by muscle layers, show considerable anisotropy associated with muscle fiber orientation. Distortion produced by fat layers shows smaller-scale, granular structure associated with scattering from the septa surrounding individual fat lobules. Thick layers of fat may be expected to cause poor image quality due to both scattering and bulk absorption effects, while thick muscle layers may be expected to cause focus aberration due to large arrival time fluctuations. Correction of aberrated focuses using time-shift compensation shows more complete correction for muscle sections than for fat sections, so that correction methods based on phase screen models may be more appropriate for muscle layers than for fat layers.

Passive imaging with pulsed ultrasound insonations

Previously, passive cavitation imaging has been described in the context of continuous-wave high-intensity focused ultrasound thermal ablation. However, the technique has potential use as a feedback mechanism for pulsed-wave therapies, such as ultrasound-mediated drug delivery. In this paper, results of experiments and simulations are reported to demonstrate the feasibility of passive cavitation imaging using pulsed ultrasound insonations and how the images depend on pulsed ultrasound parameters. The passive cavitation images were formed from channel data that was beamformed in the frequency domain. Experiments were performed in an invitro flow phantom with an experimental echo contrast agent, echogenic liposomes, as cavitation nuclei. It was found that the pulse duration and envelope have minimal impact on the image resolution achieved. The passive cavitation image amplitude scales linearly with the cavitation emission energy. Cavitation images for both stable and inertial cavitation can be obtained from the same received data set.

Simulation of ultrasonic focus aberration and correction through human tissue

Ultrasonic focusing in two dimensions has been investigated by calculating the propagation of ultrasonic pulses through cross-sectional models of human abdominal wall and breast. Propagation calculations used a full-wave k-space method that accounts for spatial variations in density, sound speed, and frequency-dependent absorption and includes perfectly matched layer absorbing boundary conditions. To obtain a distorted receive wavefront, propagation from a point source through the tissue path was computed. Receive focusing used an angular spectrum method. Transmit focusing was accomplished by propagating a pressure wavefront from a virtual array through the tissue path. As well as uncompensated focusing, focusing that employed time-shift compensation and time-shift compensation after backpropagation was investigated in both transmit and receive and time reversal was investigated for transmit focusing in addition. The results indicate, consistent with measurements, that breast causes greater focus degradation than abdominal wall. The investigated compensation methods corrected the receive focus better than the transmit focus. Time-shift compensation after backpropagation improved the focus from that obtained using time-shift compensation alone but the improvement was less in transmit focusing than in receive focusing. Transmit focusing by time reversal resulted in lower sidelobes but larger mainlobes than the other investigated transmit focus compensation methods.

Simulation of ultrasonic pulse propagation, distortion, and attenuation in the human chest wall

A finite-difference time-domain model for ultrasonic pulse propagation through soft tissue has been extended to incorporate absorption effects as well as longitudinal-wave propagation in cartilage and bone. This extended model has been used to simulate ultrasonic propagation through anatomically detailed representations of chest wall structure. The inhomogeneous chest wall tissue is represented by two-dimensional maps determined by staining chest wall cross sections to distinguish between tissue types, digitally scanning the stained cross sections, and mapping each pixel of the scanned images to fat, muscle, connective tissue, cartilage, or bone. Each pixel of the tissue map is then assigned a sound speed, density, and absorption value determined from published measurements and assumed to be representative of the local tissue type. Computational results for energy level fluctuations and arrival time fluctuations show qualitative agreement with measurements performed on the same specimens, but show significantly less waveform distortion than measurements. Visualization of simulated tissue-ultrasound interactions in the chest wall shows possible mechanisms for image aberration in echocardiography, including effects associated with reflection and diffraction caused by rib structures. A comparison of distortion effects for varying pulse center frequencies shows that, for soft tissue paths through the chest wall, energy level and waveform distortion increase markedly with rising ultrasonic frequency and that arrival-time fluctuations increase to a lesser degree.