Mapping cavitation activity

Abstract

An apparatus for imaging cavitations in a subject volume of a subject comprises a plurality of transducer elements and a control means configured to control at least one first transducer element among the transducer elements to generate ultrasound waves having a focal region, receive passive detection signals from a first group of transducer elements and generate a cavitation image of the cavitation in the focal region from the passive detection signals, control at least one second transducer element among the transducer elements to generate reflected imaging ultrasound waves, receive reflected imaging detection signals from the second group of transducer elements and generate a reflected image from the reflected imaging detection signals, register the reflected image with a 3D image of the subject volume, perform a transformation between a coordinate system of the transducer elements of the first group and a coordinate system of the 3D image, and apply the transformation to the cavitation image to align it with the 3D image.

Description

[Technical Field]

[0001] The present invention relates to therapeutic ultrasound systems, and in particular to mapping and monitoring treatments that use acoustic (ultrasound-induced) cavitation. [Background technology]

[0002] The use of focused ultrasound (FUS) for cancer treatment offers several significant advantages over other more established treatments: it is inexpensive, non-invasive, and has minimal side effects. However, widespread acceptance of FUS has been hindered by the lack of a reliable real-time monitoring system.

[0003] Above a certain pressure threshold, propagating high-amplitude acoustic waves passing through tissue can spontaneously nucleate and excite small nano- or micron-sized bubbles. This phenomenon is known as acoustic cavitation. The addition or injection of exogenous bubbles that act as cavitation nuclei, whether they form shell bubbles on the surface of solid particles or stable bubbles, can be achieved with smaller amplitude acoustic waves, lowering the pressure threshold and generating acoustic cavitation at the nucleus. Depending on the desired application, cavitating bubbles can be used to produce desired biological effects. In the case of tissue ablation, these biological effects can result in thermal necrosis or mechanical fractionation of the tissue. In drug delivery, this can be cavitation-induced microstreaming or micropumping, vasculature penetration, and cell perforation, all of which can aid or enhance transport of drug substances across tissue membranes or act directly to rupture drug delivery vehicles for targeted drug delivery.

[0004] Additionally, bubbles can re-emit a portion of the incident ultrasound across a frequency range different from the FUS excitation frequency, which is useful for two reasons. First, the broadband acoustic emissions associated with this acoustic cavitation can serve as an indicator or surrogate marker of treatment efficacy for ablation and drug delivery. Second, emissions with higher frequency components than the original FUS source are more easily absorbed by surrounding tissue, increasing heat accumulation during thermal ablation [Coussios CC, Farny CH, Haar GT, Roy RA. “Role of acoustic cavitation in the delivery and monitoring of cancer treatment by high-intensity focused ultrasound (HIFU)”, International Journal of Hyperthermia, vol. 23, pp. 105–120, 2007]. The field of FUS is broad and covers all biomedical applications and system configurations involving focused ultrasound, although the more specific term high intensity focused ultrasound (HIFU) is commonly used when the amplitude or intensity of the incident ultrasound is higher than that achieved by diagnostic ultrasound imaging systems.

[0005] WO20100052494 discloses a system for imaging areas of acoustic cavitation during a FUS procedure. However, while this system can effectively image cavitation in real time, it does not describe how to determine the location of cavitation in the patient's frame of reference, i.e., relative to the patient's anatomy. Because cavitation activity is a predictor of drug delivery efficacy and safety in the case of mechanical or thermal ablation, being able to image and visualize cavitation in 3D offers potential advantages in improving treatment decisions and post-treatment evaluation. In particular, 3D volumetric images of the patient, such as X-rays or MR images, generally have higher resolution and contrast than ultrasound imaging, making it possible to display cavitation in high-quality 3D images. Summary of the Invention

[0006] The present invention provides an apparatus for imaging cavitations in an imaging volume of a subject, the apparatus comprising a plurality of transducer elements and control means configured to control at least one first element among the transducer elements to generate ultrasound waves having a focal region, the ultrasound waves may be therapeutic ultrasound waves, to receive passive detection signals from the first group of transducer elements and generate a cavitation image of the cavitation in the focal region from the passive detection signals, to control at least one second element among the transducer elements to generate reflected imaging ultrasound waves, to receive reflected imaging detection signals from the second group of transducer elements and generate a reflected image from the reflected imaging detection signals, to align the reflected image with a 3D image of the subject volume to obtain a transformation between the coordinate system of the transducer elements of the first group and the coordinate system of the 3D image, and to apply the transformation to the cavitation image to align the cavitation image with the 3D image.

[0007] Reflective imaging may be pulse-echo imaging, for example, B-mode ultrasound imaging, contrast-enhanced ultrasound, pulse-inversion ultrasound, or harmonic ultrasound imaging. At least one first element of the transducer elements is configured to generate focused ultrasound waves and may be, for example, a geometrically focused transducer with a fixed focus, a geometrically focused transducer array with a stationary focus that can be electronically moved or steered, or a linear or planar transducer array. A linear or planar transducer array may not be perfectly straight or perfectly planar; however, the focusing is all or substantially all electronic. Thus, focusing can be performed geometrically or electronically, or a combination of the two.

[0008] A first element of the transducer elements may be one of the first group of transducer elements, one of the second group of transducer elements, or none of the groups, and similarly, a second element of the transducer elements may be one of the first group of transducer elements, one of the second group of transducer elements, or none of the groups.

[0009] The transducer elements of the first group may be in a fixed position relative to the transducer elements of the second group. The system may further include a probe, which may be portable or robotically operated, and the first group of transducer elements and the second group of transducer elements may form part of the probe, for example, be mounted within or on the probe.

[0010] The first and / or second groups of transducer elements may be linear, specifically, linear or convex linear transducer element arrays. The first and / or second groups of transducer elements may be planar, specifically, flat or convex planar transducer element arrays. Other configurations, such as concave linear or concave planar transducer arrays or annular arrays, may also be used.

[0011] At least one of the transducer elements of the first group may be one of the transducer elements of the second group, and indeed the transducer elements of the first group may be, i.e., include, the same transducer elements as the transducer elements of the second group.

[0012] For example, if the relative positions of the first and second groups of transducers are known or if the first and second groups of transducers are the same, the conversion can be direct from the alignment process, or if the first and second groups of transducers are movable relative to one another, the conversion can be indirect from the alignment process, again based on measurements of the relative positions of the two groups of transducer elements.

[0013] The present invention also includes a method for imaging cavitations in an imaging volume of a subject, the method including the steps of generating ultrasound waves having a focal region, receiving passive detection signals from a first group of transducer elements and generating a cavitation image of the cavitations in the focal region from the passive detection signals, generating reflected imaging ultrasound waves, receiving reflected imaging detection signals from a second group of transducer elements and generating a reflected image from the reflected imaging detection signals, registering the reflected image with a 3D image of the imaging volume to transform between the coordinate system of the first group of transducer elements and the coordinate system of the 3D image, and applying the transformation to the cavitation image to align it with the 3D image.

[0014] The present invention further provides an apparatus for imaging cavitations in an imaging volume of a subject, the apparatus comprising a plurality of transducer elements and control means configured to control at least one first element among the transducer elements to generate focused ultrasound waves having a focal region, receive passive detection signals from the first group of transducer elements, generate a cavitation image of the cavitations in the focal region from the passive detection signals, control at least one second element among the transducer elements to generate reflected imaging ultrasound waves, receive reflected imaging detection signals from the second group of transducer elements, generate a reflected body structure image from the reflected imaging detection signals, and combine the cavitation image and the reflected body structure image to generate a 3D image of the cavitations in the imaging volume.

[0015] Furthermore, the system may include any one or more features of the embodiments of the invention illustrated in the accompanying drawings, in any operable combination. The accompanying drawings are now described. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 is a schematic diagram of an ultrasound system in accordance with an embodiment of the present invention. [Figure 2] 2 is a schematic diagram of the system of FIG. 1 transmitting ultrasound for imaging body structures; [Figure 3] FIG. 2 is a schematic diagram of the system of FIG. 1 transmitting ultrasound for a therapeutic treatment. [Figure 4] FIG. 2 is a schematic functional block diagram of the ultrasound system of FIG. 1. [Figure 5] FIG. 2 is a timing diagram illustrating the operation of a system according to an embodiment of the present invention. [Figure 6] 2 is a flow diagram illustrating an imaging method performed on the system of FIG. 1. [Figure 7] FIG. 1 is a schematic diagram of an ultrasound system in accordance with another embodiment of the present invention. [Figure 8] FIG. 10 is a schematic diagram of an external ultrasound probe according to another embodiment of the present invention. [Figure 9] 1 is a schematic diagram of an internal ultrasound probe according to another embodiment of the present invention. [Figure 10] FIG. 10 is a schematic diagram of an ultrasound system with separate arrays for transmitting and receiving ultrasound for ultrasound imaging, transmitting ultrasound for therapeutic ultrasound, and receiving passive detection signals for cavitation imaging, in accordance with another embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0017] Referring to FIG. 1, an ultrasound system 200 may include a geometrically focused ultrasound transducer 201 having an array of ultrasound transducer elements 202 disposed within an aperture 203 at the center of the transducer 201. Each of the transducer elements 202 may be operable to generate and detect ultrasound waves. Thus, they may be used in an active mode, where they generate and detect ultrasound waves to generate a reflected (e.g., B-mode) ultrasound image, or in a passive mode, where they only detect ultrasound waves. The array may be a linear or convex linear array, as shown in FIG. 2, extending primarily in a direction hereafter referred to as the x-direction. The direction perpendicular to the x-direction, along the axis of the transducer, is referred to as the z-direction. Thus, the imaging plane of the array is the xz-plane. The direction perpendicular to both the x- and z-directions is referred to as the y-direction.

[0018] The control unit 204 is configured to control the generation of ultrasound signals by each of the transducer elements 202 and to receive detection signals from each of the transducer elements 202. The control unit 204 may include a preamplifier and filter block 206 and an oscillator 208. The control unit 204 is also configured to control the transducer 201 to control the power and frequency of ultrasound waves generated by the transducer 201, for example, using a signal from the oscillator 208 to control the frequency of the ultrasound waves. While the control unit 204 is described functionally, it will be appreciated that it may be implemented as a single processor or as two or more separate processors performing different functions within the system, e.g., control and analysis functions. The control unit is connected to a display screen 210, on which data derived from the detection signals may be displayed in a suitable format. In this case, the therapeutic transducer 201 has a focal point within a focal region 214 where it generates ultrasound waves of the highest intensity.

[0019] While the configuration of Figure 1 can be implemented using a variety of components and systems, in one embodiment, an ultrasound data acquisition system may be used, enabling the acquisition of raw radio frequency (RF) data or in-phase / quadrature (I / Q) data that can be demodulated back to RF simultaneously from multiple individual elements 202 across a wide ultrasound bandwidth (e.g., 1-15 MHz). If the array is to be used in passive mode, pulse transmission can be switched off so that the array operates in receive mode only. In one mode, one group of transducer elements 202 is used in active mode and another group in passive mode, allowing for simultaneous active and passive detection. To make this system clinically applicable, a therapeutic ultrasound transducer 201 may be used, having a central aperture 203 for a linear (rectilinear or convex) detector array 202.

[0020] The theory behind the operation of passive acoustic mapping will now be briefly described, but is described in more detail in WO 2010 / 052494. Active detection involves pulse-echo (e.g., B-mode) imaging and involves an ultrasound generator configured to generate ultrasound waves, typically in pulses; a detector or receiver that detects ultrasound waves reflected or re-emitted from the cavitation region; and a processing system that uses the time interval between the generation and detection of the ultrasound waves when determining the location of the detected cavitation. In contrast, passive localization and mapping does not provide direct information about the propagation time from the source to the receiver. Instead, cross-correlation of detected signals from a pair of receivers provides an estimate of the differential time of arrival (DTOF), i.e., the difference in the time of arrival of a signal from the source at the receiver. This allows the difference in distance between the receiver and the source to be estimated. Using a set of cross-correlation pairs enables localization of individual sources and extended source mapping. It will be appreciated that a single detector can handle both active and passive detection, depending on the processing performed on the sensor signal. Passive localization and imaging is described in more detail below.

[0021] Typically, when there is a large cavitation region, a spatial map of the cavitation is required. A commonly employed approach is one of passive beamforming, and one method is described in Coviello, et al. "Passive acoustic mapping utilizing optimal beamforming in ultrasound therapy monitoring", J. Acoust. Soc. Am. 137 (5), May 2015. If a regular pixel grid is defined in the imaging plane to create the spatial map, each pixel has a 3D coordinate x = [x, y, z]. T and the center defined by [dx, dy, dz]T The space in each dimension is defined by the pixel location x and the pixel location x. j We define the distance to receiver j at

[0022]

number

[0023] For each pixel, a time delay applied to each receiver signal is used to pre-steer the data at the receiver to compensate for the propagation time from the imaging pixel to the receiver. Assuming there are N receivers in total, the intensity of the sound field at that pixel location is

[0024]

number

[0025] Here, s j (t) is the signal recorded at receiver (sensor) j, and τ j (x) = d j (x) / c is the propagation time from position x to sensor j, a is the piezoelectric coefficient characteristic of each receiver (sensor) element, and c is the propagation velocity. j Multiplying by (x) compensates for the reduction in source signal intensity due to spherical spreading of the wavefront. The image of the source energy at a pixel is generated by integrating the square of the source intensity over the acquisition period length T, assuming uniform detector weights, and is given by:

[0026]

number

[0027] where ρ is the density of the medium and c is the propagation velocity. This energy is then calculated for each desired pixel location in the image. 2 and 3, the control unit 204 can be configured to control the transducer elements 202 as a phased array. For example, the control unit can be configured to generate a transmit signal to each of the transducer elements 202 to control the frequency and timing of vibration, i.e., the relative phase, and therefore the frequency and timing of the ultrasound waves generated by each transducer element. Typically, the frequency of vibration of each of the transducer elements is controlled to be the same, and the phase or timing of each of these elements is varied to manipulate the ultrasound waves generated by the array as a whole. The transducer elements can be configured to vibrate in phase with each other, thereby generating ultrasound waves with straight, parallel wavefronts 220 that all travel in the same direction, as shown in FIG. 2. This is suitable for anatomic ultrasound (B-mode or other reflection) imaging. Dephasing the vibration of the elements 202 so that those at the outer edges of the array are in phase with each other and the delay increases toward the center of the array, as shown in FIG. 3, generates ultrasound waves with curved wavefronts 222 that converge at a focal region 224.

[0028] It will be appreciated that, rather than having a separate transducer 201 for focused ultrasound transmission, an array of ultrasound elements 204 can be used to generate ultrasound waves for both anatomy imaging and therapeutic FUS by rapidly switching between two different phase configurations. Furthermore, because anatomy ultrasound imaging and passive acoustic mapping as described above both require detection of ultrasound waves reflected or generated by the tissue being imaged, this detection can, in some embodiments of the present invention, be performed by the same transducer elements 202 used to transmit ultrasound. However, this requires additional time division, and it is often preferable to have separate transducer arrays for detecting or receiving ultrasound waves. Thus, when reference is made to transmit and receive arrays in the following description, these will typically be separate arrays, but they may alternatively be the same array.

[0029] Referring to FIG. 4, in a practical implementation of the system of FIG. 1, the transducer elements 202 are divided into two groups, each arranged in an array: a transmit array 202a and a receive array 202b, both of which are implemented within a probe 230. The probe 230 also includes a position sensor 232. Each of these arrays 202a, 202b may be a linear array, as previously described. Thus, the separate geometric FUS transducer 201 of FIG. 1 is omitted. In a modification to this configuration, the transducer elements are organized into a treatment group and an imaging group. The transducer elements in the treatment group can then be configured to generate focused ultrasound waves, while the transducer elements in the imaging group are configured to both transmit and receive reflected imaging ultrasound waves and also receive passive cavitation mapping signals. The imaging group can be configured to transmit flat planar ultrasound waves or focused ultrasound waves, for example, with subgroups of transducer elements controlled to provide different focal points at a common focal depth and provide high-quality images at this depth.

[0030] The position sensor can be compatible with any of several known position and orientation sensing systems. For example, it can be a sensor in an electromagnetic motion tracking system, a stereoscopic optical camera, an infrared camera, or it can include one or more markers that allow the position of the probe to be tracked by a laser tracker.

[0031] The control unit 204 includes a main processor 204a and an ultrasound front-end processor 204b. The ultrasound front-end 204b includes a transmit side and a receive side. The transmit side includes generators configured to generate each of the ultrasound signals transmitted by the transmit array 202a. For example, these may include a therapeutic signal generator 240 and an imaging signal generator 242. These signal generators 240, 242 are configured to output transmit signals to the individual transducer elements of the transmit array 202a so that the individual transducer elements transmit ultrasound signals in the manner required for therapeutic FUS and B-mode ultrasound imaging, respectively, as shown in FIGS. 2 and 3. The ultrasound front end 204b further includes two amplifiers 244, 246 configured to amplify the transmit signals from each of the signal generators 240, 242, respectively, and a multiplexer 248 configured to receive both amplified transmit signals and route each of them to the correct transmit array 202a at the appropriate time in a time division multiplexed manner. A timing controller 264 provides trigger or synchronization signals to arrange the timing of the signal generators and multiplexer, as described in more detail below.

[0032] The receive side of the ultrasound front end 204b includes a multiplexer 250. The multiplexer 250 receives all of the detection signals from the receive array 202b and is configured to separate the anatomy ultrasound imaging signals (e.g., B-mode) from the passive acoustic mapping signals into anatomy ultrasound imaging channels and PAM channels. This separation is based on timing because the received anatomy imaging signals are reflections of the transmitted anatomy imaging signals, and the received PAM signals are generated by cavitation caused by the transmitted FUS signals. The anatomy imaging signals are time-gain compensated by a TGC module 252, digitized by an ADC 254, and filtered by a digital filter 256. The PAM signals are filtered by an analog filter 258 to separate the high-frequency broadband signals used for PAM, amplified by a low-noise amplifier 260, and then digitized by an ADC 262.

[0033] The main processor 204a includes a timing controller 264 that is configured to provide timing inputs to the ultrasound signal generators 240, 242, the multiplexers 248, 250, and the ADCs 254, 262. The timing inputs to the ultrasound signal generators 240, 242 are configured to trigger the generation of alternating therapeutic FUS signals and structural ultrasound imaging signals, each during a short time period of a respective sequence. The multiplexer 248 uses the timing signals received from the timing controller 264 to multiplex the two types of ultrasound-generated signals onto a control input to the transmitter array 202a, causing the transmitter array 202a to generate alternating pulses of therapeutic FUS and focused or unfocused imaging ultrasound. The receive multiplexer 250 is controlled by a timing controller 264 to switch signals from the receive array 202b between the B-mode channel and the PAM channel based on the transmission times of the two different types of ultrasound waves and the known or expected delays between the transmission and reception of the associated ultrasound signals. The timing controller 264 also provides timing inputs to the ADCs 254, 262 to control the sampling rate of the analog signals by the ADCs.

[0034] Referring to Figure 5, as an example of the timing of different transmitted and received ultrasound signals, it may be desirable to transmit a therapeutic FUS pulse with a frequency of 1 MHz and a duration of 1000 cycles per second. It may also be desirable to maintain a sufficient imaging frame rate (>30 frames / second) to a depth of d = 20 cm, but to increase the imaging signal-to-noise ratio (assuming 50 pulses / frame), it may also be desirable to transmit various pulse-echo imaging pulses to construct one image frame. Assuming a therapeutic pulse rate of 1 second, all pulse transmission, propagation, and processing times must fit within this 1 second.

[0035] example: Therapeutic ultrasound frequency = 1MHz Therapeutic pulse PRF = 1Hz or 1s period Number of cycles per therapeutic pulse N = 1000 cycles Therapeutic transmit time per pulse T trans =1ms Treatment transmission time + propagation time T trans+prop ~2ms After each pulse, T is calculated to include the passive acoustic mapping (PAM) processing time. trans+prop+PAMproc =502ms Therefore, it takes half a one-second period to transmit one therapeutic pulse, detect and process the cavitation-generated US, and determine the PAM.

[0036] Time remaining = 498ms. If the system is synchronous, this remaining time can be used for B-mode imaging. If the system is asynchronous, the B-mode imaging pulse transmission is T trans+prop This example covers only the synchronous case for the sake of simplicity. Assume that the propagation speed c = 1500 m / s, and that it takes 10 ms to reproduce all the imaging pulses in an image. Imaging US frequency = 5MHz, The number of cycles in each imaging pulse is N = 2 cycles. Image transmission time T trans =0.4μs, Included propagation time T trans+Prop =26.4μs For 50 pulses per image frame, T frame =50×26.4μs=1.3ms Image frame reconstruction and processing time is included.

[0037] T frame +T recon =1.3ms+10ms=11.3ms Frame rate = 498ms / 11.3ms = 44 frames / sec The main processor 204a also includes an apodization unit 266 and an image reconstruction unit 268. These units 266, 268 are configured to receive digital B-mode signals from the ultrasound front-end 204b and generate anatomic ultrasound images therefrom, for example, in the form of a 2D B-mode ultrasound imaging stream, which may comprise a sequence of time-stamped 2D image frames. The main processor 204a also includes a PAM imaging unit 270. The PAM imaging unit 270 is configured to receive digital B-mode signals from the ultrasound front-end 204b and generate anatomic ultrasound images therefrom, for example, in the form of a 2D PAM imaging stream, which may also comprise a sequence of time-stamped PAM image frames.

[0038] The main processor 204a also includes a positioning unit 272 configured to receive position and orientation data (such as translation and rotation) from the position sensor 232 on the probe 230, time-stamp this data, and output a position / orientation data stream so that the position and orientation of the probe associated with each feature in the image stream can be determined. This allows the probe to be moved to scan the imaging volume and the 2D images generated from the probe's receive array to be located in a 3D coordinate system.

[0039] The main processor 204a further includes a local memory 274 and a data processor 276. The local memory 274 is configured to receive and store image streams from the anatomy and PAM imaging channels and a position / orientation data stream from the positioning unit 272. It is also configured to receive and store 3D anatomy image data from a previous scan of the patient, for example, in the form of a set of 2D image slices obtained by CT or MRI scanning. The 2D image slices may be in DICOM format, for example. The data processor 276 is configured to process the data stored in the local memory to generate a composite image or image stream. In this composite image or image stream, a PAM image of FUS-induced cavitation is superimposed on a 3D anatomy image of the patient. The 3D anatomy image of the patient may be a pre-scanned 3D image or a 3D ultrasound image generated from composite 2D-mode ultrasound image slices. The processing method by which the composite image can be obtained will now be described.

[0040] Referring to FIG. 6 , local memory 274 is also configured to store position system calibration data. The position system calibration data defines the position and orientation of a 2D ultrasound imaging plane of a B-mode image generated from the receiver array signals relative to the probe position and orientation determined by position sensor 232. This calibration data can be obtained to determine the position and orientation of the imaging plane relative to the probe by imaging a known 3D structure at a known position and orientation relative to probe 230 and registering the resulting 2D ultrasound image with the image data of the known structure. Processor 276 is configured to apply the calibration defined by the calibration data to the position / orientation data stream in step 300 to generate image position / orientation data that defines the position and orientation of the imaging plane for each image frame in a 3D coordinate system. This 3D coordinate system may be referred to as the probe coordinate system.

[0041] Because the PAM images are generated from the same transducer element receive array 202b as the 2D anatomy imaging, the imaging planes of the 2D PAM images and the 2D anatomy imaging can be assumed to coincide, and positions within the imaging planes can be determined using the same coordinate system for the two imaging methods. Thus, the relative positions of features imaged in the PAM images and the 2D anatomy imaging are known, and the positions of each type of image are defined and recorded in a common probe coordinate system. However, a separate calibration step may be included, in which a structure in which cavitation occurs at a known location is imaged by PAM and 2D reflection (e.g., 2D-mode) ultrasound imaging to calibrate the relative positions of the imaging planes of the two imaging methods, and their positions within those planes.

[0042] In step 302, the frames of the 2D B-mode image stream and the frames of the 2D PAM image stream are time-aligned with each other. This is generally necessary because the frame rates of the two different imaging methods will likely be different, and furthermore, the individual frame times will not be the same, making it necessary to multiplex these imaging methods. This time alignment and position calibration together result in the position, orientation, and time of each frame in both image streams being defined in the same 4D coordinate system, i.e., 3D spatial coordinate system and time.

[0043] In step 304, the 2D slices of the 3D anatomical data are combined to obtain a 3D image data set for the entire 3D spatial region of the patient's anatomical structure. Of course, the anatomical structure data may be stored in a 3D format beforehand, in which case this combining step is unnecessary. Then, in step 306, each of the 2D ultrasound anatomical structure image slices is registered with the 3D (usually high-contrast) anatomical structure image. Various image registration methods are known, for example, as described in Wein, et al., "Automatic CT-ultrasound registration for diagnostic imaging and image-guided intervention," Medical Image Analysis, Vol. 12, pp. 577-585, 2008. This determines a spatial correction or transformation that can be applied to the coordinates of the 2D anatomical structure ultrasound image (and the PAM image) to properly locate them in the coordinate system of the 3D anatomical structure image. In step 308, this spatial correction or transformation is applied to the coordinates of the PAM image to determine their position and orientation in the coordinate system of the 3D anatomical structure image. As a result of this image registration and coordinate transformation, the 2D anatomy ultrasound image stream is therefore defined in the coordinate system of the 3D anatomy image, and the 2D PAM image stream is defined in the coordinate system of the 3D anatomy image, which allows the 3D high-contrast anatomy image and the 2D anatomy ultrasound and PAM images to be overlaid in various ways.

[0044] For example, in step 310, a 2D PAM image can be overlaid on a 3D high-contrast anatomical image, and then in step 312, the image can be thresholded to identify key loci of activity or fiducial points, such as cavitation maxima, minima, or midpoints. This results in an image of cavitation fiducial points located within the 3D high-contrast anatomical image. Optionally, in step 313, this image can be combined with the 2D US image stream to generate an image including the 3D PAM fiducial points overlaid on the 3D anatomical image, optionally combined with a 2D reflectance US image.

[0045] Alternatively, in step 314, the 2D PAM image can be composited after the overlay step 310 to generate a 3D PAM image of the cavitation activity located within the 3D anatomical image. This composite 3D image can then also be thresholded in step 316 so that only pixels having cavitation activity above a threshold level are shown in the PAM component of the composite image. Optionally, in step 317, this image can be combined with the 2D US image stream to generate an image including the 3D PAM image superimposed on the 3D anatomical image, optionally combined with a 2D reflective.

[0046] Additionally, the 2D ultrasound image that was registered with the 3D anatomical image in step 306 may be overlaid with the 3D image in step 319 and displayed as a combined 2D ultrasound and CT or MRI image.

[0047] In other alternative embodiments, for example, when 3D high-contrast anatomy images of the patient are not available, time-aligned and spatially aligned images from the 2D PAM image stream can be overlaid on the 2D ultrasound image stream in step 318 and thresholded and displayed as a composite image in step 320 showing key locations of the PAM in 3D superimposed on the 2D ultrasound image, but only when co-located in the 2D US image plane.

[0048] Alternatively, the superimposed 2D images obtained in step 318 can be combined in step 322 to generate a 3D image of the cavitations imaged in the PAM image superimposed on the 3D anatomy ultrasound image. The PAM image can be a full 3D image or just the fiducial points described above.

[0049] In theory, all three types of images can be combined to produce an enhanced 3D anatomic image. This is achieved by combining a 3D anatomic image and multiple 2D anatomic ultrasound images to form a 3D reflected ultrasound image, on which a 3D PAM image is superimposed. However, such an image can be difficult to interpret.

[0050] Of course, it will be appreciated that various modifications to the embodiments shown in Figures 1-5 are possible. For example, although the transmit and receive arrays 202a, 202b are both 1D linear or convex arrays, either or both may be 2D planar arrays. This means that if a full 2D array is used for transmit and receive in anatomic ultrasound imaging, the anatomic ultrasound image, or each image frame of the ultrasound image stream, may be a three-dimensional anatomic image. This also means that if a full 2D receive array is used for PAM imaging, the PAM image may be a full 3D image of the cavitation activity generated by FUS. This also means that a full 2D transmit array may be used to generate FUS.

[0051] 7-9, the systems of FIGS. 2-6 can be incorporated into a variety of different probe configurations. For example, referring to FIG. 6, the probe 230 can be connected to an electronically or manually controlled motion control system 600, such as a robotic arm or multi-axis motion system. The motion control system 600 is configured to support the probe and control its movement in six degrees of freedom (three degrees along orthogonal translational directions of motion and three degrees about orthogonal rotational axes) in response to input from an electronic control system or manual input. In this case, the position and orientation of the probe 230 can be determined from position sensors mounted on the probe, as described above, or from the operation of the motion control system.

[0052] 8, the probe can also be a portable external probe 730. The portable external probe 730 has a contact surface 700 configured to be placed in contact with the patient's skin, with transmit and receive arrays 702a, 702b mounted within or adjacent to the contact surface 700. In this case, a position sensor 732 is mounted within or fixed to the body of the probe 730 so that any manual movement of the probe can be recorded, as described above.

[0053] 9, the probe may be a portable internal or intra-operative probe 830. The probe 830 has a contact surface 800 configured to be placed in contact with the interior of a patient, with transmit and receive arrays 802a, 802b mounted within or adjacent to the contact surface 800. Again, as previously described, a position sensor 832 is mounted within the body of the probe 830 so that any manual movement of the probe can be recorded.

[0054] Referring to FIG. 10 , instead of all being mounted on a common probe, the system can include separate probes, each supporting a different group of transducer elements. For example, the system can include an anatomy imaging probe 900 having an array 902 of transducer elements supported thereon. The array 902 can be a linear or convex array and can be configured, for example, to transmit reflected imaging ultrasound waves as shown in FIG. 2 and receive reflected ultrasound waves using the same group of transducer elements in the array 902, a different group of transducer elements in the array 902, or a different array of transducer elements. The system can also include an FUS probe 904 having an array 906 of transducer elements configured to generate therapeutic FUS waves, as shown in FIG. 3 . The system can also include a PAM probe 908 having an array 910 of transducer elements configured to receive waves. Each of the probes 900, 904, and 908 can also include position sensors 912, 914, and 916 to monitor the position of the probe and, therefore, the transducer array mounted thereon. Thus, this system can operate in the same manner as the previously described system, except that the calibration step 300 used to spatially align the PAM images with the anatomy ultrasound images is replaced with a transformation that varies over time and is determined for each image frame of the PAM image stream based on the relative positions of the two probes 900, 908.

[0055] In yet another embodiment, the system includes a FUS ultrasound transmitter mounted on a probe or robotic arm and a movable probe having both PAM imaging receive transducer elements and transmit and receive elements of a body structural ultrasound imaging system, either as separate arrays, or as one common array, or as a transmit array for body structural ultrasound imaging and a receive array for both PAM imaging and body structural ultrasound imaging.

Claims

1. 1. A system for imaging cavitations in a subject volume of a subject, comprising: a plurality of transducer elements and a control means; The control means controlling at least a first one of the transducer elements to generate an ultrasound wave having a focal region; receiving passive detection signals from a first group of transducer elements and generating a series of cavitation images from the passive detection signals of the cavitation in the focal region; controlling at least a second one of the transducer elements to generate reflected imaging ultrasound; configured to receive reflected imaging detection signals from the second group of transducer elements and generate a series of reflected images from the reflected imaging detection signals; the system further comprising a probe, the first group of transducer elements and the second group of transducer elements mounted on the probe, the probe moving to scan the subject volume; The control means further comprises: registering each of the reflection images with a 3D image of the subject volume and obtaining a respective transformation between a coordinate system of the first group of transducer elements and a coordinate system of the 3D image; applying each of said transformations to each of said cavitation images to align said cavitation images with said 3D image; The system is configured as follows:

2. 10. The system of claim 1, wherein the first group of transducer elements are in fixed positions relative to the second group of transducer elements.

3. 3. The system of claim 1 or 2, wherein the first group of transducer elements is a linear or convex linear array of transducer elements.

4. 4. The system of claim 1, wherein the second group of transducer elements is a linear or convex linear array of transducer elements.

5. 2. The system of claim 1, wherein at least one of the first group of transducer elements is also one of the second group of transducer elements.

6. 6. The system of claim 5, wherein the first group of transducer elements are also the second group of transducer elements.

7. 1. A method of imaging cavitations in a subject volume of a subject, comprising: generating focused ultrasound waves having a focal region; receiving passive detection signals from a first group of transducer elements mounted on a movable probe and generating a series of cavitation images of the cavitation in the focal region from the passive detection signals; generating a reflected imaging ultrasound wave; receiving reflected imaging detection signals from a second group of transducer elements mounted on the movable probe and generating a series of reflected images from the reflected imaging detection signals; registering each of the reflection images with a 3D image of the subject volume and obtaining a respective transformation between a coordinate system of the first group of transducer elements and a coordinate system of the 3D image; applying each of the transformations to each of the cavitation images to align the cavitation images with the 3D image; A method comprising:

Images