WO2001082777A2

WO2001082777A2 - Non-invasive tissue characterization

Info

Publication number: WO2001082777A2
Application number: PCT/US2001/013548
Authority: WO
Inventors: Narendra T. Sanghvi; Adam J. Wunderlich
Original assignee: Focus Surgery, Inc.
Priority date: 2000-04-29
Filing date: 2001-04-27
Publication date: 2001-11-08
Also published as: WO2001082777A3; AU2001255724A1

Abstract

Apparatus for controlling high intensity focused ultrasound (HIFU) tissue treatment includes at least one ultrasound transducer (128), a first device (130) coupled to the at least one transducer (128) for driving the at least one transducer (128), and a second device (132) coupled to the first device (130) to control the first device (130) and to the at least one transducer (128) to receive data of return echoes received by the at least one transducer (128). The second device (132) controls the first device (130) to: (a) develop data of the untreated tissue; (b) store the data of the untreated tissue; (c) treat the tissue to a cycle of HIFU from the at least one transducer (128); (d) develop data of cycle (c); (e) compare the data developed at (d) to the data stored at (b); (f) repeat steps (c) - (e) until a desired value of a tissue modification parameter (α) is obtained; and (g) provide an indication once the desired value of the tissue modification parameter (α) has been obtained. A method for controlling high intensity focused ultrasound (HIFU) tissue treatment thus includes: (a) developing data of the untreated tissue; (b) storing the data of the untreated tissue; (c) treating the tissue to a cycle of HIFU from at least one ultrasound treatment transducer (128); (d) developing data of cycle (c); (e) comparing the data developed at (d) to the data stored at (b); (f) repeating steps (c) - (e) until a desired value of a tissue modification parameter (α) is obtained; and, (g) terminating the treatment.

Description

NON-LNNASINE TISSUE CHARACTERIZATION

Field of the Invention

This invention relates to the investigation and treatment of the body using high-intensity focused ultrasound energy, or HIFU. It is disclosed in the context of treatment of diseases of the prostate, such as prostate cancer and benign prostatic hyperplasia, or BPH, but it is believed to be useful in other applications as well.

Cross Reference to Related Applications

This application claims priority to U. S. S. N. 60/200,695, filed April 29, 2000, the disclosure of which is hereby incorporated herein by reference.

Background of the Invention Non-surgical therapy of prostate cancer has been previously performed by irradiation and cryosurgery. Both technologies have significant drawbacks, such as lack of control, untoward side effects, and invasiveness. Recently, HIFU has been established as a highly effective means of inducing contact-free, ionizing radiation- free intraprostatic coagulative necrosis, the changing of the character of diseased tissue of the prostate on a cellular level. Studies have been conducted which indicate that, indeed, sharply delineated coagulative necrosis of predictable size and location can be achieved while avoiding macroscopic or microscopic change to the surrounding tissue structures. Lesion sizes increase multifold with ultrasound intensity at the focal site of the therapy transducer. The lesion spreads toward the transducer with increasing focal site intensity.

Issues still remain to be resolved, however, before treatment of soft tissue disease with HIFU becomes widely accepted. For example, the characteristics of tissue, even the same tissue, even in the same organ, vary over a sufficiently broad range that HIFU treatment without some sort of feedback becomes problematic. Ideally, alternating intervals of treatment by the therapy transducer and investigation by, for example, a visualization transducer used in the setup of the HLFU treatment regimen, could provide the necessary information to control the application of HTFU energy in accordance with results being achieved by earlier application of HIFU. The results of such investigation would then be fed back to the controller for the therapy transducer to control it in a closed feedback loop based upon results it has previously achieved during the therapy session.

Disclosure of the Invention

According to one aspect of the invention, a method for controlling high intensity focused ultrasound (HIFU) tissue treatment includes: (a) developing data of the untreated tissue; (b) storing the data of the untreated tissue; (c) treating the tissue to a cycle of HIFU from at least one ultrasound treatment transducer; (d) developing data of cycle (c); (e) comparing the data developed at (d) to the data stored at (b); (f) repeating steps (c) - (e) until a desired value of a tissue modification parameter is obtained; and, (g) providing an indication once the desired value of the tissue modification parameter has been obtained. Illustratively according to this aspect of the invention, developing data of the untreated tissue includes using pulse-echo visualization magnitude ultrasound energy and developing the data of the untreated tissue from the return echoes.

Further illustratively according to this aspect of the invention, the method includes developing a treatment regimen from the data of the untreated tissue. Additionally illustratively according to this aspect of the invention, developing a treatment regimen includes establishing at least one of the HIFU power and HIFU duty cycle of the treatment.

Illustratively according to this aspect of the invention, developing the treatment regimen includes basing the at least one of the HLFU power and HIFU duty cycle upon initial assumptions about the value of the tissue modification parameter. Further illustratively according to this aspect of the invention, developing the treatment regimen includes testing the tissue to be treated before the application of the first cycle of HIFU treatment to determine the initial value of the tissue modification parameter. Additionally illustratively according to this aspect of the invention, developing a treatment regimen includes establishing at least one of the HIFU power and HLFU duty cycle of the treatment to increase the temperature of the tissue a desired amount.

Illustratively according to this aspect of the invention, treating the tissue to a cycle of HIFU includes treating the tissue to a cycle of HIFU having a duration in the range of about .125 sec. - about .5 sec.

Further illustratively according to this aspect of the invention, treating the tissue to a cycle of HIFU includes turning off the HIFU at intervals of about .05 sec - about .1 sec. during the cycle of HIFU for about 50 μsec, and developing during the intervals data of the tissue from the portion of the cycle of HIFU which has been conducted prior to the intervals.

Additionally illustratively according to this aspect of the invention, developing data of the tissue from the portion of the cycle of HIFU which has been conducted prior to the intervals includes using pulse-echo visualization magnitude ultrasound energy and developing the data of the tissue treated during the portion of the cycle of HIFU which has been conducted prior to the intervals from the return echoes.

Illustratively according to this aspect of the invention, developing data of the cycle of HLFU includes developing data of the tissue treated to a cycle of HIFU using pulse-echo visualization magnitude ultrasound energy and developing the data of the tissue treated to a cycle of HIFU from the return echoes.

Further illustratively according to this aspect of the invention, the method includes processing the data of the untreated tissue before storing the data of the untreated tissue.

Additionally illustratively according to this aspect of the invention, processing the data of the untreated tissue before storing the data of the untreated tissue includes determining an average value of multiple tissue echo profiles.

Illustratively according to this aspect of the invention, the method further includes processing the data of a cycle of HIFU after developing data of the cycle of HIFU. Further illustratively according to this aspect of the invention, comparing the data developed from a cycle of HTFU to the stored data includes comparing processed data developed from a cycle of HLFU to processed stored data. Additionally illustratively according to this aspect of the invention, developing data of the untreated tissue includes developing the tissue modification parameter for the untreated tissue.

Illustratively according to this aspect of the invention, developing data of a cycle of HIFU includes developing the tissue modification parameter for the tissue treated to the cycle of HLFU.

Further according to this aspect of the invention, the method includes generating an image of the tissue undergoing treatment to provide a visual representation of the effect of the therapy. Additionally illustratively according to this aspect of the invention, the method includes generating such an image after each cycle of HLFU.

Illustratively according to this aspect of the invention, (c) treating the tissue to a cycle of HIFU, (d) developing data of cycle (c), (e) comparing the data developed at (d) to the data stored at (b), and (f) repeating steps (c) - (e) until a desired value of a tissue modification parameter is obtained include (c) treating the tissue to a cycle of HIFU, (d) developing data of cycle (c), (e) comparing the data developed at (d) to the data stored at (b), and (f repeating steps (c) - (e) until a desired value of a tissue modification parameter is obtained in a closed feedback loop. The method further includes providing a controller for controlling the closed feedback loop. The controller provides an indication once the desired value of the tissue modification parameter has been obtained.

Further illustratively according to this aspect of the present invention, the method includes providing at least one variable focus ultrasound transducer.

Additionally illustratively according to this aspect of the present invention, providing at least one variable focus ultrasound transducer includes providing at least one ultrasound transducer whose focus is determined by the phasing of the drive signal to its radiating surface or surfaces.

Illustratively according to this aspect of the invention, the tissue modification parameter is the attenuation coefficient of tissue between the at least one ultrasound treatment transducer and the tissue being treated.

Further illustratively according to this aspect of the invention, the method includes testing the attenuation coefficient for change greater than a selected threshold, storing the attenuation coefficient, and generating from stored attenuation coefficient data an image of the tissue being treated.

Additionally illustratively according to this aspect of the invention, storing the attenuation coefficient includes storing multiple attenuation coefficient data, and generating from stored attenuation coefficient data an image of the tissue being treated includes generating a composite image of the tissue being treated from the multiple stored data.

Illustratively according to this aspect of the invention, generating from the stored attenuation coefficient data an image of the tissue being treated includes generating from the stored attenuation coefficient data a B-mode image or a composite B-mode image of the tissue being treated.

According to another aspect of the invention, apparatus for controlling high intensity focused ultrasound (HIFU) tissue treatment includes at least one ultrasound transducer, a first device coupled to the at least one transducer for driving the at least one transducer, and a second device coupled to the first device to control the first device and to the at least one transducer to receive data of return echoes received by the at least one transducer. The second device controls the first device to:

(a) develop data of the untreated tissue; (b) store the data of the untreated tissue; (c) treat the tissue to a cycle of HIFU from the at least one transducer; (d) develop data of cycle (c); (e) compare the data developed at (d) to the data stored at (b); (f) repeat steps (c) - (e) until a desired value of a tissue modification parameter is obtained; and

(g) provide an indication once the desired value of the tissue modification parameter has been obtained.

Illustratively according to this aspect of the invention, the second device is a second device for using pulse-echo visualization magnitude ultrasound energy and developing the data of the untreated tissue from the return echoes.

Further illustratively according to this aspect of the invention, the second device is a second device for developing a treatment regimen from the data of the untreated tissue. Additionally illustratively according to this aspect of the invention, the second device is a second device for developing a treatment regimen by establishing at least one of the HIFU power and HIFU duty cycle of the treatment. Illustratively according to this aspect of the invention, the second device is a second device for developing the treatment regimen by basing the at least one of the HTFU power and HTFU duty cycle upon initial assumptions about the value of the tissue modification parameter. Further illustratively according to this aspect of the invention, the second device is a second device for developing the treatment regimen by testing the tissue to be treated before the application of the first cycle of HIFU treatment to determine the initial value of the tissue modification parameter.

Additionally illustratively according to this aspect of the invention, the second device is a second device for developing a treatment regimen by establishing at least one of the HIFU power and HTFU duty cycle of the treatment to increase the temperature of the tissue a desired amount.

Illustratively according to this aspect of the invention, the second device is a second device for treating the tissue to a cycle of HIFU having a duration in the range of about .125 sec. - about .5 sec.

Further illustratively according to this aspect of the invention, the second device is a second device for treating the tissue to a cycle of HIFU by turning off the HLFU at intervals of about .05 sec - about .1 sec. during the cycle of HTFU for about 50 μsec, and developing during the intervals data of the tissue from the portion of the cycle of HIFU which has been conducted prior to the intervals.

Additionally illustratively according to this aspect of the invention, the second device is a second device for developing data of the tissue from the portion of the cycle of HIFU which has been conducted prior to the intervals by using pulse- echo visualization magnitude ultrasound energy and developing the data of the tissue treated during the portion of the cycle of HIFU which has been conducted prior to the intervals from the return echoes.

Illustratively according to this aspect of the invention, the second device is a second device for developing data of the tissue treated to a cycle of HIFU using pulse-echo visualization magnitude ultrasound energy and developing the data of the tissue treated to a cycle of HIFU from the return echoes. Further illustratively according to this aspect of the invention, the second device is a second device for processing the data of the untreated tissue before storing the data of the untreated tissue.

Additionally illustratively according to this aspect of the invention, the second device is a second device for processing the data of the untreated tissue before storing the data of the untreated tissue by determining an average value of multiple tissue echo profiles.

Illustratively according to this aspect of the invention, the second device is a second device for processing the data of a cycle of HLFU after developing data of the cycle of HIFU.

Further illustratively according to this aspect of the invention, the second device is a second device for comparing the data developed from a cycle of HTFU to the stored data by comparing processed data developed from a cycle of HLFU to processed stored data. Additionally illustratively according to this aspect of the invention, the second device is a second device for developing data of the untreated tissue by developing the tissue modification parameter for the untreated tissue.

Illustratively according to this aspect of the invention, the second device is a second device for developing data of a cycle of HLFU by developing the tissue modification parameter for the tissue treated to the cycle of HIFU.

Further illustratively according to this aspect of the invention, the second device is a second device for generating an image of the tissue undergoing treatment to provide a visual representation of the effect of the therapy.

Additionally illustratively according to this aspect of the invention, the second device is a second device for generating such an image after each cycle of HIFU.

Illustratively according to this aspect of the invention, the at least one transducer, the first device and the second device are coupled in a closed feedback loop, the second device controlling the closed feedback loop. Further illustratively according to this aspect of the invention, the at least one transducer includes at least one variable focus ultrasound transducer. Additionally illustratively according to this aspect of the invention, the first and second devices control the at least one variable focus transducer by the phasing of the drive signal to the at least one variable focus transducer's radiating surface or surfaces. Illustratively according to this aspect of the invention, the second device for repeating steps (c) - (e) until a desired value of a tissue modification parameter is obtained is a second device for repeat steps (c) - (e) until a desired value of the attenuation coefficient of tissue between the at least one ultrasound treatment transducer and the tissue being treated is obtained. Further illustratively according to this aspect of the invention, the second device is a second device for testing the attenuation coefficient for change greater than a selected threshold, storing the attenuation coefficient, and generating from stored attenuation coefficient data an image of the tissue being treated.

Additionally illustratively according to this aspect of the invention, the second device for storing the attenuation coefficient is a second device for storing multiple attenuation coefficient data, and for generating from stored attenuation coefficient data a composite image of the tissue being treated from the multiple stored data.

Further illustratively according to this aspect of the invention, the second device for generating from the stored attenuation coefficient data a composite image of the tissue being treated is a second device for generating from the stored attenuation coefficient data a B-mode image or a composite B-mode image of the tissue being treated.

Illustratively according to this aspect of the invention, the second device for generating from the multiple stored attenuation coefficient data a composite image of the tissue being treated is a second device for generating from the multiple stored attenuation coefficient data a B-mode image or a composite B-mode image of the tissue being treated.

Brief Description of the Drawings

The invention may best be understood by referring to the following detailed description and drawings which illustrate the invention. In the drawings: Fig. 1 illustrates a plot of an ultrasound visualization/HIFU transducer excitation cycle according to the present invention;

Figs. 2-9 illustrate plots of averages over a number of pulse/echo imaging cycles of integrated backscatter from tissue being treated during progressive stages of its treatment;

Figs. lOa-d- 15a-c illustrate plots of MATLAB simulations of certain constants, namely attenuation, signal power (as represented by integrated backscatter), cross-correlation maximum, K, p and c, with the constants plotted on a log₁₀ scale;

Figs. 16a-c illustrate plots of the attenuation intercept in dB versus amplitude, dB/MHz of signal frequency/cm of tissue depth versus frequency and dB/MHz of signal frequency/cm of tissue depth versus phase, respectively;

Figs. 17-22 illustrate M-mode false color images using each of the constants on one data set;

Fig. 23 illustrates an algorithm according to the invention; and, Fig. 24 illustrates a block diagram of an experimental setup to test methods according to the invention.

Detailed Descriptions of Illustrative Embodiments

In an illustrative treatment of a diseased prostate, of a sufferer of prostate cancer or BPH, for example, the prostate is first imaged using imaging intensity ultrasound in the range of, for example, a watt per square centimeter. Baseline, untreated data results. This baseline data is stored. Contemporaneously, the treatment region is visualized, and a treatment regimen is established. Thus, the target region is visualized and the power and duty cycle of the therapy transducer are established. The therapy beam power and duty cycle are selected, based upon initial assumptions about the absorption coefficient of the tissue to be treated or prior testing to determine the actual absorption coefficient of the tissue undergoing treatment (see, for example, U. S. Patent 5,873,902), to provide a desired temperature elevation at the treatment site. An initial HIFU therapy pulse, for example, in the KW/cm² range, is applied to the target region. The therapy transducer may be of a variable focus type, whose focal length is determined by the phasing of the drive signal to its various active surfaces. Or a therapy transducer may be selected based upon the depth d, that is, the distance of the target treatment region from the surface of the therapy transducer.

Referring to Fig. 1, a plot of an illustrative visualizatiori/HIFU transducer excitation cycle, the tissue may first be exposed to a characterization of its parameters, for example, integrated backscatter χ₀ at any depth d in the tissue at time t

= 0, that is, before any HLFU treatment is initiated. The tissue can be characterized, for example, by subjecting it to a number, M, of pulses 24 of visualizing ultrasound, receiving the return echoes from these visualizing pulses 24, and obtaining the mean

Λ Λ λo( of the return echoes to establish the pretreatment integrated backscatter % ²(d), where

Λ M χ₀(d) = Σ χi _o(d)/M. j=l

The plot of integrated backscatter illustrated in Fig. 2 results. Additionally, χ(d) can be FFTed to X(ω), where the ωs are the radian frequencies present in the ultrasound visualization pulses 24. The tissue is then exposed to a first burst 20 of HTFU having a duration t,_ in the range of, for example, .125 sec. - .5 sec. At intervals 22 of, for example, .05 sec - .1 sec. during this first burst 20 of HIFU, the HIFU is turned off for, for example, 50 μsec, and the visualization transducer is energized (or the visualization HIFU transducer is operated in visualization mode) 24 and return echoes from the treatment field and intervening tissue are recovered. Interrogation of the tissue this way, during the HIFU burst 20, provides additional data that can be used in the characterization of the progress of HTFU treatment intra-HIFU burst 20. The plot of integrated backscatter illustrated in Fig. 3 results. The visualization protocol is then repeated as illustrated at 28, through the portion 26 of the HIFU duty cycle when the HIFU is not being administered, in order to characterize further changes in the tissue during the time 26 after administration of the first HTFU treatment pulse 20. This visualization interval yields an integrated backscatter

Λ M χ_tt(d) = ∑ XJ _tι(d)/M. The nature ofthe visualization pulses 24, 28 may vary. For example, the visualization during intervals 22 may be RF and/or two-dimensional imaging, and the visualization during intervals 28 may be RF and B-mode imaging. Whatever form the imaging pulses take, tissue echo profiles ofthe treatment field from the visualization pulses 24 are taken and stored, or taken, processed (for example, by determining a mean value of multiple tissue echo profiles) and stored (or the thus-processed tissue echo profiles are stored). In an illustrative embodiment, during the "off portion of each therapy beam duty cycle, additional echo profiles ofthe treatment field from pulses 24 are taken, and their mean is calculated as a composite ofthe state ofthe tissue undergoing therapy after the "on" portion 20 ofthe first duty cycle 20, 26. The plot of integrated backscatter measured during the first such post-HIFU administration interval 26 is illustrated in Fig. 4.

The attenuation coefficient, a, at depth d based upon the received echo(es) from this (these) first post-therapy visualization pulse(s) 24 is calculated from the relation

T = T p-2ai

^■'^•received ^•'^•transmitted*- ? where T_ransmi_tted is the intensity ofthe transmitted ultrasound visualization pulses 24, T-_recei_ved is the intensity ofthe received ultrasound visualization pulses 24, and e is the base ofthe natural logarithms, α is then tested for any significant change, and stored. A B-mode image (or a composite B-mode image if multiple post-therapy echo pulses 24 have been generated) ofthe tissue undergoing treatment may be generated from the data collected thus far to provide a visual representation ofthe effect ofthe first duty cycle 20, 26 of therapy.

The next burst 20 of HIFU is then applied, illustratively, but not necessarily using the same duty cycle and treatment power. Indeed, it is contemplated that these variables may be among those adjusted based upon feedback ofthe progress ofthe treatment. The same format 20, 22, 24, 26, 28 can be followed. That is, during and after the second burst 20, (a) second treatment tissue echo profile(s) produced by visualization pulse(s) 24 is (are) taken and stored, or taken, processed and stored. This visualization interval 28 yields an integrated backscatter

Λ M χ_a(d) = ∑ ri _a(d)M. M

, at depth d based upon the received echo(es) from this (these) second post-therapy visualization pulse(s) 24 is calculated, tested for any significant change in the attenuation coefficient, and stored. Another B-mode image ofthe tissue undergoing treatment can be generated to provide a visual representation of the effect of the second duty cycle 20, 26 of therapy. Again, a plot of integrated backscatter can be generated from the return echo data. Such a plot is illustrated in Fig. 5.

This process is repeated, yielding the integrated backscatter plots illustrated in Figs. 6-9, until the desired change in the integrated backscatter indicating a corresponding change in the tissue, echoes from which are represented by the integrated backscatter, is detected at the treatment site, indicating the desired change in the character ofthe tissue at the cellular level. This indicates that the treatment is completed at the first treatment site, and the imaging and therapy transducer(s) is (are) re-aimed to treat another site as dictated by the treatment regimen. See, for example, U. S. Patent 5,873,902. The same process is conducted at that site, then the imaging and therapy transducers are re-aimed to treat another site, and so on.

The application of HIFU can be monitored and controlled in order to induce a sufficient intensity I_d at the site for a sufficient time t to achieve a desired change in temperature ΔT = (T_t - T₀). Turning now to descriptions of some types of processing ofthe return echoes which can provide useful information about the character ofthe tissue from which they are echoes, the rehrrn echoes are first digitized and stored as lines in a raster or display. Before any further signal processing is performed on the digitized return echoes, each set of echoes, sometimes referred to hereinafter as RF, can be averaged line by line to created a composite RF display. The composite RF lines can then be fast Fourier transformed (FFTed) using a sliding window technique, where each RF line is broken up into multiple, overlapping windows. This permits windows from different RF lines to be compared via a constant measuring their similarity. In general, windows from a given RF line were compared to windows in a reference RF line (that is, a line corresponding to the same tissue depth from the composite RF display created before any application ofthe therapy beam). Columns of constants relate the windows of each subsequent line to the windows vertically above them in the first line. These constants may further be normalized by dividing them by the constants relating the first line to the second. This further enhances the changes from RF line to RF line.

After the matrix of constants which describes the relationships of subsequent RF lines to the first RF line is computed, the display is enlarged to its original size. For regions which are contained in overlapping windows, the constants representing the overlapping windows are averaged. This provides a smoothing ofthe image. Six different constants are investigated herein for their ability to characterize tissue changes during therapy. It is believed that other constants may be equally useful, and perhaps more useful, in characterizing the changes in tissue subject to the HLFU treatment. However, these six constants are capable of characterizing such changes sufficiently well to permit their use in feedback control of HLFU treatment according to the invention. These constants include: attenuation; signal power (represented by integrated backscatter); cross-correlation maximum; and three constants referred to hereinafter as K, p and c. Attenuation is represented in the illustrated results by attenuation change ΔA between two vectors S_x and S₂ of length L. It can be calculated as follows: χ(I) = .42 - .5cos(2πi/L) + .08cos(4πi/L), S₁f= 20 1ogj FFT(χ(I) .* S₁ )l and S₂f= 20 1ogj FFT(χ(I) .* S₂)l where ,* indicates the component-wise multiplication operation. Continuing with this calculation,

ΔA is the slope ofthe line that is the best fit to the first half of the frequency range over which diff is calculated. The attenuation intercept ofthe best fit line yields similar results. Other methods of calculating attenuation may yield comparable, or better, results, and the invention is not limited to a particular method of calculating or estimating attenuation or change in attenuation.

The second set of constants investigated are the above-mentioned integrated backscatters. Integrated backscatters can be thought of as the signal powers present in each ofthe vectors Si and S₂. However, care must be exercised in the use ofthe term integrated backscatter because there are numerous definitions of it in the literature. The powers were calculated as follows:

P₂ ⁼ k S₂, where ^τ indicates the transpose operator. Signal power is a highly accurate indicator ofthe extent of a lesion. However, it may not be an appropriate mechanism for ' feedback control of HTFU treatment in every instance, because it is quite sensitive to patient movement.

The third set of constants evaluated are the constants designated as K. These are calculated as follows. Recall that χ(I) = .42 - .5cos(2πi/L) + .08cos(4πi/L), S₁f= 20 1og₁₀l FFT(χ(I) .* S₁ )l and S₂f= 20 1ogj FFT(χ(I) .* S₂)l , where .* again indicates the componentwise multiplication operation. Continuing with this calculation,

diff2 = 20 1ogj diffl . ΔK is defined as the attenuation axis intercept ofthe best fit line to the first half of diff2. The other three sets of constants result from correlation schemes, p is defined as the correlation coefficient between the two vectors Si and S₂ as follows: p = CON(S, S₂)/Ν(NAR(S₁)NAR(S₂)), where COV(Sι S₂) is the covariance of S,_. and S₂, VA ^S]) is the variance of S_t and NAR(S₂) is the variance of S₂. The fifth constants are defined as

where ^τ once again indicates the transpose operator and II II indicates the Euclidean norm operator. The value of c is the cosine ofthe angle between the vectors Si and S₂.

The last scheme is cross-correlation maximum. These constants can be expressed as follows:

M L-l

Max(cross corr(S, S₂)) = Max ( Σ Σ S,(I)S₂(I + j)), j=-M 1=0 where 2M + 1 is the correlation width and the maximum cross correlation which occurs at an index j is used as the correlation constant.

MATLAB simulations were run plotting these constants against amplitude, frequency and phase, with the other two independent variables in each plot being held constant. Plots of these simulations, with the constants plotted on a log₁₀ scale, are illustrated in Figs. lOa-d - 15a-c. Plots ofthe attenuation intercept in dB versus amplitude, dB/MHz of signal frequency/cm of tissue depth versus frequency and dB/MHz of signal frequency/cm of tissue depth versus phase are illustrated in Figs. 16a-c, respectively. M-mode false color images using each ofthe constants on one data set are illustrated in Figs. 17-22. Another method for developing feedback control ofthe therapy transducer was also investigated. This method permitted the beginning of each window to have a variable position in each RF line. The beginning location of each window was determined by sliding the window around in the vicinity of its designated original position and choosing its position based upon how closely its contents correlated with the contents ofthe corresponding window in the RF reference line. That is, a matching algorithm identified the starting location for each window that provided the best match with the contents ofthe corresponding window in the reference line. One possible advantage of such a strategy is that it may permit changes in the character of tissue to be distinguished from thermal expansion ofthe tissue. Thermal expansion of tissue in the range of interest is fairly linear. Thus, if the coefficients correlating windows in different RF lines are linearly related, it can be concluded that the differences are related to thermal expansion ofthe tissue during treatment, not to changes in the character ofthe tissue at the cellular level. The signal processing algorithm can be made to adjust the coefficients dynamically to account for these thermal expansion effects. On the other hand, if the coefficients are not linearly related, it can be concluded that the character ofthe tissue has been affected by the therapy beam. Such an algorithm is only useful if there is relatively high correlation in the RF data. If there is not, that is, if there is substantial change in the tissue, such an algorithm would not be useful. Thus, it may be useful in an implementation of such an algorithm to establish some threshold below which the amount of shift between consecutive windows is made the same as the amount of shift between windows ofthe previous set. Such an algorithm was employed with all of the correlation coefficients, and some modest improvement in the processed M-mode images was noted.

Other techniques for determining whether the character ofthe tissue at the cellular level has been changed include investigation ofthe normalized cross- correlation coefficient A = crosscorr(S 1 ,S2)/ (autocorr(S 1 ,S 1 *)autocorr(S2,S2*)) where SI and S2 are complex with positive- valued frequency, and determination of the speckle size ofthe tissue which can be used for the range ofthe lags in the cross correlations and autocorrelations. Correlation filtering, that is, applying a digital filter to the normalized cross-correlation function, can also be used. The stability and utility of this technique require that the changes between consecutive waveforms be relatively small. If the changes are too large, longer time sampling is required to recover meaningful information.

A centroid or other similar method can also be used to recover from the tissue images data which can be developed into information on whether the character ofthe tissue at the cellular level has been changed. A description ofthe use ofthe centroid and auto-regressive spectral analysis to implement an accurate measurement of relative attenuation in a general sense is contained in T. Baldeweck, P. Laugier, A Herment and G. Berger, "Application of Autoregressive Spectral Analysis for Ultrasound Attenuation Estimation: Interest in Highly Attenuating Medium," IEEE Trans. Ultrason. Ferr. & Freq. Control vol. 42, no. 1, pp. 99-110, Jan. 1995, the disclosure of which is incorporated herein by reference. Another approach to the determination of whether the character of tissue at the cellular level has been changed is described in the general context of signal processing in M. Ribault, J. Y. Chapelon, D. Cathignol and A. Gelet, "Differential Attenuation Imaging for the Characterization of High Intensity Focused Ultrasound Lesions," Ultrasound Imaging. 20, pp. 160-177, 1998, the disclosure of which is incorporated herein by reference.

An illustration of an algorithm according to the invention operating on one set of data is illustrated in Fig. 23. In the algorithm, imaging ofthe prostate is initiated at 40, and the tissue to be treated is located. At 42, using the image mode of the ultrasound transducer apparatus, RF (that is, image) data is collected from the site at which the treatment is to be effected. This data is stored as the reference RF line of data. At 44, a burst 20 of HLFU therapy is initiated. Again, the profile ofthe therapy and imaging cycle 20, 22, 24, 26, 28 is illustrated in Fig. 1. At 46, after the burst 20, a visualization cycle 26, 28 is initiated and RF data and perhaps other data, such as B- mode image data, are obtained. At 48, these data are processed as described above to generate the constants, and the processed data are tested for indications ofthe desired tissue changes due to the HIFU treatment application 20. If the processed data indicate that the desired changes in the character ofthe tissue at the treatment site have been achieved, 50, the HIFU and visualization transducer(s) is (are) reaimed 54 at the next treatment site. If not, 52, the algorithm returns to step 44.

In addition to determining whether the desired change in the character of tissue subject to HLFU treatment has been effected, the application of an optimal dose of HLFU provides another opportunity for the use of feedback in HLFU treatment. One method for continuously updating the applied HIFU intensity is to assume that the tissue subject to treatment lies in the focal zone, that is, that the beam intensity is substantially constant, that the average speed of sound in a particular sample of tissue is approximately constant, and that the transducer power as a function of distance has not changed since the last calibration. The attenuation, a, can be estimated by comparing the latest RF (image) line to a reference line taken in water from a perfect reflector. If the attenuation change for tissue of thickness D can be estimated, then the necessary acoustic power needed to produce a given site intensity can be calculated: I_site = (TAP/TI)e-^{(α0 + Δα)D} where TAP is the total acoustic power and TI is the transducer index, or beam area. It should be noted that the tissue thickness D can be estimated from the pulse/echo signal. Therefore, if Δ and D are estimated after each interval of HLFU, the TAP can be adjusted accordingly. If temperature feedback information is desired, that information may also be obtained. See, for example, R. Seip, "Feedback for Ultrasound Thermotherapy," Ph. D. Dissertation, University of Michigan at Ann Arbor, 1996, the disclosure of which is incorporated herein by reference.

An experimental setup to test methods according to the invention is illustrated in block diagram fashion in Fig. 24. There, tissue 120, for example, a 1.5 inch by 1.5 inch by 1 inch (about 3.8 cm by 3.8 cm by 2.5 cm) sample of thawed turkey breast containing homogeneous tissue to reduce reflections due to tissue interfaces, is immersed in a degassed water bath 122 and permitted to equilibrate at the temperature ofthe water bath, 37°C. Thermocouple 124 and hydrophone 126 probes are inserted into a target region in the tissue 120. Thermocouple probe 124 illustratively is a Physitemp model T150, T-type, .002 inch (about .05 mm) diameter, copper-constantan thermocouple. Hydrophone probe 126 illustratively is a DAPCO Yale model B-D 19 needle hydrophone. The target region is the focal zone of an ultrasound transducer 128 which is, for example, a dual-element transducer used for both HLFU and pulse/echo image acquisition and having an outer element with a focal length of 3.5 cm and a resonant frequency of 4 MHz and an inner element with a focal length of 3.5 cm and a resonant frequency of 6 MHz.

The transducer 128 is driven by an ultrasound generator/driver 130 such as, for example, a Focus Surgery, Inc., model Sonablate™ 200™ ultrasound generator/driver. Since the imaging element ofthe transducer 128 had a resonant frequency of 6 MHz, the input filter on the receiving amplifier ofthe ultrasound generator/driver 130 was modified from a 2-5 MHz passband to a 5-10 MHz passband. The pulser/receiver portion ofthe ultrasound generator/driver 130 was only used during image acquisition. The images generated during image acquisition were printed on a screen printer. The ultrasound generator/driver 130 is controlled by a personal computer (PC) 132 such as, for example, a 400 MHz Intel machine equipped with a Gage A/D board. The LPT1 port of PC 132 is coupled to a function generator 134 such as, for example, a Hewlett-Packard model 8116A pulse/function generator, and directly to the ultrasound generator/driver 130.

The output port ofthe function generator 134 is coupled to an input port of an ultrasound power amplifier 136 such as, for example, an ENI model AP400B controllable power amplifier. The output port of amplifier 136 is coupled to the HLFU control input port ofthe ultrasound generator/driver 130. The HLFU output port of ultrasound generator/driver 130 is coupled to the outer, HIFU element of transducer 128. Data is acquired from the output of amplifier 136 by coupling the output port of amplifier 136 to the channel 2 input port of an oscilloscope such as, for example, a Tektronix model 7603 oscilloscope. The Transmit/Receive port of a pulser/receiver 138 such as, for example, a Panametrics model 5050PR pulser/receiver, is coupled to the imaging control port ofthe ultrasound generator/driver 130. The imaging port of ultrasound generator/driver 130 is coupled to the inner, imaging element of transducer 128. The signal output port of pulser/receiver 138 is coupled to the channel A input port of PC 132. The + sync output port of pulser/receiver 38 is coupled to the Trigger input port of PC 132.

The output of hydrophone 126 is processed using an RF amplifier 142 and a spectrum analyzer 144 such as, for example, a Hewlett-Packard model HP 3585A spectrum analyzer. The output of thermocouple 124 is processed using a thermometry system such as, for example, a Labthermics Technologies model LT-100 multichannel thermometry system 145, and is recorded on a PC 146 such as, for example, a Texas struments model Extensa 515 laptop PC. The temperature ofthe water bath 122 is maintained substantially constant by a closed loop thennometry system including a thermocouple 148, a temperature controller 150 and a heater 152. Illustratively, temperature controller 150 is an Omega model CN9000 A temperature controller and heater 152 is an Aquarium Systems model Visitherm aquarium heater. A water pump (not shown) was used to circulate the water continuously to promote even water temperature.

In some ofthe experiments conducted using this setup, raw RF data for the image was acquired using the Gage A/D board in the PC 132. In these experiments, the A D board received a trigger signal from the ultrasound generator/driver 130. In these experiments, the PC 132 also received a synchronization signal from the ultrasound generator/driver 130 through the PC 132's LPT1 port for digitizing the images. The purpose ofthe hydrophone 126, RF amplifier 142 and spectrum analyzer 144 was to detect half-harmonic emissions, which would indicate that cavitation was taking place in the tissue 120. The setup illustrated in Fig. 24, operating according to the algorithm illustrated in Fig. 23, was used to generate the echo profiles illustrated in Figs. 2-9. The prominent echoes were generated at tissue interfaces. Of course, the character of the tissue from which the composite echo profile illustrated in Fig. 2 was generated was unaffected, since no HIFU treatment had yet been applied. The echo profile illustrated in Fig. 3 was generated after a first duration, illustratively, a half-second of HIFU pulse 20 on-time. The HLFU treatment was stopped, 26, as discussed above, and visualization pulses 28 were directed into the tissue. The composite echo profile illustrated in Fig. 4 was generated. As can be seen from a comparison of Figs. 2, 3 and 4, the tissue was affected somewhat by this first HIFU pulse 20. The effect is most noticeable at a depth corresponding to the 3.5 cm focal length ofthe transducer 128 when it is operated in HLFU mode. After the visualization interval 26 which generated the echo profile illustrated in Fig. 4, another illustratively half-second pulse 20 of HIFU is applied, after which another visualization interval 26 is applied. The effect ofthe second HIFU pulse 20 again is most noticeable in the region ofthe focus ofthe transducer 128 when the transducer 128 is operating in HLFU mode. It will be appreciated from a comparison ofthe echo profiles illustrated in Figs. 4 and 6 that there is some "spreading" ofthe region of tissue affected by the HIFU treatment toward the surface ofthe transducer 128. This is predicted by the regions ofthe false color images illustrated in Figs. 17-22. Continuing, another burst 20 of HLFU is applied to the tissue, followed by another visualization interval 26. The effect of this third burst can be appreciated by comparing the echo profiles illustrated in Figs. 7 and 8. Again, it will be appreciated from a comparison of these Figs, that spreading ofthe region of tissue affected by the HLFU treatment toward the surface ofthe transducer 128 continues. Additionally, the effect ofthe additional pulse of HLFU on the tissue in the region ofthe focal zone ofthe transducer 128 when it is operated in HLFU mode is more pronounced, indicating that the tissue in the focal zone, and continuously back from the focal zone toward the surface ofthe transducer 128 is being affected by the application ofthe HLFU according to this protocol.

We have also found that, owing, we believe, to the buildup of heat from the HLFU treatment in the tissue, the changing ofthe character ofthe tissue continues for some time after the conclusion ofthe HLFU treatment. This is demonstrated by comparing the echo profile illustrated in Fig. 8, the echo profile taken immediately after the application ofthe second HLFU treatment pulse, and Fig. 9, an echo profile generated during the illustratively half-second after the visualization pulses 28 which resulted in the echo profile illustrated in Fig. 8. As can be seen from a comparison of these two profiles, the changing ofthe character ofthe tissue continues even after the conclusion ofthe HLFU treatment. The software algorithm can be made to accommodate this known effect of HIFU treatment according to the invention as well. That is, the continuing change in the character ofthe treated tissue can be characterized, and the algorithm written to predict this continuing change. This effect can result in a somewhat shorter HTFU pulse cycle 20, or in the application of fewer treatment cycles 20, 22, 24, 26, 28, before the effect on the character ofthe tissue is judged sufficient by the treatment algorithm to have achieved the desired treatment.

Claims

CLATJVIS:

1. A method for controlling high intensity focused ultrasound (HLFU) tissue treatment including (a) developing data ofthe untreated tissue, (b) storing the data ofthe untreated tissue, (c) treating the tissue to a cycle of HLFU from at least one ultrasound treatment transducer, (d) developing data of cycle (c), (e) comparing the data developed at (d) to the data stored at (b), (f) repeating steps (c) - (e) until a desired value of a tissue modification parameter is obtained, and (g) providing an indication once the desired value ofthe tissue modification parameter has been obtained.

2. The method of claim 1 wherein developing data ofthe untreated tissue includes using pulse-echo visualization magnitude ultrasound energy and developing the data ofthe untreated tissue from the return echoes.

3. The method of claim 1 further including developing a treatment regimen from the data of the untreated tissue.

4. The method of claim 3 wherein developing a treatment regimen includes establishing at least one ofthe HLFU power and HIFU duty cycle ofthe treatment.

5. The method of claim 4 wherein developing the treatment regimen includes basing the at least one ofthe HLFU power and HLFU duty cycle upon initial assumptions about the value ofthe tissue modification parameter.

6. The method of claim 4 wherein developing the treatment regimen includes testing the tissue to be treated before the application ofthe first cycle of HIFU treatment to determine the initial value ofthe tissue modification parameter.

7. The method of claim 4 wherein developing a treatment regimen includes establishing at least one ofthe HLFU power and HLFU duty cycle ofthe treatment to increase the temperature ofthe tissue a desired amount.

8. The method of claim 5 wherein developing a treatment regimen includes establishing at least one ofthe HLFU power and HLFU duty cycle ofthe treatment to increase the temperature ofthe tissue a desired amount.

9. The method of claim 6 wherein developing a treatment regimen includes establishing at least one ofthe HLFU power and HLFU duty cycle ofthe treatment to increase the temperature ofthe tissue a desired amount.

10. The method of claim 1 wherein treating the tissue to a cycle of HLFU includes treating the tissue to a cycle of HIFU having a duration in the range of about .125 sec. - about .5 sec.

11. The method of claim 10 wherein treating the tissue to a cycle of HLFU includes turning off the HIFU at intervals of about .05 sec - about .1 sec. during the cycle of HIFU for about 50 μsec, and developing during the intervals data ofthe tissue from the portion ofthe cycle of HLFU which has been conducted prior to the intervals.

12. The method of claim 11 wherein developing data ofthe tissue from the portion ofthe cycle of HLFU which has been conducted prior to the intervals includes using pulse-echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated during the portion ofthe cycle of HIFU which has been conducted prior to the intervals from the return echoes.

13. The method of claim 12 wherein developing data ofthe cycle of HLFU includes developing data ofthe tissue treated to a cycle of HIFU using pulse- echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated to a cycle of HLFU from the return echoes.

14. The method of claiml 1 wherein developing data ofthe cycle of HLFU includes developing data ofthe tissue treated to a cycle of HIFU using pulse- echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated to a cycle of HLFU from the return echoes.

15. The method of claim 1 further including processing the data of the untreated tissue before storing the data ofthe untreated tissue.

16. The method of claim 15 wherein processing the data of the untreated tissue before storing the data ofthe untreated tissue includes determining an average value of multiple tissue echo profiles.

17. The method of claimlό further including processing the data of a cycle of HLFU after developing data ofthe cycle of HLFU.

18. The method of claim 17 wherein comparing the data developed from a cycle of HLFU to the stored data includes comparing processed data developed from a cycle of HLFU to processed stored data.

19. The method of claiml 5 further including processing the data of a cycle of HLFU after developing data ofthe cycle of HLFU.

20. The method of claim 19 wherein comparing the data developed from a cycle of HLFU to the stored data includes comparing processed data developed from a cycle of HIFU to processed stored data.

21. The method of claim 1 wherein developing data of the untreated tissue includes developing the tissue modification parameter for the untreated tissue.

22. The method of claim 21 wherein developing data of a cycle of HLFU includes developing the tissue modification parameter for the tissue treated to the cycle of HIFU.

23. The method of claim 1 further including generating an image of the tissue undergoing treatment to provide a visual representation ofthe effect ofthe therapy.

24. The method of claim 23 wherein such an image is generated after each cycle of HLFU.

25. The method of claim 1 wherein (c) treating the tissue to a cycle of HLFU, (d) developing data of cycle (c), (e) comparing the data developed at (d) to the data stored at (b), and (f) repeating steps (c) - (e) until a desired value of a tissue modification parameter is obtained include (c) treating the tissue to a cycle of HLFU, (d) developing data of cycle (c), (e) comparing the data developed at (d) to the data stored at (b), and (f) repeating steps (c) - (e) until a desired value of a tissue modification parameter is obtained in a closed feedback loop, and further including providing a controller for controlling the closed feedback loop, the controller (g) providing an indication once the desired value ofthe tissue modification parameter has been obtained.

26. The method of claim 1 further including providing at least one variable focus ultrasound transducer.

27. The method of claim 26 wherein providing at least one variable focus ultrasound transducer includes providing at least one ultrasound transducer whose focus is determined by the phasing ofthe drive signal to its radiating surface or surfaces.

28. The method of claim 1 , 3, 4, 5, 6, 7, 21 22 or 25 wherein the tissue modification parameter is the attenuation coefficient of tissue between the at least one ultrasound treatment transducer and the tissue being treated.

29. The method of claim 28 further including testing the attenuation coefficient for change greater than a selected threshold, storing the attenuation coefficient, and generating from stored attenuation coefficient data an image ofthe tissue being treated.

30. The method of claim 29 wherein storing the attenuation coefficient includes storing multiple attenuation coefficient data, and generating from stored attenuation coefficient data an image ofthe tissue being treated includes generating a composite image ofthe tissue being treated from the multiple stored data.

31. The method of claim 30 wherein generating from the stored attenuation coefficient data an image ofthe tissue being treated includes generating from the stored attenuation coefficient data a B-mode image or a composite B-mode image ofthe tissue being treated.

32. The method of claim 29 wherein generating from the stored attenuation coefficient data an image ofthe tissue being treated includes generating from the stored attenuation coefficient data a B-mode image or a composite B-mode image ofthe tissue being treated.

33. The method of claim 1 wherein treating the tissue to a cycle of HIFU includes turning off the HLFU at intervals of about .05 sec - about .1 sec. during the cycle of HIFU for about 50 μsec, and developing during the intervals data ofthe tissue from the portion ofthe cycle of HLFU which has been conducted prior to the intervals.

34. The method of claim 33 wherein developing data ofthe tissue from the portion ofthe cycle of HLFU which has been conducted prior to the intervals includes using pulse-echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated during the portion ofthe cycle of HLFU which has been conducted prior to the intervals from the return echoes.

35. The method of claim 34 wherein developing data of the cycle of HLFU includes developing data ofthe tissue treated to a cycle of HLFU using pulse- echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated to a cycle of HIFU from the return echoes.

36. The method of claim 1 wherein developing data ofthe cycle of HLFU includes developing data ofthe tissue treated to a cycle of HLFU using pulse- echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated to a cycle of HLFU from the return echoes.

37. The method of claim 1 further including processing the data of a cycle of HLFU after developing data ofthe cycle of HLFU.

38. The method of claim 37 wherein comparing the data developed from a cycle of HLFU to the stored data includes comparing processed data developed from a cycle of HLFU to processed stored data.

39. Apparatus for controlling high intensity focused ultrasound (HIFU) tissue treatment including at least one ultrasound transducer, a first device coupled to the at least one transducer for driving the at least one transducer, and a second device coupled to the first device to control the first device and to the at least one transducer to receive data of return echoes received by the at least one transducer, the second device controlling the first device to (a) develop data ofthe untreated tissue, (b) store the data ofthe untreated tissue, (c) treat the tissue to a cycle of HLFU from the at least one transducer, (d) develop data of cycle (c), (e) compare the data developed at (d) to the data stored at (b), (f) repeat steps (c) - (e) until a desired value of a tissue modification parameter is obtained, and (g) provide an indication once the desired value ofthe tissue modification parameter has been obtained.

40. The apparatus of claim 39 wherein the second device is a second device for using pulse-echo visualization magnitude ultrasound energy and developing the data ofthe untreated tissue from the return echoes.

41. The apparatus of claim 39 wherein the second device is a second device for developing a treatment regimen from the data ofthe untreated tissue.

42. The apparatus of claim 41 wherein the second device is a second device for developing a treatment regimen by establishing at least one ofthe HLFU power and HLFU duty cycle ofthe treatment.

43. The apparatus of claim 42 wherein the second device is a second device for developing the treatment regimen by basing the at least one ofthe HLFU power and HIFU duty cycle upon initial assumptions about the value ofthe tissue modification parameter.

44. The apparatus of claim 42 wherein the second device is a second device for developing the treatment regimen by testing the tissue to be treated before the application ofthe first cycle of HLFU treatment to determine the initial value ofthe tissue modification parameter.

45. The apparatus of claim 42 wherein the second device is a second device for developing a treatment regimen by establishing at least one ofthe HLFU power and HIFU duty cycle ofthe treatment to increase the temperature ofthe tissue a desired amount.

46. The apparatus of claim 43 wherein the second device is a second device for developing a treatment regimen by establishing at least one ofthe HLFU power and HLFU duty cycle ofthe treatment to increase the temperature ofthe tissue a desired amount.

47. The apparatus of claim 44 wherein the second device is a second device for developing a treatment regimen by establishing at least one ofthe HLFU power and HIFU duty cycle ofthe treatment to increase the temperature ofthe tissue a desired amount.

48. The apparatus of claim 39 wherein the second device is a second device for treating the tissue to a cycle of HLFU having a duration in the range of about .125 sec. - about .5 sec.

49. The apparatus of claim 48 wherein the second device is a second device for treating the tissue to a cycle of HLFU by turning off the HLFU at intervals of about .05 sec - about .1 sec. during the cycle of HLFU for about 50 μsec, and developing during the intervals data ofthe tissue from the portion ofthe cycle of HLFU which has been conducted prior to the intervals.

50. The apparatus of claim 49 wherein the second device is a second device for developing data ofthe tissue from the portion ofthe cycle of HLFU which has been conducted prior to the intervals by using pulse-echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated during the portion ofthe cycle of HLFU which has been conducted prior to the intervals from the return echoes.

51. The apparatus of claim 50 wherein the second device is a second device for developing data ofthe tissue treated to a cycle of HLFU using pulse- echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated to a cycle of HIFU from the return echoes.

52. The apparatus of claim 49 wherein the second device is a second device for developing data ofthe tissue treated to a cycle of HIFU using pulse- echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated to a cycle of HIFU from the return echoes.

53. The apparatus of claim 39 wherein the second device is a second device for processing the data ofthe untreated tissue before storing the data of the untreated tissue.

54. The apparatus of claim 53 wherein the second device is a second device for processing the data ofthe untreated tissue before storing the data of the untreated tissue by determining an average value of multiple tissue echo profiles.

55. The apparatus of claim 54 wherein the second device is a second device for processing the data of a cycle of HLFU after developing data ofthe cycle of HIFU.

56. The apparatus of claim 55 wherein the second device is a second device for comparing the data developed from a cycle of HLFU to the stored data by comparing processed data developed from a cycle of HIFU to processed stored data.

57. The apparatus of claim 53 wherein the second device is a second device for processing the data of a cycle of HLFU after developing data ofthe cycle of HLFU.

58. The apparatus of claim 57 wherein the second device is a second device for comparing the data developed from a cycle of HLFU to the stored data by comparing processed data developed from a cycle of HLFU to processed stored data.

59. The apparatus of claim 39 wherein the second device is a second device for developing data ofthe untreated tissue by developing the tissue modification parameter for the untreated tissue.

60. The apparatus of claim 59 wherein the second device is a second device for developing data of a cycle of HIFU by developing the tissue modification parameter for the tissue treated to the cycle of HLFU.

61. The apparatus of claim 39 wherein the second device is a second device for generating an image ofthe tissue undergoing treatment to provide a visual representation ofthe effect ofthe therapy.

62. The apparatus of claim 61 wherein the second device is a second device for generating such an image after each cycle of HLFU.

63. The apparatus of claim 39 wherein the at least one transducer, the first device and the second device are coupled in a closed feedback loop, the second device controlling the closed feedback loop.

64. The apparatus of claim 39 wherein the at least one transducer includes at least one variable focus ultrasound transducer.

65. The apparatus of claim 64 wherein the first and second devices control the at least one variable focus transducer by the phasing ofthe drive signal to the at least one variable focus transducer's radiating surface or surfaces.

66. The apparatus of claim 39, 41, 42, 43, 44, 45, 59, 60 or 63 wherein the second device for repeating steps (c) - (e) until a desired value of a tissue modification parameter is obtained is a second device for repeat steps (c) - (e) until a desired value ofthe attenuation coefficient of tissue between the at least one ultrasound treatment transducer and the tissue being treated is obtained.

67. The apparatus of claim 66 wherein the second device is a second device for testing the attenuation coefficient for change greater than a selected threshold, storing the attenuation coefficient, and generating from stored attenuation coefficient data an image of the tissue being treated.

68. The apparatus of claim 67 wherein the second device for storing the attenuation coefficient is a second device for storing multiple attenuation coefficient data, and for generating from stored attenuation coefficient data a composite image ofthe tissue being treated from the multiple stored data.

69. The apparatus of claim 68 wherein the second device for generating from the multiple stored attenuation coefficient data a composite image of the tissue being treated is a second device for generating from the multiple stored attenuation, coefficient data a B-mode image or a composite B-mode image ofthe tissue being treated.

70. The apparatus of claim 67 wherein the second device for generating from the stored attenuation coefficient data a composite image ofthe tissue being treated is a second device for generating from the stored attenuation coefficient data a B-mode image or a composite B-mode image ofthe tissue being treated.

71. The apparatus of claim 39 wherein the second device is a second device for treating the tissue to a cycle of HIFU by turning off the HLFU at intervals of about .05 sec - about .1 sec. during the cycle of HLFU for about 50 μsec, and developing during the intervals data ofthe tissue from the portion ofthe cycle of HIFU which has been conducted prior to the intervals.

72. The apparatus of claim 71 wherein the second device is a second device for developing data ofthe tissue from the portion ofthe cycle of HIFU which has been conducted prior to the intervals by using pulse-echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated during the portion ofthe cycle of HLFU which has been conducted prior to the intervals from the return echoes.

73. The apparatus of claim 72 wherein the second device is a second device for developing data ofthe cycle of HIFU by developing data ofthe tissue treated to a cycle of HIFU using pulse-echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated to a cycle of HLFU from the return echoes.

74. The apparatus of claim 39 wherein the second device is a second device for developing data ofthe cycle of HLFU by developing data ofthe tissue treated to a cycle of HLFU using pulse-echo visualization magnitude ultrasound energy and developing the data ofthe tissue treated to a cycle of HLFU from the return echoes.

75. The apparatus of claim 39 wherein the second device is a second device for processing the data of a cycle of HLFU after developing data ofthe cycle of HLFU.

76. The apparatus of claim 75 wherein the second device is a second device for comparing the data developed from a cycle of HLFU to the stored data by comparing processed data developed from a cycle of HLFU to processed stored data.