PARAMETERS AFFECTING THE IMAGING AND DETECTION OF MICROBUBBLES IN BLOOD

Stabilized micron-sized bubbles, known as contrast agents, are often injected into the body to enhance ultrasound imaging of blood flow. The ability to detect such bubbles in blood depends on the relative magnitude of the acoustic power backscattered from the microbubbles (‘signal’) to the power backscattered from the red blood cells (‘noise’). Erythrocytes are acoustically small (Rayleigh regime), weak scatterers, and therefore the backscatter coefficient (BSC) of blood increases as the fourth power of frequency throughout the diagnostic frequency range. Microbubbles, on the other hand, are either resonant or super-resonant in the range 5-30 MHz. Above resonance, their total scattering cross-section remains constant with increasing frequency. In the present thesis, a theoretical model of the BSC of a suspension of red blood cells is presented and compared to the BSC of Optison® contrast agent microbubbles. It is predicted that, as the frequency increases, the BSC of red blood cell suspensions eventually exceeds the BSC of the strong scattering microbubbles, leading to a dramatic reduction in signal-to-noise ratio (SNR). This decrease in SNR with increasing frequency was also confirmed experimentally by use of an active cavitation detector for different concentrations of Optison® microbubbles in erythrocyte suspensions of different hematocrits. The magnitude of the observed decrease in SNR correlated well with theoretical predictions in most cases, except for very dense suspensions of red blood cells, where it is hypothesized that the close proximity of erythrocytes inhibits the acoustic response of the microbubbles.

THE ROLE OF ACOUSTIC CAVITATION IN ENHANCED ULTRASOUND-INDUCED HEATING IN A TISSUE-MIMICKING PHANTOM

A complete understanding of high-intensity focused ultrasound-induced temperature changes in tissue requires insight into all potential mechanisms for heat deposition. Applications of therapeutic ultrasound often utilize acoustic pressures capable of producing cavitation activity. Recognizing the ability of bubbles to transfer acoustic energy into heat generation, a study of the role bubbles play in tissue hyperthermia becomes necessary. These bubbles are typically less than 50μm. This dissertation examines the contribution of bubbles and their motion to an enhanced heating effect observed in a tissue-mimicking phantom. A series of experiments established a relationship between bubble activity and an enhanced temperature rise in the phantom by simultaneously measuring both the temperature change and acoustic emissions from bubbles. It was found that a strong correlation exists between the onset of the enhanced heating effect and observable cavitation activity. In addition, the likelihood of observing the enhanced heating effect was largely unaffected by the insonation duration for all but the shortest of insonation times, 0.1 seconds. Numerical simulations were used investigate the relative importance of two candidate mechanisms for heat deposition from bubbles as a means to quantify the number of bubbles required to produce the enhanced temperature rise. The energy deposition from viscous dissipation and the absorption of radiated sound from bubbles were considered as a function of the bubble size and the viscosity of the surrounding medium. Although both mechanisms were capable of producing the level of energy required for the enhanced heating effect, it was found that inertial cavitation, associated with high acoustic radiation and low viscous dissipation, coincided with the the nature of the cavitation best detected by the experimental system. The number of bubbles required to account for the enhanced heating effect was determined through the numerical study to be on the order of 150 or less.

APPLICATION OF THE KHOKHLOV-ZABOLOTSKAYA-KUZNETSOV EQUATION TO MODELING HIGH-INTENSITY FOCUSED ULTRASOUND BEAMS

High-intensity focused ultrasound is a form of therapeutic ultrasound which uses high amplitude acoustic waves to heat and ablate tissue. HIFU employs acoustic amplitudes that are high enough that nonlinear propagation effects are important in the evolution of the sound field. A common model for HIFU beams is the Khokhlov-Zabolotskaya-Kuznetsov (KZK) equation which accounts for nonlinearity, diffraction, and absorption. The KZK equation models diffraction using the parabolic or paraxial approximation. Many HIFU sources have an aperture diameter similar to the focal length and the paraxial approximation may not be appropriate. Here, results obtained using the “Texas code,” a time-domain numerical solution to the KZK equation, were used to assess when the KZK equation can be employed. In a linear water case comparison with the O’Neil solution, the KZK equation accurately predicts the pressure field in the focal region. The KZK equation was also compared to simulations of the exact fluid dynamics equations (no paraxial approximation). The exact equations were solved using the Fourier-Continuation (FC) method to approximate derivatives in the equations. Results have been obtained for a focused HIFU source in tissue. For a low focusing gain transducer (focal length 50λ and radius 10λ), the KZK and FC models showed excellent agreement, however, as the source radius was increased to 30λ, discrepancies started to appear. Modeling was extended to the case of tissue with the appropriate power law using a relaxation model. The relaxation model resulted in a higher peak pressure and a shift in the location of the peak pressure, highlighting the importance of employing the correct attenuation model. Simulations from the code that were compared to experimental data in water showed good agreement through the focal plane.

SCANNING ACOUSTIC MICROSCOPE FOR CHARACTERIZATION OF ARTERIAL PLAQUE

Unstable arterial plaque is likely the key component of atherosclerosis, a disease which is responsible for two-thirds of heart attacks and strokes, leading to approximately 1 million deaths in the United States. Ultrasound imaging is able to detect plaque but as of yet is not able to distinguish unstable plaque from stable plaque. In this work a scanning acoustic microscope (SAM) was implemented and validated as tool to measure the acoustic properties of a sample. The goal for the SAM is to be able to provide quantitative measurements of the acoustic properties of different plaque types, to understand the physical basis by which plaque may be identified acoustically. The SAM consists of a spherically focused transducer which operates in pulse-echo mode and is scanned in a 2D raster pattern over a sample. A plane wave analysis is presented which allows the impedance, attenuation and phase velocity of a sample to be de- termined from measurements of the echoes from the front and back of the sample. After the measurements, the attenuation and phase velocity were analysed to ensure that they were consistent with causality. The backscatter coefficient of the samples was obtained using the technique outlined by Chen et al [8]. The transducer used here was able to determine acoustic properties from 10-40 MHz. The results for the impedance, attenuation and phase velocity were validated for high and low-density polyethylene against published results. The plane wave approximation was validated by measuring the properties throughout the focal region and throughout a range of incidence angles from the transducer. The SAM was used to characterize a set of recipes for tissue-mimicking phantoms which demonstrate indepen- dent control over the impedance, attenuation, phase velocity and backscatter coefficient. An initial feasibility study on a human artery was performed.

EVALUATION OF HARMONIC MOTION ELASTOGRAPHY AND ACOUSTO-­OPTIC IMAGING FOR MONITORING LESION FORMATION BY HIGH INTENSITY FOCUSED ULTRASOUND

Malignant or benign tumors may be ablated with high‐intensity focused ultrasound (HIFU). This technique, known as focused ultrasound surgery (FUS), has been actively investigated for decades, but slow to be implemented and difficult to control due to lack of real‐time feedback during ablation. Two methods of imaging and monitoring HIFU lesions during formation were implemented simultaneously, in order to investigate the efficacy of each and to increase confidence in the detection of the lesion. The first, Acousto‐Optic Imaging (AOI) detects the increasing optical absorption and scattering in the lesion. The intensity of a diffuse optical field in illuminated tissue is mapped at the spatial resolution of an ultrasound focal spot, using the acousto‐optic effect. The second, Harmonic Motion Imaging (HMI), detects the changing stiffness in the lesion. The HIFU beam is modulated to force oscillatory motion in the tissue, and the amplitude of this motion, measured by ultrasound pulse‐echo techniques, is influenced by the stiffness. Experiments were performed on store‐bought chicken breast and freshly slaughtered bovine liver. The AOI results correlated with the onset and relative size of forming lesions much better than prior knowledge of the HIFU power and duration. For HMI, a significant artifact was discovered due to acoustic nonlinearity. The artifact was mitigated by adjusting the phase of the HIFU and imaging pulses. A more detailed model of the HMI process than previously published was made using finite element analysis. The model showed that the amplitude of harmonic motion was primarily affected by increases in acoustic attenuation and stiffness as the lesion formed and the interaction of these effects was complex and often counteracted each other. Further biological variability in tissue properties meant that changes in motion were masked by sample‐to‐sample variation. The HMI experiments predicted lesion formation in only about a quarter of the lesions made. In simultaneous AOI/HMI experiments it appeared that AOI was a more robust method for lesion detection.

A study of stone fragmentation in shock wave lithotripsy by customizing the acoustic field and waveform shape

Shock wave lithotripsy is the preferred treatment modality for kidney stones in the United States. Despite clinical use for over twenty-five years, the mechanisms of stone fragmentation are still under debate. A piezoelectric array was employed to examine the effect of waveform shape and pressure distribution on stone fragmentation in lithotripsy. The array consisted of 170 elements placed on the inner surface of a 15 cm-radius spherical cap. Each element was driven independently using a 170 individual pulsers, each capable of generating 1.2 kV. The acoustic field was characterized using a fiber optic probe hydrophone with a bandwidth of 30 MHz and a spatial resolution of 100 μm. When all elements were driven simultaneously, the focal waveform was a shock wave with peak pressures p+ =65±3MPa and p−=−16±2MPa and the −6 dB focal region was 13 mm long and 2 mm wide. The delay for each element was the only control parameter for customizing the acoustic field and waveform shape, which was done with the aim of investigating the hypothesized mechanisms of stone fragmentation such as spallation, shear, squeezing, and cavitation. The acoustic field customization was achieved by employing the angular spectrum approach for modeling the forward wave propagation and regression of least square errors to determine the optimal set of delays. Results from the acoustic field customization routine and its implications on stone fragmentation will be discussed.

HEATING IN VASCULAR TISSUE AND FLOW-THROUGH TISSUE PHANTOMS INDUCED BY FOCUSED ULTRASOUND

High intensity focused ultrasound (HIFU) can be used to control bleeding, both from individual blood vessels as well as from gross damage to the capillary bed. This process, called acoustic hemostasis, is being studied in the hope that such a method would ultimately provide a lifesaving treatment during the so-called "golden hour", a brief grace period after a severe trauma in which prompt therapy can save the life of an injured person. Thermal effects play a major role in occlusion of small vessels and also appear to contribute to the sealing of punctures in major blood vessels. However, aggressive ultrasound-induced tissue heating can also impact healthy tissue and can lead to deleterious mechanical bioeffects. Moreover, the presence of vascularity can limit one’s ability to elevate the temperature of blood vessel walls owing to convective heat transport. In an effort to better understand the heating process in tissues with vascular structure we have developed a numerical simulation that couples models for ultrasound propagation, acoustic streaming, ultrasound heating and blood cooling in Newtonian viscous media. The 3-D simulation allows for the study of complicated biological structures and insonation geometries. We have also undertaken a series of in vitro experiments, in non-uniform flow-through tissue phantoms, designed to provide a ground truth verification of the model predictions. The calculated and measured results were compared over a range of values for insonation pressure, insonation time, and flow rate; we show good agreement between predictions and measurements. We then conducted a series of simulations that address two limiting problems of interest: hemostasis in small and large vessels. We employed realistic human tissue properties and considered more complex geometries. Results show that the heating pattern in and around a blood vessel is different for different vessel sizes, flow rates and for varying beam orientations relative to the flow axis. Complete occlusion and wall- puncture sealing are both possible depending on the exposure conditions. These results concur with prior clinical observations and may prove useful for planning of a more effective procedure in HIFU treatments.

IDENTIFYING AND MONITORING THE ROLES OF CAVITATION IN HEATING FROM HIGH-INTENSITY FOCUSED ULTRASOUND

For high-intensity focused ultrasound (HIFU) to continue to gain acceptance for cancer treatment it is necessary to understand how the applied ultrasound interacts with gas trapped in the tissue. The presence of bubbles in the target location have been thought to be responsible for shielding the incoming pressure and increasing local heat deposition due to the bubble dynamics. We lack adequate tools for monitoring the cavitation process, due to both limited visualization methods and understanding of the underlying physics. The goal of this project was to elucidate the role of inertial cavitation in HIFU exposures in the hope of applying noise diagnostics to monitor cavitation activity and control HIFU-induced cavitation in a beneficial manner. A number of approaches were taken to understand the relationship between inertial cavitation signals, bubble heating, and bubble shielding in agar-graphite tissue phantoms. Passive cavitation detection (PCD) techniques were employed to detect inertial bubble collapses while the temperature was monitored with an embedded thermocouple. Results indicate that the broadband noise amplitude is correlated to bubble-enhanced heating. Monitoring inertial cavitation at multiple positions throughout the focal region demonstrated that bubble activity increased prefocally as it diminished near the focus. Lowering the HIFU duty cycle had the effect of maintaining a more or less constant cavitation signal, suggesting the shielding effect diminished when the bubbles had a chance to dissolve during the HIFU off-time. Modeling the effect of increasing the ambient temperature showed that bubbles do not collapse as violently at higher temperatures due to increased vapor pressure inside the bubble. Our conclusion is that inertial cavitation heating is less effective at higher temperatures and bubble shielding is involved in shifting energy deposition at the focus. The use of a diagnostic ultrasound imaging system as a PCD array was explored. Filtering out the scattered harmonics from the received RF signals resulted in a spatially- resolved inertial cavitation signal, while the amplitude of the harmonics showed a correlation with temperatures approaching the onset of boiling. The result is a new tool for detecting a broader spectrum of bubble activity and thus enhancing HIFU treatment visualization and feedback.

Nonlinear Acoustics in Underwater and Biomedical Applications: Array Performance Degradation and Time Reversal Invariance

This dissertation describes a model for acoustic propagation in inhomogeneous flu- ids, and explores the focusing by arrays onto targets under various conditions. The work explores the use of arrays, in particular the time reversal array, for underwater and biomedical applications. Aspects of propagation and phasing which can lead to reduced focusing effectiveness are described. An acoustic wave equation was derived for the propagation of finite-amplitude waves in lossy time-varying inhomogeneous fluid media. The equation was solved numerically in both Cartesian and cylindrical geometries using the finite-difference time-domain (FDTD) method. It was found that time reversal arrays are sensitive to several debilitating factors. Focusing ability was determined to be adequate in the presence of temporal jitter in the time reversed signal only up to about one-sixth of a period. Thermoviscous absorption also had a debilitating effect on focal pressure for both linear and nonlinear propagation. It was also found that nonlinearity leads to degradation of focal pressure through amplification of the received signal at the array, and enhanced absorption in the shocked waveforms. This dissertation also examined the heating effects of focused ultrasound in a tissue-like medium. The application considered is therapeutic heating for hyperther- mia. The acoustic model and a thermal model for tissue were coupled to solve for transient and steady temperature profiles in tissue-like media. The Pennes bioheat equation was solved using the FDTD method to calculate the temperature fields in tissue-like media from focused acoustic sources. It was found that the temperature-dependence of the medium's background prop- erties can play an important role in the temperature predictions. Finite-amplitude effects contributed excess heat when source conditions were provided for nonlinear ef- fects to manifest themselves. The effect of medium heterogeneity was also found to be important in redistributing the acoustic and temperature fields, creating regions with hotter and colder temperatures than the mean by local scattering and lensing action. These temperature excursions from the mean were found to increase monotonically with increasing contrast in the medium's properties.

A FLOW-THROUGH ACOUSTIC WAVEGUIDE FOR TWO-PHASE BUBBLY FLOW VOID FRACTION MEASUREMENT

In the Spallation Neutron Source (SNS) facility at Oak Ridge National Laboratory (ORNL), the deposition of a high-energy proton beam into the liquid mercury target forms bubbles whose asymmetric collapse cause Cavitation Damage Erosion (CDE) to the container walls, thereby reducing its usable lifetime. One proposed solution for mitigation of this damage is to inject a population of microbubbles into the mercury, yielding a compliant and attenuative medium that will reduce the resulting cavitation damage. This potential solution presents the task of creating a diagnostic tool to monitor bubble population in the mercury flow in order to correlate void fraction and damage. Details of an acoustic waveguide for the eventual measurement of two-phase mercury-helium flow void fraction are discussed. The assembly’s waveguide is a vertically oriented stainless steel cylinder with 5.08cm ID, 1.27cm wall thickness and 40cm length. For water experiments, a 2.54cm thick stainless steel plate at the bottom supports the fluid, provides an acoustically rigid boundary condition, and is the mounting point for a hydrophone. A port near the bottom is the inlet for the fluid of interest. A spillover reservoir welded to the upper portion of the main tube allows for a flow-through design, yielding a pressure release top boundary condition for the waveguide. A cover on the reservoir supports an electrodynamic shaker that is driven by linear frequency sweeps to excite the tube. The hydrophone captures the frequency response of the waveguide. The sound speed of the flowing medium is calculated, assuming a linear dependence of axial mode number on modal frequency (plane wave). Assuming that the medium has an effective-mixture sound speed, and that it contains bubbles which are much smaller than the resonance radii at the highest frequency of interest (Wood’s limit), the void fraction of the flow is calculated. Results for water and bubbly water of varying void fraction are presented, and serve to demonstrate the accuracy and precision of the apparatus.

Notes on the Effect of Different Access Patterns on the Intensity of Mistreatment in Distributed Caching Groups

In this report, we extend our study of the intensity of mistreatment in distributed caching groups due to state interaction. In our earlier work (published as BUCS-TR-2006-003), we analytically showed how this type of mistreatment may appear under homogeneous demand distributions. We provided a simple setting where mistreatment due to state interaction may occur. According to this setting, one or more "overactive" nodes generate disproportionately more requests than the other nodes. In this report, we extend our experimental evaluation of the intensity of mistreatment to which non-overactive nodes are subjected, when the demand distributions are not homogeneous.

A Neural Network for Synthesizing the Pitch of an Acoustic Source

This article describes a neural network model capable of generating a spatial representation of the pitch of an acoustic source. Pitch is one of several auditory percepts used by humans to separate multiple sound sources in the environment from each other. The model provides a neural instantiation of a type of "harmonic sieve". It is capable of quantitatively simulating a large body of psychoacoustical data, including new data on octave shift perception.