Safety and feasibility of arterial wall targeting with robot-assisted high intensity focused ultrasound: a preclinical study.

PURPOSE: High-intensity focused ultrasound (HIFU) is a potential noninvasive thermal ablation method for the treatment of peripheral artery disease. Dual-mode ultrasound arrays (DMUA) offer the possibility of simultaneous imaging and treatment. In this study, safety and feasibility of femoral artery robot-assisted HIFU/DMUA therapy was assessed. METHODS: In 18 pigs (∼50kg), angiography and diagnostic ultrasound were used to visualize diameter and blood flow of the external femoral arteries (EFA). HIFU/DMUA-therapy was unilaterally applied to the EFA dorsal wall using a 3.5 MHz, 64-element transducer, closed-loop-control was used to automatically adjust energy delivery to control thermal lesion formation. A continuous lesion of at least 25 mm was created by delivering 6-8 HIFU shots per imaging plane perpendicular to the artery spaced 1 mm apart. Directly after HIFU/DMUA-therapy and after 0, 3 or 14 days follow up, diameter and blood flow were measured and the skin was macroscopically examined for thermal damage. The tissue was removed for histological analysis. RESULTS: No complications were observed. The most frequently observed treatment effect was formation of scar tissue, predominantly in the adventitia and the surrounding tissue. No damage to the endothelium or excessive damage of the surrounding tissue was observed. There was no significant decrease in the mean arterial diameter after HIFU/DMUA-therapy. CONCLUSION: HIFU/DMUA therapy successfully targeted the vessel walls of healthy porcine arteries, without causing endothelial damage or other vascular complications. Therefore, this therapy can be safely applied to healthy arterial walls in animals. Future studies should focus on safety and dose-finding in atherosclerotic diseased arteries.

High intensity focused ultrasound effect on cardiac tissues: potential for clinical application.

High intensity focused ultrasound (HIFU) is an evolving technology with potential therapeutic applications. Utilizing frequencies of 500 kHz to 10 MHz, HIFU causes localized hyperthermia at predictable depths without injuring intervening tissue. Applications in neurosurgery, urology, oncology and, more recently, cardiology for selective cardiac conduction tissue ablation have been promising. A 'noninvasive' technique for causing localized tissue damage to relieve hemodynamic and life-threatening obstruction in patients with congenital cardiac anomalies could replace more invasive procedures. We, therefore, investigated the ability of HIFU to create lesions in mammalian cardiac tissues ex vivo. Porcine valve leaflet, canine pericardium, human newborn atrial septum, and right atrial appendage were studied. Specimens were mounted and immersed in a water bath at room temperature. Using a 1-MHz phased array transducer, ultrasound energy was applied with an acoustic intensity of 1630 W/cm(2) or 2547 W/cm(2) until a visible defect was created (duration 3 to 25 sec). Macroscopic and microscopic examination demonstrated precise defects ranging from 3 to 4 mm in diameter. No damage was identified to the surrounding tissues. Our study concluded that HIFU can create precise defects in different cardiac tissue without damage to the surrounding tissue. Further investigation is needed to assess potential clinical uses of this technology.

New piezoelectric transducers for therapeutic ultrasound.

Therapeutic ultrasound (US) has been of increasing interest during the past few years. However, the development of this technique depends on the availability of high-performance transducers. These transducers have to be optimised for focusing and steering high-power ultrasonic energy within the target volume. Recently developed high-power 1-3 piezocomposite materials bring to therapeutic US the exceptional electroacoustical properties of piezocomposite technology: these are high efficiency, large bandwidth, predictable beam pattern, more flexibility in terms of shaping and definition of sampling in annular arrays, linear arrays or matrix arrays. The construction and evaluation of several prototypes illustrates the benefit of this new approach that opens the way to further progress in therapeutic US.

Ultrasonic focusing through inhomogeneous media by application of the inverse scattering problem.

A new approach is introduced for self-focusing phased arrays through inhomogeneous media for therapeutic and imaging applications. This algorithm utilizes solutions to the inverse scattering problem to estimate the impulse response (Green's function) of the desired focal point(s) at the elements of the array. This approach is a two-stage procedure, where in the first stage the Green's functions is estimated from measurements of the scattered field taken outside the region of interest. In the second stage, these estimates are used in the pseudoinverse method to compute excitation weights satisfying predefined set of constraints on the structure of the field at the focus points. These scalar, complex valued excitation weights are used to modulate the incident field for retransmission. The pseudoinverse pattern synthesis method requires knowing the Green's function between the focus points and the array, which is difficult to attain for an unknown inhomogeneous medium. However, the solution to the inverse scattering problem, the scattering function, can be used directly to compute the required inhomogeneous Green's function. This inverse scattering based self-focusing is noninvasive and does not require a strong point scatterer at or near the desired focus point. It simply requires measurements of the scattered field outside the region of interest. It can be used for high resolution imaging and enhanced therapeutic effects through inhomogeneous media without making any assumptions on the shape, size, or location of the inhomogeneity. This technique is outlined and numerical simulations are shown which validate this technique for single and multiple focusing using a circular array.

Filter-based coded-excitation system for high-speed ultrasonic imaging.

We have recently presented a new algorithm for high-speed parallel processing of ultrasound pulse-echo data for real-time three-dimensional (3-D) imaging. The approach utilizes a discretized linear model of the echo data received from the region of interest (ROI) using a conventional beam former. The transmitter array elements are fed with binary codes designed to produce distinct impulse responses from different directions in ROI. Image reconstruction in ROI is achieved with a regularized pseudoinverse operator derived from the linear receive signal model. The reconstruction operator can be implemented using a transversal filter bank with every filter in the bank designed to extract echoes from a specific direction in the ROI. The number of filters in the bank determines the number of image lines acquired simultaneously. In this paper, we present images of a cyst phantom reconstructed based on our formulation. A number of issues of practical significance in image reconstruction are addressed. Specifically, an augmented model is introduced to account for imperfect blocking of echoes from outside the ROI. We have also introduced a column-weighting algorithm for minimizing the number of filter coefficients. In addition, a detailed illustration of a full image reconstruction using subimage acquisition and compounding is given. Experimental results have shown that the new approach is valid for phased-array pulse-echo imaging of speckle-generating phantoms typically used in characterizing medical imaging systems. Such coded-excitation-based image reconstruction from speckle-generating phantoms, to the best of our knowledge, have not been reported previously.

Two-step hybrid virtual array ray (VAR) technique for focusing through the rib cage.

A new methodology for focusing ultrasonic beams noninvasively in the presence of the rib cage is investigated. This investigation is motivated by the need to employ high intensity focused ultrasound (HIFU) using phased array applicators for the treatment of liver tumors partially shadowed by the rib obstacles. This approach enables us to efficiently perform the ultrasound computational analysis and pattern synthesis in the interior region of the rib cage. The proposed technique consists of two main steps. First, a virtual array is introduced along the intercostal spacings between the solid ribs to generate the prespecified intensity levels at a set of control points within the target region. The second step involves the design of the actual feed array that induces the virtual sources between the intercostal spacings. This design optimization is carried out via the pseudo-inverse technique (minimum norm least squares solution) and by enforcing a constrained preconditioned pseudo-inverse method. The proposed procedure calculates the required primary sources (feed array) while maintaining minimal power deposition over the solid obstacles.

Two-dimensional temperature estimation using diagnostic ultrasound.

A two-dimensional temperature estimation method was developed based on the detection of shifts in echo location of backscattered ultrasound from a region of tissue undergoing thermal therapy. The echo shifts are due to the combination of the local temperature dependence of speed of sound and thermal expansion in the heated region. A linear relationship between these shifts and the underlying tissue temperature rise is derived from first principles and experimentally validated. The echo shifts are estimated from the correlation of successive backscattered ultrasound frames, and the axial derivative of the accumulated echo shifts is shown to be proportional to the temperature rise. Sharp lateral gradients in the temperature distribution introduce ripple on the estimates of the echo shifts due to a thermo-acoustic lens effect. This ripple can be effectively reduced by filtering the echo shifts along the axial and lateral directions upon differentiation. However, this is achieved at the expense of spatial resolution. Experimental evaluation of the accuracy (0.5 degrees C) and spatial resolution (2 mm) of the algorithm in tissue mimicking phantoms was conducted using a diagnostic ultrasound imaging scanner and a therapeutic ultrasound unit. The estimated temperature maps were overlaid on the gray-scale ultrasound images to illustrate the applicability of this technique for image guidance of focused ultrasound thermal therapy.

Imaging strongly scattering media using a multiple frequency distorted Born iterative method.

The distorted Born iterative (DBI) method is a powerful approach for solving the inverse scattering problem for ultrasound tomographic imaging. This method alternates between solving the inverse scattering problem for the scattering function and the forward scattering problem for the total field and the inhomogeneous Green's function. The algorithm is initialized using the basic Born inverse solution. One fundamental problem is the algorithm diverges for strongly scattering media. This is caused by the limitation of the Born assumption in estimating the initial step of the algorithm. We present a multiple frequency DBI approach to alleviate this problem, thus extending the applicability of the DBI method to the level of dealing with biological tissue. In this multiple frequency approach, a low frequency DBI-based solution, is used to initialize the algorithm at higher frequencies. The low frequency allows convergence of the algorithm to a contrast level that is close to the true level, however, with a poor spatial resolution. The high frequency improves the spatial resolution while preserving convergence because the difference between the true contrast and the initial contrast is relatively small. We present numerical simulations that demonstrate the ability of this method to reconstruct strongly scattering regions.

A hybrid computational model for ultrasound phased-array heating in presence of strongly scattering obstacles.

A computationally efficient hybrid ray-physical optics (HRPO) model is presented for the analysis and synthesis of multiple-focus ultrasound heating patterns through the human rib cage. In particular, a ray method is used to propagate the ultrasound fields from the source to the frontal plane of the rib cage. The physical-optics integration method is then employed to obtain the intensity pattern inside the rib cage. The solution of the matrix system is carried out by using the pseudo inverse technique to synthesize the desired heating pattern. The proposed technique guides the fields through the intercostal spacings between the solid ribs and, thus, minimal intensity levels are observed over the solid ribs. This simulation model allows for the design and optimization of large-aperture phased-array applicator systems for noninvasive ablative thermal surgery in the heart and liver through the rib cage.

Noninvasive estimation of tissue temperature response to heating fields using diagnostic ultrasound.

A noninvasive technique for monitoring tissue temperature changes due to heating fields using diagnostic ultrasound is described in this paper. The approach is based on the discrete scattering model used in the tissue characterization literature and the observation that most biological tissues are semi-regular scattering lattices. It has been demonstrated by many researchers and verified by us that the spectrum of the backscattered radio frequency (RF) signal collected with a diagnostic ultrasound transducer from a semi-regular tissue sample exhibits harmonically related resonances at frequencies determined by the average spacing between scatterers along a segment of the A-line. It is shown theoretically and demonstrated experimentally (for phantom, in vitro, and in vivo media) that these resonances change with changes in the tissue temperature within the processing window. In fact, changes in the resonances (delta f) are linearly proportional to changes in the temperature (delta T), with the proportionality constant being determined by changes in the speed of sound with temperature and the linear coefficient of thermal expansion of the tissue. Autoregressive (AR) model-based methods aid in the estimation of delta f. It should be emphasized that this new technique is not a time of flight velocimetric one, so it represents a departure from previously used ultrasonic methods for tissue temperature estimation.

Multipoint temperature control during hyperthermia treatments: theory and simulation.

A real-time multipoint feedback temperature control system has been designed and implemented with an ultrasound phased-array applicator for hyperthermia. The control parameters are the total power available from the supply and the dwell times at a sequence of preselected heating patterns. Thermocouple measurements are assumed for temperature feedback. The spatial operator linking available heating patterns to temperature measurements is measured at the outset of the treatment and can be remeasured on line an adaptive implementation. A significant advantage of this approach is that the controller does not require a priori knowledge of either the placement of the thermocouples or the power distribution of the ultrasound heating patterns. Furthermore, the control loop uses a proportional integral (PI) gain in conjunction with a singular value decomposition (SVD) of the spatial transfer operator. This approach is advantageous for robust implementation and is shown to properly balance the power applied to the individual patterns. The controller also deals with saturation in the inputs without integrator windup and, therefore, without temperature overshoot. In this paper, we present the theoretical formulation and representative simulation results of the proposed controller. The control algorithm has been verified experimentally, both in vitro and in vivo. A subsequent paper describing these results and the practical implementation of the controller will follow.

Mode scanning: heating pattern synthesis with ultrasound phased arrays.

Modes, the characteristic symmetric focal patterns of an ultrasound phased array, prove especially useful for hyperthermia. Modes cancel the complex pressure fields exactly along the central axis, eliminating axial constructive interference both proximal and distal to the treatment volume. A simple calculation exploits planar or rotational array symmetry and produces the driving signals which generate modal focal patterns. Results show that temporal mode scanning improves heating patterns considerably, expanding the maximum treatable size of the tumour volume.

Dynamic focusing in ultrasound hyperthermia treatments using implantable hydrophone arrays.

A prototype 16-element needle hydrophone array has been designed, fabricated and characterized. The primary use of this array is to provide acoustic feedback during ultrasound hyperthermia treatments. This feedback can be used to compensate for patient motion and tissue inhomogeneities by controlling the phased array driving patterns. It can also be used in adaptive dynamic focusing, a procedure which enables the phased array to focus at points away from specified control points. The hydrophone array consists of a PVDF sheet, which covers a silicon substrate carrier that contains the signal electrodes of the individual acoustic sensors. A complete description of the hydrophone array and its characteristics is given in this paper. The aberration correction and motion compensation algorithms are also described, and some experimental results are shown. Finally, a Taylor series based adaptive dynamic focusing method for phased arrays based on a set of discrete hydrophone array measurements is described. This algorithm does not require any prior knowledge of the applicator geometry and all the parameters needed for correction can be measured directly at the hydrophone array sensor locations.

Blocked element compensation in phased array imaging.

In clinical applications using large apertures, a significant number of phased array elements may be blocked due to discontinuous acoustic windows into the body. These blocked elements produce undesired beamforming artifacts, degrading spatial and contrast resolution. To minimize these artifacts, an algorithm using multiple receive beams and the total-least-squares method is proposed. Simulations and experimental results show that this algorithm can effectively reduce imperfections in the point spread function of the imager. Combined with first-and second-order scatterer statistics derived from multiple receive beams, the algorithm is modified for blocked element compensation on distributed scattering sources. Results also indicate that compensated images are comparable to full array images, and that even full array images can be improved by removing undesired sidelobe contributions. This method, therefore, can enhance detection of low contrast lesions using large phased-array apertures.

Direct computation of ultrasound phased-array driving signals from a specified temperature distribution for hyperthermia.

This paper presents a new method which obtains ultrasound hyperthermia applicator phased-array element driving signals from a desired temperature distribution. The approach combines a technique which computes array element driving signals from focal point locations and intensities with a new technique which calculates focal point locations and power deposition values from temperature requirements. Temperature specifications appear here as upper and lower bounds within the tumor volume, and a focal point placement algorithm chooses focal patterns capable of achieving the temperature range objective. The linear algebraic structure of the method allows rapid calculation of both the phased-array driving signals and an approximate temperature field response. Computer simulations verify the method with a spherical section array (SSA) for a variety of temperature specifications and blood perfusion values. This scheme, which applies to any phased-array geometry, completes an essential step in both treatment planning and feedback for hyperthermia with ultrasound phased-array applicators.

A new filter design technique for coded excitation systems.

To increase range resolution and produce acceptable range sidelobe levels, filtering techniques rather than direct complex correlation are applied in coded excitation systems. A filter design technique based on both peak sidelobe levels and minimum sidelobe energy criteria is developed. In comparison to a classic inverse filter, this approach reduces sidelobe levels under a prespecified threshold. Further reduction can be achieved by extending the filter length. This technique can be more generally applied to similar signal processing problems. Both the mathematical formulation and simulation results demonstrating the utility of the technique are presented. A discussion of quantization effects is included.

Optimization of the intensity gain of multiple-focus phased-array heating patterns.

A new technique for enhancing the intensity gain at the focal points in multiple-focus patterns is introduced. The new technique is shown to be effective in reducing the interference typically associated with multiple-focus patterns. This reduction in interference patterns allows multiple-focus scanning to generate highly localized heating. Simulation results indicate that multiple-focus scanning not only provides an alternative to single-focus scanning, but also achieves better localization in the heating pattern. The maximization of intensity gain of multiple-focus heating patterns significantly reduces the pre-focal-depth high-temperature regions that can be caused by single-focus scanning. This is shown by computer simulation of a two-dimensional cylindrical-section array (CSA2D) as a heating applicator. Two series of simulations are presented in which different scan trajectories were used to therapeutically heat a small deep-seated target volume. In every case the heating pattern was generated using single-focus scanning and multiple-focus scanning (with and without intensity gain maximization). Multiple-focus scanning with gain maximization offers the best localization of heating to the target volume of the three methods.

A spherical-section ultrasound phased array applicator for deep localized hyperthermia.

Computer simulation shows that a new ultrasound phased-array with nonplanar geometry has considerable potential as an applicator for deep localized hyperthermia. The array provides precise control over the heating pattern in three dimensions. The array elements form a rectangular lattice on a section of a sphere. Therefore, the array has a natural focus at its geometric center when all its elements are driven in phase. When compared to a planar array with similar dimensions, the spherical-section array provides higher focal intensity gain which is useful for deep penetration and heat localization. Furthermore, the relative grating-lobe level (with respect to the focus) is lower for scanned foci synthesized with this array (compared to a planar array with equal center-to-center spacing and number of elements). This could be the key to the realization of phased-array applicator systems with a realistic number of elements. The spherical-section array is simulated as a spot-scanning applicator and, using the pseudo-inverse pattern synthesis method, to directly synthesize heating patterns overlaying the tumor geometry. A combination of the above two methods can be used to achieve the desired heating pattern in the rapidly varying tumor environment.

Effect of phase errors on field patterns generated by an ultrasound phased-array hyperthermia applicator.

The effect of phase quantization errors and Gaussian distributed random phase errors on field patterns synthesized by a rectangular ultrasound phased array hyperthermia applicator is studied. The parameters defined show that, over the range of four-bit to one-bit quantization, the simulated, patterns degrade with increasing phase errors. However, the overall shape and position of the foci remain unchanged. Simulation results show that, even with one-bit phase quantization, or with a Gaussian distributed random phase error of standard deviation of about 52 degrees , the applicator can still produce useful, if not particularly clean, power deposition patterns. Thus, the power deposition patterns are remarkably stable tolerating quite large phase error levels. This suggests that the power deposition patterns inside the body may be relatively insensitive to phase errors due to tissue inhomogeneities.

Experimental evaluation of a prototype cylindrical section ultrasound hyperthermia phased-array applicator.

A prototype 64-element, 75 degrees cylindrical-section ultrasonic phased-array hyperthermia applicator has been designed and constructed. The ability of this applicator to focus ultrasonic energy at its geometric focus is verified in a water medium. The array is then driven by excitation vectors obtained using the pseudoinverse pattern synthesis method to generate shifted-focus and multiple-focus field patterns. Experimental results of single and multiple-focus patterns at 500 kHz are given and are in good agreement with theory. The results indicate that the main beam in single-focus patterns is generally insensitive to errors in the phases and amplitudes of the particle velocities of the array elements. The effect of such errors is largely exhibited in the sidelobes which, for all practical purposes, remain at levels acceptable for hyperthermia. This is true for both the geometric focus and shifted foci.