Patent Description:
Applications of the present invention relate to acoustic field characterization, measurement, and mapping. More specifically, the present invention relates to apparatus for use while a focal region of high intensity focused ultrasound (HIFU) energy is applied.

High intensity focused ultrasound (HIFU), also known as high intensity therapeutic ultrasound (HITU), is a method for non-invasive treatment of internal organs and tissue, e.g., tumors. Ultrasound energy is often used as well for imaging of internal organs and tissue. An ultrasonic A-line, also known as an RF-line, is acquired by using an ultrasound transducer to send an ultrasonic pulse into a medium or a subject's body and receiving an echo of the pulse reflecting off of inhomogeneities within the medium, e.g., a scatterer, a particle, or a boundary. The echo data is detected by the transducer, digitized, and processed. The length of time it takes the echo to reach the ultrasound transducer is indicative of the distance between the transducer and the inhomogeneity. Multiple A-lines, e.g., <NUM> A-lines, at equally spaced positions and angles, may be used to create a sonogram.

An ultrasonic A-line may be repeatedly pulsed at a pulse repetition frequency (PRF). For any given A-line, a desired penetration depth will limit the PRF, i.e., will limit the time between successive pulses, as each pulse generally cannot be sent before the echo from the immediately previous pulse has been received. If a target, off of which the A-line pulse is reflecting, is moving then the respective echoes from two successive pulses echoing off the target will be shifted (translated) in time. If the velocity of the target is constant over the time interval between the two pulses, then the velocity of the target will be proportional to the shift in time and may be calculated.

A <NPL>et al. , describes a blood flow imaging system that combines a conventional pulsed Doppler device and an autocorrelator. Blood flow within a given cross section of a live organ is described as being displayed in real time, with the direction of blood flow and its variance expressed by means of a difference in color and hue respectively. Experiments were conducted with a mechanical and an electrical scanner using phantoms, and a good agreement with the theory is described as being obtained. Studies on clinical significance for normal and diseased hearts are described as having successful results.

A <NPL>et al. , describes that real-time blood flow imaging has become possible thanks to the development of a velocity estimator based on phase-shift measurements of successive echoes, but that the method suffers from well-known limitations of pulse-Doppler instruments. The article presents a new formulation that describes the pulse-Doppler effect on the successive echoes from a cloud of moving targets as a progressive translation in time due to the displacement of the scatterers between two excitations.

The approach is described in the article as allowing the efficient generation of computer-simulated data in order to accurately evaluate various processing techniques. Furthermore, the approach is described as leading to a novel class of velocity estimators in the time domain which measure the time shifts which are proportional to the local blood velocity. A local cross-correlation function is first calculated from a pair of range-gated echoes, and the time shift is then determined by searching for the time position with the maximum correlation. The time-correlation technique is described as providing accurate velocity profiles with broadband transducers. The article describes that classical velocity limitations of pulse-Doppler are overcome because there is no ambiguity in measuring a time shift instead of a phase shift.

The dissertation of <NPL>, describes additional ultrasound techniques.

A <NPL>, describes the implementation of real-time blood velocity estimators using time-domain cross-correlation. An algorithm is presented for doing stationary echo canceling, cross-correlation estimation, and subsequent velocity estimation. Sampled data acquired at rates of approximately <NUM> are used in the algorithm. The algorithm is analyzed with regard to the high sampling frequency, and a method for performing real-time high-speed data movement and cross-correlation is suggested. Implementation schemes based on using the sign of the data as well as the full precision are proposed. From analysis of the process, the article concludes that the sign data implementation can attain real-time processing. The article describes that real-time processing can be obtained for the full precision data as well, but at the expense of using a number of dedicated signal processing chips. Both implantations suggested are described as being able to handle the estimation of velocities for A-lines acquired from multiple directions.

<CIT> relates to ultrasound imaging, and discloses systems for providing feedback for high intensity focused ultrasound.

<CIT> relates to an ultrasonic therapy apparatus for high intensity focused ultrasound and ultrasound images.

<CIT> relates to noise-free real time ultrasonic imaging of a treatment site undergoing high intensity focused ultrasound therapy.

<CIT> relates to an ultrasonic medical apparatus that measures coagulation of a tissue.

<CIT> relates to systems and methods for making noninvasive physiological assessments from data acquired by detecting acoustic properties of tissue using ultrasound interrogation pulses.

In accordance with the present invention, there is provided apparatus for use with a focal region of high intensity focused ultrasound energy, as defined in appended claim <NUM>. Embodiments of the present invention are defined in appended claims dependent on independent claim <NUM>.

Methods are described and apparatus provided for assessing a characteristic, e.g., displacement amplitude, particle-velocity, or intensity, of an acoustic field, in accordance with some applications of the present disclosure. A first acoustic transducer generates a first acoustic field at a first frequency in a region of a medium, which generates oscillatory motion of scatterers disposed within the medium in the region, each scatterer oscillating around a respective equilibrium position. The oscillatory motion of these particles is known as the particle-velocity of the acoustic field and the oscillations occur at the frequency of the first acoustic field. A second acoustic transducer transmits successive pulses into the region and receives respective echoes of each pulse scattering off an oscillating scatterer in the region. Each acoustic pulse has a center frequency that is higher than the first frequency.

In accordance with some applications of the present disclosure, two pulses that are synchronized with the first acoustic field are used to obtain a measurement of the displacement amplitude of the oscillating scatterer. The time interval between the transmission of first and second pulses is n+<NUM> times the period of the first acoustic field, n being a positive integer that is at least <NUM> and/or less than or equal to <NUM>, and the two pulses are synchronized with the first acoustic field such that the first pulse scatters off the oscillating scatterer when the oscillating scatterer is at a first displacement extremum, e.g., a maximum positive displacement, with respect to the equilibrium position, and the second pulse scatters off the oscillating scatterer when the oscillating scatterer is at a second displacement extremum that is opposite the first displacement extremum, e.g., a maximum negative displacement, with respect to the equilibrium position. Due to the motion of the oscillating scatterer and the synchronization with the first acoustic field, the displacement that the scatterer undergoes in the time interval between the two pulses is the displacement amplitude of the scatterer. The respective echoes are received at different respective times, each echo being measured from the time that its respective pulse was transmitted. A computer processor is used to extract the time shift between the received echoes and, based on the extracted time shift, calculate the displacement amplitude of the oscillating scatterer.

Alternatively, in accordance with some applications of the present disclosure, the acoustic pulses are not synchronized with the first acoustic field, e.g., the acoustic pulses are not equally spaced in time and/or are not transmitted at controlled time intervals. The second transducer may transmit at least <NUM> acoustic pulses into the region, and receive respective echoes of each pulse scattering off an oscillating scatterer. A computer processor is used to extract a series of time shifts. Each time shift in this case may be between any two of the received echoes. A series of displacements may be estimated based on the extracted time shifts, and statistical analysis may be applied to derive the displacement amplitude of the oscillating scatterer.

In accordance with some applications of the present disclosure, apparatus is provided for determining the location and size of a focal region of HIFU energy emitted at a first frequency into a region in a medium. Location and size of the focal region can be determined by mapping the displacement amplitude, or velocity amplitude of particles in the acoustic field generated by the HIFU energy using acoustic pulses that are transmitted into the region, each pulse having a center frequency that is higher than the first frequency. Imaging ultrasound may be used for guidance of the focal region during treatment. A first acoustic transducer emits HIFU energy to generate a first acoustic field in the region, generating oscillatory motion of scatterers in the region, and an acoustic probe is used for generating imaging ultrasound. Either the acoustic probe or a second transducer transmits two acoustic pulses that are synchronized with the first acoustic field as described hereinabove, and receives respective echoes of the pulses scattering off an oscillating scatterer in the region. A computer processor is used to (a) generate a real-time sonogram of the medium, (b) extract a time shift between the received echoes, (c) based on the extracted time shift, calculate a displacement amplitude of the first acoustic field in the region, and (d) generate a map of displacement amplitudes on a portion of the sonogram corresponding to the region. The area within the region having the highest displacement amplitude corresponds to the area where the intensity of the HIFU energy is the highest, i.e., the focal region of the HIFU energy.

There is therefore provided, in accordance with some applications of the present invention, apparatus for use with a focal region of high intensity focused ultrasound (HIFU) energy, the apparatus including:.

For some applications, the acoustic element includes the second ultrasound transducer.

For some applications, the acoustic element includes the acoustic probe.

For some applications, the acoustic element includes the first ultrasound transducer.

For some applications, the first frequency is <NUM> - <NUM>.

For some applications, the center frequency of each pulse is at least <NUM> to <NUM> higher than the first frequency.

For some applications, the imaging frequency is <NUM> - <NUM>.

For some applications, the computer processor is further configured to (a) based on the displacement amplitude, calculate a velocity amplitude of the first acoustic field in the region, and (b) generate a map of velocity amplitudes on a portion of the sonogram corresponding to the region.

For some applications, the computer processor is further configured to (a) based on the velocity amplitude, calculate an intensity of the first acoustic field in the region, and (b) generate a map of intensities of the first acoustic field on a portion of the sonogram corresponding to the region.

For some applications, the medium is tissue of a body of a subject and wherein the first ultrasound transducer is configured to cause a therapeutic effect in the tissue by emitting the HIFU energy into the tissue.

For some applications, the oscillating scatterer is an inhomogeneity in the tissue.

For some applications, the first ultrasound transducer is configured to cause the therapeutic effect in the tissue by heating the tissue.

For some applications, the computer processor is further configured to monitor a change in a mechanical property of the tissue by monitoring a time variation of the displacement amplitude; and
in response to the monitoring, terminating the first acoustic field when the mechanical property of the tissue reaches a threshold value.

For some applications, the mechanical property of the tissue is mechanical impedance of the tissue, and wherein the computer processor is configured to (a) monitor a change in the mechanical impedance of the tissue by monitoring a time variation of the displacement amplitude, and (b) in response to the monitoring, terminate the first acoustic field when the mechanical impedance of the tissue reaches a threshold value.

For some applications, the computer processor is configured to monitor the change in the characteristic over a time period that is <NUM> - <NUM> seconds long.

For some applications, the computer processor is configured to vary a duration of a HIFU-pulse of the HIFU energy, such that when the first ultrasound transducer operates in the therapeutic mode the duration of the HIFU-pulse is longer than the duration of the HIFU-pulse is when the first ultrasound transducer operates in the calibration mode.

For some applications, the computer processor is configured to vary a duty-cycle of the HIFU energy, such that when the first ultrasound transducer operates in the therapeutic mode the duty-cycle is higher than the duty-cycle is when the first ultrasound transducer operates in the calibration mode.

For some applications, the computer processor is configured to vary a power of the HIFU energy, such that when the first ultrasound transducer operates in the therapeutic mode the power of the HIFU energy is higher than the power of the HIFU energy is when the first ultrasound transducer operates in the calibration mode.

For some applications, the computer processor is configured to monitor the tissue when the first ultrasound transducer operates in the therapeutic mode and to vary the parameters of the therapeutic mode according to the monitoring in order to alter an effect on the tissue.

For some applications, the apparatus includes a targeting unit configured to move the focal region of the HIFU energy when the first ultrasound transducer operates in the calibration mode.

For some applications, the targeting unit is configured such that manual movement of the targeting unit moves the focal region of the HIFU energy within the medium by moving the first ultrasound transducer with respect to the medium.

For some applications, the targeting unit includes (i) a first-transducer controller and (ii) targeting circuitry configured to (a) obtain data corresponding to the focal region of the HIFU energy on a map selected from the group consisting of: the map of displacement amplitudes, the map of velocity amplitudes, and the map of intensities, (b) obtain data corresponding to a target location in the medium, and (c) send an electric signal to the first-transducer controller, wherein the first-transducer controller is configured to receive the electric signal and in response thereto move the focal region of the HIFU energy toward the target location within the medium.

For some applications, the first-transducer controller is configured to (a) move the focal region of the HIFU energy with respect to the first ultrasound transducer, and (b) change a size of the focal region of the HIFU energy by applying phased-array control to the HIFU energy emitted by the first ultrasound transducer.

For some applications, the first-transducer controller is configured to move the focal region of the HIFU energy by moving the first ultrasound transducer with respect to the medium.

For some applications, the apparatus further includes a single housing to which the first ultrasound transducer and the acoustic element are coupled, wherein the housing aligns the first acoustic field and the acoustic pulses to be parallel or anti-parallel.

An acoustic field propagating in a medium generates oscillatory motion of particles, or scatterers, within the medium, a phenomenon known as the particle-velocity of the acoustic field. The oscillations occur at the frequency of the acoustic field. The intensity of the acoustic field relates to (a) pressure p and (b) particle-velocity u. In harmonic fields, with frequency f, particle-velocity amplitude U is related to displacement amplitude D, as shown hereinbelow in Equation <NUM>. Pressure and particle-velocity are related through the mechanical impedance of the medium, by the equation Z = p/u. Therefore, assuming a medium of constant mechanical impedance Z, the displacement amplitude and the velocity amplitude of the oscillating scatterers in a region of higher intensity are higher than the displacement amplitude and velocity amplitude of the oscillating scatterers are in a region of lower intensity, i.e., in regions with constant mechanical impedance Z, the particle-velocity of the acoustic field is highest in the region of highest intensity within the field.

Intensity of an acoustic field is the product of pressure p and particle-velocity u, as given by the following equation: <MAT> where I is the instantaneous intensity at some position in space, p is the pressure, and u is the particle-velocity at that position.

The local complex mechanical impedance Z of the medium is defined by: <MAT> where p and u are the complex amplitudes of harmonic waves of pressure and particle-velocity correspondingly, at a specific frequency. Mechanical impedance Z is a characteristic of the medium, and it may be position-dependent and frequency-dependent. An illustrative example, utilizing numbers that are close to those of therapeutic ultrasound, is as follows:.

The time-averaged intensity of the acoustic field can be written in the form: <MAT> providing intensity I in terms of pressure amplitude p. Equivalently, pressure p can be substituted in Equation <NUM> by the product of impedance Z and particle-velocity u to derive <MAT> which gives intensity I in terms of particle-velocity u.

Particle-velocity u is a function of intensity I and impedance Z, as given by the following equation: <MAT> thus, for a given intensity I, changes in impedance Z will result in a change in particle-velocity u.

The position z(t) of the oscillating scatterer at a given point in time t may be written in the form: <MAT> where z0 is the equilibrium position of the scatterer, D is the displacement amplitude measured from the equilibrium position, phi is phase, and f is the frequency of the acoustic field.

In harmonic fields, with frequency f, particle velocity u(t) may be written in the form: <MAT> where U is the particle-velocity amplitude U.

Particle velocity amplitude U is related to displacement amplitude D, as given by the following equation: <MAT>.

Reference is now made to <FIG>, which is a schematic illustration of first acoustic transducer <NUM> transmitting a first acoustic field <NUM> into a region <NUM> of a medium <NUM>, an oscillating scatterer <NUM> in region <NUM>, and a second acoustic transducer <NUM> transmitting a diagnostic field <NUM> into the region and transmitting acoustic pulses toward oscillating scatterer <NUM>. First acoustic transducer <NUM> and second acoustic transducer <NUM> may be coupled to a single housing, such as housing <NUM> in <FIG>, that aligns first acoustic field <NUM> and the acoustic pulses to be parallel or anti-parallel, i.e., housing <NUM> aligns the axis of first acoustic field <NUM> and the direction of propagation of the acoustic pulses to be parallel or anti-parallel. First acoustic transducer <NUM> transmits first acoustic field <NUM>, e.g., by emitting high intensity focused ultrasound (HIFU) energy, into region <NUM> at a first frequency f1, which is typically at least <NUM> and/or less than <NUM>. First acoustic field <NUM> may be, for example, a focused field with a focal point or focal volume positioned some distance in front of the transducer. First acoustic field <NUM> generates oscillatory motion of scatterers, such as scatterer <NUM>, disposed in region <NUM>. The oscillations of the scatterers is the particle-velocity of first acoustic field <NUM>, and is a fundamental characteristic of the acoustic field. The scatterers oscillate at first frequency f1, each scatterer oscillating around a respective equilibrium position, such as equilibrium position z0 shown in <FIG>.

For some applications, second acoustic transducer <NUM> generates A-lines by transmitting acoustic pulses into region <NUM>, such as first acoustic pulse <NUM> and second acoustic pulse <NUM> shown in <FIG>. First and second acoustic pulses <NUM> and <NUM> each have a center frequency f2 that is higher than first frequency f1, e.g., at least <NUM> and/or less than <NUM> times higher than first frequency f1. The time interval between successive A-lines, e.g., the time interval between first acoustic pulse <NUM> and second acoustic pulse <NUM>, is n+<NUM> times the period T1 of first acoustic field <NUM>, where n is a positive integer. Setting the time interval to be n+<NUM> times period T1 means the scatterer will perform exactly n+<NUM> oscillations between the A-lines. If first acoustic pulse <NUM> and second acoustic pulse <NUM> are synchronized with first acoustic field <NUM>, as further described hereinbelow with respect to <FIG>, then each pulse will scatter off scatterer <NUM> when scatterer <NUM> is either at a maximum negative position z- in its trajectory or at a maximum positive position z+ in its trajectory.

Reference is now made to <FIG>, which is a graph showing multiple A-lines on the x-axis and the time at which each respective echo was received by the second transducer on the y-axis. Synchronization with first acoustic field <NUM>, as further described hereinbelow with respect to <FIG>, enables receiving a first echo from first pulse <NUM> scattering off scatterer <NUM> at maximum negative position z-, and a second echo from second pulse <NUM> scattering off scatterer <NUM> at maximum positive position z+. By way of example, <NUM> A-lines are shown on the graph, with equal time intervals Tprf between them, Tprf being equal to n+<NUM> times period T1. Due to the synchronization, echoes <NUM> from A-lines <NUM>, <NUM>, <NUM>, and <NUM> are received from an acoustic pulse scattering off scatterer <NUM> at z-, and echoes <NUM> from A-lines <NUM>, <NUM>, <NUM>, and <NUM> are received from an acoustic pulse scattering off scatterer <NUM> at z+. The respective received echoes from each A-line are plotted against time on the y-axis, representing the time at which each respective echo is received, each time measured with respect to the time each respective pulse was transmitted. A time shift dT between successive echoes emerges. The time scale of <NUM> - <NUM> microseconds is shown as an arbitrary example.

Reference is now made to <FIG>, which is a schematic illustration of synchronization between the acoustic pulses and first acoustic field <NUM>. During the oscillations of each scatterer under influence of first acoustic field <NUM>, each scatterer reaches a maximum positive displacement z0+D from equilibrium position z0 and a maximum negative displacement z0-D from equilibrium position z0. The total displacement of each oscillating scatterer is therefore equal to 2D. The oscillations are consistent in time and would appear as a continuous sine wave when displacement Z(t) is plotted against time (t); however, for the purpose of clearly showing synchronization, as described hereinbelow, only a few distinct periods of the oscillation appear in <FIG>.

First pulse <NUM> and second pulse <NUM> may be synchronized with first acoustic field <NUM> such that (a) first pulse <NUM> scatters off an oscillating scatterer, such as scatterer <NUM> in <FIG>, when scatterer <NUM> is at a first displacement extremum <NUM>, e.g., maximum positive displacement +D, with respect to equilibrium position z0, and (b) second pulse scatters off scatterer <NUM> when scatterer <NUM> is at a second displacement extremum <NUM> that is opposite the first displacement extremum, e.g., maximum negative displacement -D, with respect to equilibrium position z0. Pulse <NUM>' represents first acoustic pulse <NUM> scattering off scatterer <NUM> when scatterer <NUM> is located at first displacement extremum <NUM>. Pulse <NUM>' represents second acoustic pulse <NUM> scattering off scatterer <NUM> when scatterer <NUM> is located at second displacement extremum <NUM>. Echo <NUM> is the echo received from first acoustic pulse <NUM>, and echo <NUM> is the echo received from second acoustic pulse <NUM>.

Time interval Tprf between first and second acoustic pulses <NUM> and <NUM> is limited by a desired penetration depth. Between each transmitted pulse there must be at least enough time for the first transmitted pulse to reach the penetration depth, scatter off the scatterer, and for the echo to be received. For example, Tprf is likely to be at least <NUM> microseconds, i.e., the A-lines are pulsed at a PRF of less than <NUM>, while first frequency f1 of first acoustic field <NUM> may be as high as <NUM>. Therefore scatterer <NUM> may exhibit hundreds of oscillations between each A-line. Synchronizing the pulses with first acoustic field <NUM>, as described hereinabove, allows the scatterer to perform n+<NUM> oscillations while still ensuring that each echo is received from the scatterer when it is at a displacement extremum. The synchronization includes (a) setting the time intervals Tprf to be n+<NUM> times period T1, as well as (b) synchronizing the pulses with the phase of oscillations to ensure that after the n+<NUM> oscillations the scatterer is at an extremum of its displacement and not, for example, at equilibrium position z0.

The result is that between each pair of received echoes, scatterer <NUM> undergoes a total displacement of 2D. Echo <NUM> is received at time t1 after the transmission of first acoustic pulse <NUM>, and echo <NUM> is received at time t2 after the transmission of second acoustic pulse <NUM>. Time shift dT is equal to t2-t1 and is related to displacement 2D of the scatterer. At least one computer processor <NUM> is used to extract time shift dT between the received echoes and based on extracted time shift dT, calculate displacement amplitude D of oscillating scatterer <NUM>, which is related to the local particle velocity (Equation <NUM>), and therefore to the local intensity of first acoustic field <NUM> at the location of the oscillating scatterer (Equation <NUM>). The location of oscillating scatterer <NUM> refers to a location in region <NUM> that includes the entire space over which the oscillating scatterer is oscillating. Computer processor <NUM> outputs, or drives an output device such as output device <NUM> shown in <FIG> to output, an indication of the displacement amplitude D of oscillating scatterer <NUM>.

Displacement D may be used to derive at least one parameter of first acoustic field <NUM>, such as velocity amplitude. Based on the displacement amplitude D, computer processor <NUM> may use Equation <NUM> to calculate a velocity amplitude of oscillating scatterer <NUM>. Knowing the mechanical impedance of the medium, computer processor <NUM> may also use Equation <NUM> to calculate intensity of first acoustic field <NUM> at the location of oscillating scatterer <NUM>, or use Equation <NUM> to calculate pressure of first acoustic field <NUM> at the location of oscillating scatterer <NUM>. If a pressure amplitude at the location of oscillating scatterer <NUM> is known, then computer processor <NUM> may use Equation <NUM> to calculate the mechanical impedance of the medium at the location of oscillating scatterer <NUM>. Computer processor <NUM> outputs, or drives an output device such as output device <NUM>, to output indications of the abovementioned parameters of first acoustic field <NUM>, e.g., velocity amplitude, intensity, and mechanical impedance in terms of root-mean-squared value, variance, maximum value, peak-to-peak value, amplitude, and/or phase.

For some applications, second acoustic transducer <NUM> transmits a plurality of pairs of first and second acoustic pulses <NUM> and <NUM> in a plurality of respective directions in region <NUM>, and receives respective echoes of each pulse scattering off respective oscillating scatterers. Each pair of pulses is synchronized with first acoustic field <NUM> as described hereinabove. Computer processor <NUM> extracts respective time shifts dT between respective pairs of received echoes <NUM> and <NUM>. Based on the extracted time shifts, computer processor <NUM> may calculate respective displacement amplitudes D of the respective oscillating scatterers, and output, or drive an output device to output, respective indications of the respective displacement amplitudes, and generate a two-dimensional image, e.g., a map, of the respective displacement amplitudes in the region.

As described hereinabove, respective velocity amplitudes of the respective oscillating scatterers may be calculated based on the respective displacement amplitudes, and respective intensities of first acoustic field <NUM> in the region may be calculated based on the respective velocity amplitudes. Computer processor <NUM> can output, or drive an output device to output, respective indications of the velocity amplitudes and intensities, and generate respective two-dimensional images, e.g., respective maps, of the respective velocity amplitudes in the region and the respective intensities of first acoustic field <NUM> in the region.

For some applications, second acoustic transducer <NUM> may be, for example, a linear array probe, a convex array probe, a phased array probe, or any other standard design for a diagnostic probe that is configured for beam-forming and pulse-echo operation, including color-Doppler imaging. Computer processor <NUM> is configured to work in pulse-echo mode and to perform beam forming techniques in order to acquire the echo data from a specific location in medium <NUM>. Usually, the same array of piezoelectric elements is used for generating a sonogram and the respective maps of first acoustic field <NUM>: first, the sonogram is generated using pulse-echo ultrasound at an imaging frequency, and then, the respective maps are generated as described hereinabove. The sonogram provides guidance capabilities. For example, a target location <NUM>, e.g., a tumor, can be seen on the sonogram, and the focal region of first acoustic field <NUM> can be seen on the map. When fused into one image, real-time feedback of the location of the focal region with respect to target location <NUM> is provided. A targeting unit, such as is shown in <FIG> may be used to move the focal region to target location <NUM>.

It is noted that apparatus may be sold including second acoustic transducer <NUM> and computer processor <NUM> but not first acoustic transducer <NUM>. Such apparatus would have all the same properties as described above. In such a case, second acoustic transducer <NUM> together with computer processor <NUM> may be used to assess a characteristic, e.g., displacement amplitude, or particle-velocity, of an already-existing first acoustic field.

For some applications, displacement amplitude D of oscillating scatterer <NUM> may be obtained without synchronization of the acoustic pulses with first acoustic field <NUM>. Second acoustic transducer <NUM> may transmit at least <NUM> acoustic pulses, e.g., less than <NUM> acoustic pulses, into region <NUM>. Each pulse has a center frequency that is at least <NUM> and/or less than <NUM> times higher than first frequency f1 of first acoustic field <NUM>. Respective echoes of each pulse scattering off an oscillating scatterer, such as scatterer <NUM>, are received by second acoustic transducer <NUM>. Computer processor <NUM> extracts a series of time shifts. Each individual time shift in the series does not have to be between two successive echoes, rather each time shift can be between any two of the received echoes. For example, if <NUM> echoes are received, then a total of <NUM> time shifts dT can be extracted, e.g., between echoes <NUM> and <NUM>, <NUM> and <NUM>, <NUM> and <NUM>, <NUM> and <NUM>, <NUM> and <NUM>, <NUM> and <NUM>, <NUM> and <NUM>, <NUM> and <NUM>, <NUM> and <NUM>, and <NUM> and <NUM>. For some applications, computer processor <NUM> selects two of the received echoes between which is the largest time shift.

A series of respective displacement amplitudes of scatterer <NUM> may be estimated based on the extracted series of time shifts, and then statistical analysis is used to derive the displacement amplitude of oscillating scatterer <NUM>. Once the displacement amplitude is derived computer processor <NUM> outputs, or drives an output device to output, an indication of the displacement amplitude. As described hereinabove, once the displacement amplitude of the oscillation has been obtained, the velocity amplitude of the oscillation, and intensity at the location of the scatterer may be calculated, and respective maps of first acoustic field <NUM> generated.

Standard algorithms, such as autocorrelation for phase-detection as described in the abovementioned Kasai reference, describe the calculation of an assumed constant flow velocity from a derived phase shift, using the equation <MAT> which gives the parallel component of the velocity in terms of the phase phi(T) that is acquired during the time T, where T is the time between successive A-Lines (Tprf), and f is the center frequency of the pulse. In the case of particle-velocity, however, velocity is not constant over the time interval between successive A-lines. Therefore, in accordance with some applications of the present disclosure, the displacement amplitude D is calculated using: <MAT> and the particle-velocity amplitude U is calculated using: <MAT> where f1 is the frequency of the first acoustic field <NUM>.

Similarly, cross-correlation algorithms, such as described in the above mentioned Bonnefous reference, usually derive the time shift dT and use it to estimate an assumed constant velocity by: <MAT> In the case of particle-velocity, the time shift is used to derive displacement amplitude D by: <MAT> and the particle-velocity amplitude U by: <MAT>.

Reference is now made to <FIG>, which is a graph showing <NUM> A-lines and with respective echoes shown on the A-lines, and <FIG>, which is a graph showing the value of a received signal Sk(n) for a specific sample point n across successive A-lines, where k is the index number of the A-line. For example, a sample point number <NUM> on the second A-line is written as S2(<NUM>), and the same sample point on the third A-line is written as S3(<NUM>). The index n can have values of from <NUM> to N-<NUM>, where N is the total number of sample points in the A-line. <FIG> shows <NUM> successive A-lines, all transmitted from the same direction but at different times, with time interval Tprf between each pair of lines being constant. By way of example, the length of each A-line is <NUM> microseconds and the sampling frequency for each A-line is <NUM>; therefore, there are <NUM> nanoseconds between samples along each A-line and a total of <NUM>,<NUM> sample points on each A-line. An echo is detected on each A-line from a single scatterer, such as scatterer <NUM>, that exhibits oscillations in space. The pulses are synchronized with first acoustic field <NUM>, as described hereinabove, so that odd echoes are received from the scatterer at maximum negative position z- and even echoes are received from the scatterer at maximum positive position z+. Accordingly, the respective times of the received echoes alternate back and forth, with a time shift dT emerging that is related to the total displacement 2D of oscillating scatterer <NUM>. The dashed horizontal line N in <FIG> represents a specific sample point number n=M across the successive A-lines, the value of M representing a specific depth in medium <NUM>. S1(M) is the sample point number M on the first A-line, and S2(M) is the same sample point number M on the second A-line. The graph in <FIG> shows the variation of the signal value of sample point number M over successive A-lines. As can be seen in <FIG>, S1(M) is at a maximum on the echo e1 on the first A-line, and S2(M) is at a minimum on the echo e2 on the second A-line. Correspondingly, as shown in <FIG>, signal value v1 of sample point S1(M) is at a maximum value and signal value v2 of sample point S2(M) is at a minimum value. Across the successive A-lines, the sampling point number M on the odd-numbered A-lines all have approximately the same value, and the sampling point number M on the even-numbered A-lines all have approximately the same value (that is different from the value on the odd-numbered A-lines). An amplitude A of the variation of the signal from the same sample point across the successive A-lines is related to displacement amplitude D of oscillating scatterer <NUM>, and can be written in the form: <MAT> where f2 is the center frequency of the pulse, D is the displacement amplitude of the oscillating scatterer, and c is the speed of sound in the medium. The variation is at a frequency of PRF/<NUM>, as can be seen in <FIG>.

Reference is now made to <FIG>, which is a schematic illustration of a HIFU transducer and an acoustic probe both placed against skin of a subject, according to some applications of the present invention. Apparatus is provided for determining in real-time the location and size of a focal region <NUM> of a beam of HIFU energy <NUM> within region <NUM> of medium <NUM>. It is noted that described hereinbelow is a method for locating focal region <NUM> in real-time without the use of magnetic resonance imaging (MRI). (MRI is a more expensive way of achieving a corresponding result. ) An ultrasound transducer <NUM> generates first acoustic field <NUM> (such as is shown in <FIG>) into region <NUM> of medium <NUM> of a subject, by emitting HIFU energy <NUM> into region <NUM> at first frequency f1. HIFU energy <NUM> generates oscillatory motion of scatterers within medium <NUM>, e.g., tissue <NUM> of a subject, the scatterers oscillating at first frequency f1. Typically, ultrasound transducer <NUM> emits HIFU energy <NUM> at a frequency of at least <NUM> and/or less than <NUM>. An acoustic probe <NUM> emits pulse-echo ultrasound energy <NUM> into medium <NUM> at an imaging frequency, e.g., at a frequency of at least <NUM> and/or less than <NUM>. Ultrasonic A-lines, such as A-line <NUM>, comprising acoustic pulses, such as first acoustic pulse <NUM> and second acoustic pulse <NUM> as described hereinabove, are transmitted into region <NUM> of medium <NUM> by either acoustic probe <NUM>, ultrasound transducer <NUM>, or a second ultrasound transducer <NUM> (configuration not shown). Each acoustic pulse has a center frequency f2 that is higher, e.g., at least <NUM> and/or less than <NUM> times higher, than first frequency f1 of HIFU energy <NUM>, and a time interval between the pulses is n+<NUM> times the period T1 of HIFU energy <NUM>, n being a positive integer as described hereinabove. (It is noted that all options that are described herein with respect to the second acoustic field being transmitted by either ultrasound transducer <NUM>, acoustic probe <NUM>, or second ultrasound transducer <NUM> are interchangeable. ) The acoustic pulses are synchronized with HIFU energy, as described hereinabove, and scatter off oscillating scatterers, such as scatterer <NUM>, in medium <NUM>, resulting in respective echoes that are received by acoustic probe <NUM>. (It is noted that all options and features of the disclosure as described hereinabove with respect to the pulses not being synchronized with first acoustic field <NUM> can be applied here as well.

Computer processor <NUM> (a) generates a real-time sonogram <NUM> of medium <NUM> from reflections of pulse-echo ultrasound energy <NUM>, (b) extracts a time shift dT between the received echoes, (c) based on the extracted time shift dT, calculates a displacement amplitude D of scatterer <NUM>, and (d) generates a map <NUM> of displacement amplitudes on a portion <NUM> of sonogram <NUM> that corresponds to region <NUM>. As described hereinabove, velocity amplitudes and intensity may be mapped as well.

Map <NUM> shows where the displacement amplitude or velocity amplitude of oscillating scatterers in first acoustic field <NUM> is highest, thereby showing where the intensity of first acoustic field <NUM> is highest, i.e., where focal region <NUM> is. Due to map <NUM> being overlaid on top of sonogram <NUM> of medium <NUM>, focal region <NUM> can be seen with respect to region <NUM> in medium <NUM>. Focal region <NUM> can then be relocated, for example by using a targeting unit as described hereinbelow, as appropriate so as to focus HIFU energy <NUM> on target location <NUM> within region <NUM> of medium <NUM>.

For some applications, medium <NUM> is tissue <NUM> of a subject <NUM> (<FIG>). Ultrasound transducer <NUM> causes a therapeutic effect in tissue <NUM> by emitting HIFU energy <NUM> into tissue <NUM>. For some applications, the therapeutic affect is caused by HIFU energy <NUM> heating tissue <NUM>. Other, non-thermal therapeutic effects can be caused by HIFU energy <NUM> as well, such as, for example, cavitation, tissue liquefaction, cell necrosis, and cell apoptosis.

For some applications, computer processor <NUM> also monitors a change in a mechanical property of tissue <NUM> by monitoring a time variation of displacement amplitude D over a time period of at least <NUM> and/or less than <NUM> seconds. When the mechanical property of tissue <NUM> being monitored reaches a threshold value, computer processor <NUM> terminates transmission of HIFU energy <NUM>. For example, due to exposure to HIFU energy <NUM> the mechanical impedance of tissue <NUM> changes. As the mechanical impedance of tissue <NUM> changes, displacement amplitude D of the oscillating scatterer <NUM>, e.g., an inhomogeneity in tissue <NUM>, changes as well. When the mechanical impedance of tissue <NUM> reaches a threshold value, computer processor <NUM> terminates transmission of HIFU energy <NUM> into tissue <NUM>.

In order to facilitate application of HIFU energy <NUM> to target location <NUM> in tissue <NUM>, ultrasound transducer <NUM> may operate in distinct calibration and therapy modes. In each of the modes ultrasound transducer <NUM> emits HIFU energy <NUM> with one or more differing respective parameters. Computer processor <NUM> varies the respective parameters of the calibration and therapeutic modes such that when ultrasound transducer <NUM> operates in the therapeutic mode, HIFU energy <NUM> causes a therapeutic effect in tissue <NUM>, whereas when ultrasound transducer <NUM> operates in the calibration mode, HIFU energy <NUM> does not cause a therapeutic effect in tissue <NUM>. For example, computer processor <NUM> may vary one or more parameters from the following set:.

Operating ultrasound transducer <NUM> in calibration mode allows the displacement amplitude, velocity amplitude, and/or intensity of first acoustic field <NUM> to be mapped and focal region <NUM> located while not causing any damage to tissue <NUM>. The beam of HIFU energy <NUM> can then be reoriented in order to relocate focal region <NUM>, and/or the size of focal region <NUM> can be changed such that target location <NUM> is inside focal region <NUM>. Thus, focal region <NUM> can be monitored and guided while ultrasound transducer <NUM> is in calibration mode, and once focal region <NUM> is in the right location, ultrasound transducer <NUM> can be switched to therapeutic mode in order for HIFU energy <NUM> to cause a therapeutic effect in tissue <NUM>. For some applications, computer processor <NUM> monitors tissue <NUM> while ultrasound transducer <NUM> operates in therapeutic mode in order to monitor how treatment is progressing. If appropriate, computer processor <NUM> may vary the abovementioned parameters of ultrasound transducer <NUM> while ultrasound transducer <NUM> is operating in therapeutic mode in order to alter an effect on tissue <NUM> during treatment.

A targeting unit <NUM> may be used to move focal region <NUM> of HIFU energy <NUM>. For some applications, targeting unit <NUM> is configured such that manual movement, e.g., by an operator of ultrasound transducer <NUM>, moves ultrasound transducer <NUM> with respect to medium <NUM>, thereby moving focal region <NUM> of HIFU energy <NUM> within medium <NUM>.

Alternatively or additionally, targeting unit <NUM> may comprise a first-transducer controller <NUM> and targeting circuitry <NUM>. Targeting circuitry <NUM> (a) obtains data corresponding to the location of focal region <NUM> of HIFU energy <NUM> on map <NUM> of displacement amplitudes, velocity amplitudes, or intensities, (b) obtains data corresponding to target location <NUM> in medium <NUM>, and (c) sends an electric signal to first-transducer controller <NUM>. First-transducer controller <NUM> receives the electric signal and in response thereto moves focal region <NUM> of HIFU energy <NUM> toward target location <NUM> within medium <NUM>. For example, first-transducer controller <NUM> may move focal region <NUM> and/or change a size of focal region <NUM> by (a) applying phased-array control to HIFU energy <NUM>, or (b) by moving ultrasound transducer <NUM> with respect to medium <NUM>, e.g., by using a robotic arm <NUM> and gears to move ultrasound transducer <NUM> with respect to medium <NUM>. For some applications, targeting circuitry <NUM> may (a) obtain the data corresponding to the location of focal region <NUM> and target location <NUM> directly from computer processor <NUM>, thereby providing closed loop control of the treatment, i.e., computer processor <NUM> sends data corresponding to the relative positions of focal region <NUM> and target location <NUM> to targeting unit <NUM>, via targeting circuitry <NUM>, and targeting unit <NUM> responds accordingly to bring focal region <NUM> to target location <NUM>.

Alternatively or additionally, targeting circuitry <NUM> may (a) obtain real-time data from computer processor <NUM> corresponding to a size of focal region <NUM> and (b) send the data to first-transducer controller <NUM>, such that first-transducer controller <NUM> may change a size of focal region <NUM> in order to focus or defocus HIFU energy <NUM>. For example, the size of focal region <NUM> may be (a) decreased in order to increase the intensity of HIFU energy <NUM> in focal region <NUM>, or (b) increased in order to decrease the intensity of HIFU energy <NUM> in focal region <NUM>.

Reference is now made to <FIG>, which is a schematic illustration of a HIFU transducer and an acoustic probe disposed on a single unit, according to some applications of the present invention. First acoustic transducer <NUM> may be shaped to have a central hole, and second acoustic transducer <NUM> positioned behind or inside first transducer <NUM>, such that first acoustic field <NUM> and the diagnostic acoustic pulses are aligned, i.e., such that the axis of first acoustic field <NUM> and the direction of propagation of the diagnostic acoustic pulses are aligned. For example, Sonic-Concepts H184-<NUM>, as well as other models, have a central hole of diameter of about <NUM>.

Applications of the invention described herein can take the form of a computer program product accessible from a computer-usable or computer-readable medium (e.g., a non-transitory computer-readable medium) providing program code for use by or in connection with a computer or any instruction execution system, such as computer processor <NUM>. For the purpose of this description, a computer-usable or computer readable medium can be any apparatus that can comprise, store, communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device. The medium can be an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system (or apparatus or device) or a propagation medium. Typically, the computer-usable or computer readable medium is a non-transitory computer-usable or computer readable medium.

Examples of a computer-readable medium include a semiconductor or solid-state memory, magnetic tape, a removable computer diskette, a random-access memory (RAM), a read-only memory (ROM), a rigid magnetic disk and an optical disk. Current examples of optical disks include compact disk-read only memory (CD-ROM), compact disk-read/write (CD-R/W) and DVD. For some applications, cloud storage, and/or storage in a remote server is used.

A data processing system suitable for storing and/or executing program code will include at least one processor (e.g., computer processor <NUM>) coupled directly or indirectly to memory elements through a system bus. The memory elements can include local memory employed during actual execution of the program code, bulk storage, and cache memories which provide temporary storage of at least some program code in order to reduce the number of times code must be retrieved from bulk storage during execution. The system can read the inventive instructions on the program storage devices and follow these instructions to execute the methodology of the embodiments of the invention.

Network adapters may be coupled to the processor to enable the processor to become coupled to other processors or remote printers or storage devices through intervening private or public networks. Modems, cable modem and Ethernet cards are just a few of the currently available types of network adapters.

Computer program code for carrying out operations of applications of the present invention may be written in any combination of one or more programming languages, including an object-oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the C programming language or similar programming languages.

It will be understood that the methods described herein can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general-purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer (e.g., computer processor <NUM>) or other programmable data processing apparatus, create means for implementing the functions/acts specified in the methods described in the present application. These computer program instructions may also be stored in a computer-readable medium (e.g., a non-transitory computer-readable medium) that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable medium produce an article of manufacture including instruction means which implement the function/act specified in the methods described in the present application. The computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions/acts specified in the methods described in the present application.

Computer processor <NUM> is typically a hardware device programmed with computer program instructions to produce a special purpose computer. For example, when programmed to perform the methods described herein, the computer processor typically acts as a special purpose computer processor. Typically, the operations described herein that are performed by computer processors transform the physical state of a memory, which is a real physical article, to have a different magnetic polarity, electrical charge, or the like depending on the technology of the memory that is used.

Techniques and apparatus described herein may be combined with techniques and apparatus described in <CIT>, entitled, "Doppler guided ultrasound therapy," and <CIT>, which published as <CIT>, entitled, "Doppler guided ultrasound therapy".

Claim 1:
Apparatus for use while a focal region (<NUM>) of high intensity focused ultrasound (HIFU) energy (<NUM>) is applied, the apparatus comprising:
a first ultrasound transducer (<NUM>) configured to transmit a first acoustic field (<NUM>) by emitting the HIFU energy (<NUM>) into a region (<NUM>) of a medium (<NUM>) at a first frequency, the first acoustic field (<NUM>) generating oscillatory motion at the first frequency of scatterers (<NUM>) disposed in the region (<NUM>), each scatterer oscillating around a respective equilibrium position;
an acoustic probe (<NUM>),
wherein the acoustic probe (<NUM>) is configured to emit pulse-echo ultrasound energy (<NUM>) into the medium (<NUM>) at an imaging frequency, and
wherein an acoustic element selected from the group consisting of the first ultrasound transducer (<NUM>), a second ultrasound transducer (<NUM>), and the acoustic probe (<NUM>) is configured to (i) transmit first and second acoustic pulses (<NUM>,<NUM>) into the region (<NUM>), each pulse having a center frequency that is higher than the first frequency, and the time interval between the pulses being n+<NUM> times the period of the first acoustic field (<NUM>), n being a positive integer, and (ii) receive respective echoes of each pulse scattering off an oscillating scatterer (<NUM>) in the region (<NUM>),
the first and second pulses (<NUM>,<NUM>) being synchronized with the first acoustic field (<NUM>) such that the first pulse scatters (<NUM>) off the oscillating scatterer (<NUM>) when the oscillating scatterer is at a first displacement extremum with respect to the equilibrium position, and the second pulse (<NUM>) scatters off the oscillating scatterer (<NUM>) when the oscillating scatterer is at a second displacement extremum that is opposite the first displacement extremum with respect to the equilibrium position; and
a computer processor (<NUM>) configured to (a) generate a real-time sonogram (<NUM>) of the medium (<NUM>) based on reflections of the pulse-echo ultrasound energy that is transmitted by the acoustic probe (<NUM>), (b) extract a time shift between the received echoes that is due to motion of the oscillating scatterer (<NUM>), (c) based on the extracted time shift, calculate a displacement amplitude of the oscillating scatterer (<NUM>), and (d) generate a map (<NUM>) of displacement amplitudes on a portion of the sonogram (<NUM>) corresponding to the region (<NUM>).