Monitoring and control of tissue resection procedures

Abstract

A tissue resection procedure controllably causes tissue destruction in an anatomical region inside a target by: ultrasonically treating the target region with a series of acoustic pulses; detecting an ultrasonic reflection signal from the target region; controlling an ultrasound transducer to deliver a series of acoustic pulses having a sufficient amplitude to the target region to induce sufficient cavitation to mechanically rupture tissue therein; receiving data characterizing the detected reflected signal; computationally estimating a sound activity level or position or sound field distribution at the target region based on the data; and based on a plurality of sound activity level estimates or sound field distribution estimates: ceasing delivery of the sound pulses; continuing to deliver the acoustic pulse at a constant power level; increasing a power level for delivering the acoustic pulse; or a power level for delivering the acoustic pulse is reduced.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to systems and methods for monitoring and controlling tissue ablation procedures in focused ultrasound therapy. BACKGROUND

[0002] Tissue ablation involves the delivery of acoustic energy in the form of short (typically less than 50 μsec) high-amplitude acoustic pulses that deliver relatively low total energy at high peak pressure. This initiates transient cavitation to mechanically disrupt the targeted tissue. Cavitation occurs when sufficient negative pressure is applied to the tissue to vaporize the fluid and form microbubbles and release dissolved gas. Once formed, the microbubbles exhibit highly dynamic oscillation patterns and inertial collapse, resulting in cell and tissue disruption. While lesion applications, for example involving high intensity focused ultrasound, are sensitive to the amount of energy that reaches the target, tissue ablation is more sensitive to the negative peak pressure. The pulse intensity required to initiate cavitation is very high (>20 MPa).

[0003] Of course, all treatments involving tissue ablation must be monitored and controlled to ensure patient safety and treatment effectiveness. Tissue ablation initiation is primarily a threshold effect (rather than a cumulative effect), meaning that as the treatment parameter (typically the delivered power) is increased, the effect suddenly begins. Once the power level increases beyond the threshold, the degree of tissue ablation effect grows significantly with increasing power and / or number of repetitions. Thus, any increase in delivered power can trigger the effect without warning signs. At the high power levels required to initiate cavitation, the risk of injury due to excessive energy deposition (i.e., beyond that required to initiate cavitation at the level needed for treatment) is significant. Thus, fast feedback is essential for effectively and safely conducting tissue ablation-based treatments.

[0004] Achieving precise, real-time in-vivo imaging to detect the onset and degree of cavitation remains a challenge. Standard active ultrasound imaging is fast but has limited resolution, particularly in transcranial procedures where the skull produces aberrations that are different for each patient. One alternative is magnetic resonance imaging (MRI), which provides better images and is less disturbed by bone structures. However, MRI is a relatively slow technique, so it is difficult to update the image often enough to allow fine control of the tissue ablation procedure. Moreover, even if the onset of cavitation can be detected quickly and reliably, the optimal sequence of post-detection controls is not obvious. If the power is reduced or cut off too quickly, the desired treatment effect will not be achieved; if the power is kept at the current level, the cavitation can decrease below a useful level for treatment; and increasing the power risks causing harm to the patient. SUMMARY

[0005] The present disclosure provides systems and methods for monitoring and controlling tissue ablation procedures in focused ultrasound therapy.

[0006] In one aspect, a system for controllably causing tissue disruption in an internal anatomical region of a target is described. The system includes an ultrasound transducer for ultrasonically treating a target region with a series of acoustic pulses, an acoustic detection system including at least one detector for detecting ultrasonic reflection signals from the target region after at least some of the acoustic pulses, and a controller. The controller is configured to control the ultrasound transducer to deliver a series of acoustic pulses having sufficient amplitude to induce sufficient cavitation in the target region to mechanically disrupt tissue therein, each acoustic pulse having a duration of no more than 100 µsec, and receive data characterizing the detected reflection signals from the acoustic detection system. Based on at least the data characterizing the detected reflection signals, the controller is configured to estimate a level or location of acoustic activity or a sound field distribution at the target region. Based on a plurality of acoustic activity level estimates or sound field distribution estimates, the controller is configured to stop delivery of acoustic pulses, continue delivery of acoustic pulses at a constant power level, increase a power level for delivery of acoustic pulses, or decrease a power level for delivery of acoustic pulses.

[0007] In another aspect, a method for controllably causing tissue disruption in an internal anatomical region of a target is described. The method includes ultrasonically treating a target region with a series of acoustic pulses, detecting ultrasonic reflection signals from the target region after at least some of the acoustic pulses, controlling an ultrasound transducer to deliver a series of acoustic pulses having sufficient amplitude to induce sufficient cavitation in the target region to mechanically disrupt tissue therein, each acoustic pulse having a duration of no more than 100 µsec, and receiving data characterizing the detected reflection signals. Based on at least the data characterizing the detected reflection signals, the method further includes computationally estimating a level or location of acoustic activity or a sound field distribution at the target region. Based on a plurality of acoustic activity level estimates or sound field distribution estimates, the method further includes stopping delivery of acoustic pulses, continuing delivery of acoustic pulses at a constant power level, increasing a power level for delivery of acoustic pulses, or decreasing a power level for delivery of acoustic pulses. BRIEF DESCRIPTION OF DRAWINGS

[0008] In the drawings, like reference numerals refer to like parts throughout the various views. Moreover, the drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the disclosure. In the following description, various embodiments of the present disclosure are described with reference to the following drawings, in which: FIG. 1A schematically depicts an exemplary ultrasound system, in accordance with various embodiments of the present disclosure.

[0009] FIG. IB schematically depicts an exemplary MRI system, in accordance with various embodiments of the present disclosure.

[0010] FIG. 2 depicts an implementation of an acoustic reflector generally proximate to a target region, according to some embodiments.

[0011] FIG. 3 is a graph depicting an example ultrasonic treatment event, in which the applied acoustic power level is selected according to a reflected signal resulting from a tissue ablation event, according to some embodiments.

[0012] FIG. 4 is a flowchart showing an exemplary method for monitoring and controlling a tissue ablation procedure in focused ultrasound therapy, according to some embodiments. DETAILED DESCRIPTION

[0013] FIG. 1A shows an exemplary ultrasound system 100 for generating and delivering a focused acoustic energy beam to a target region 101 in a patient. The illustrated system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 that drives the phased array 102, a controller 108 in communication with the beamformer 106, and a frequency generator 110 that provides input electronic signals to the beamformer 106.

[0014] The array 102 can have a curved shape (e.g., spherical or parabolic) or other contoured shape suitable for placement on the surface of a patient's body, or can include one or more planar or otherwise shaped segments. Its dimensions can vary between a few millimeters and a few tens of centimeters. The transducer elements 104 of the array 102 can be piezoelectric ceramic elements, and can be mounted in silicone rubber or any other material suitable for attenuating mechanical coupling between the elements 104. Piezoelectric composites, or generally any material capable of converting electrical energy into acoustic energy, can also be used. To ensure maximum power transfer to the transducer elements 104, the elements 104 can be configured for electrical resonance at 50 Ω to match the input connector impedance.

[0015] The transducer array 102 is coupled to a beamformer 106 that drives the individual transducer elements 104 so that they collectively produce a focused ultrasonic beam or field. For n transducer elements, the beamformer 106 can contain n driver circuits, each circuit including or consisting of an amplifier 118 and a phase delay circuit 120; each drive circuit drives one of the transducer elements 104. The beamformer 106 receives a radio frequency (RF) input signal from a frequency generator 110, which can be, for example, a model DS345 generator available from Stanford Research Systems, Inc., the input signal typically being in the range of 0.1 MHz to 10 MHz. The input signal can be split into n channels for the n amplifiers 118 and delay circuits 120 of the beamformer 106. In some embodiments, the frequency generator 110 is integrated with the beamformer 106. The radio frequency generator 110 and the beamformer 106 are configured to drive the individual transducer elements 104 of the transducer array 102 at the same frequency but at different phases and / or different amplitudes.

[0016] The amplification or attenuation factors al-an and phase shifts al-an applied by the beamformer 106 are used to transmit and focus the ultrasound energy onto the target region 101 through intervening tissue located between the transducer elements 104 and the target region, and to account for wave distortions induced in the intervening tissue. The amplification factors and phase shifts are calculated using a controller 108, which can provide the calculation functionality by software, hardware, firmware, hardwiring, or any combination thereof. In various embodiments, the controller 108 utilizes a general or special purpose digital data processor programmed with software in a conventional manner, and without undue experimentation, determines the frequency, phase shift, and / or amplification factors needed to achieve a desired focal point or any other desired spatial field pattern at the target region 101. In certain embodiments, the calculations are based on detailed information about the characteristics (e.g., type, size, location, properties, structure, thickness, density, structure, etc.) of the intervening tissue located between the transducer elements 104 and the target, and its effect on the propagation of acoustic energy. Such information can be obtained from an imager 112. The imager 112 can be, for example, a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, a positron emission tomography (PET) device, a single photon emission computed tomography (SPECT) device, or an ultrasound imaging device. The image acquisition can be three-dimensional (3D), or alternatively, the imager 112 can provide a set of two-dimensional (2D) images suitable for reconstructing a three-dimensional image of the target region 101 and / or other regions (e.g., a region surrounding the target 101 or another target region). Image processing functionality can be implemented in the imager 112, the controller 108, or a separate device. Furthermore, as described further below, the ultrasound system 100 and / or the imager 112 can be used to detect signals from acoustic reflectors (e.g., microbubbles 202, see FIG. 2) located generally in the vicinity of the target region 101. Additionally or alternatively, the system 100 can include an acoustic signal detection device (such as a hydrophone or suitable alternative) 124 that detects transmitted or reflected ultrasound from acoustic reflectors, and can provide its received signals to the controller 108 for further processing. Furthermore, the ultrasound system 100 can include an administration system 126 for parenterally introducing acoustic reflectors into the patient's body. The imager 112, the acoustic signal detection device 124, and / or the administration system 126 can be operated using the same controller 108 that facilitates operation of the transducers; alternatively, they can be separately controlled by one or more separate controllers that communicate with each other.

[0017] FIG. IB shows an example imager, an MRI device 112. The device 112 can include a cylindrical electromagnet 134 that generates the necessary static magnetic field within a bore 136 of the electromagnet 134. During a medical procedure, a patient is placed inside the bore 136 on a moveable support table 138. A region of interest 140 within the patient (e.g., the patient's head) can be positioned within an imaging zone 142 where the electromagnet 134 generates a substantially uniform field. A set of cylindrical magnetic field gradient coils 144 can also be disposed within the bore 136 and encircle the patient. The gradient coils 144 generate magnetic field gradients of predetermined amplitudes at predetermined times and in three orthogonal directions to one another. With the field gradients, different spatial locations can be associated with different precession frequencies, thereby endowing a magnetic resonance (MR) image with its spatial resolution. An RF transmitter coil 146 encircling the imaging zone 142 transmits RF pulses into the imaging zone 142 to cause the patient's tissues to emit MR response signals. The raw MR response signals are sensed by the RF coil 146 and passed to an MR controller 148, which then computes MR images that can be displayed to a user. Alternatively, separate MR transmitter and receiver coils can be used. Images acquired using the MRI device 112 can provide radiologists and physicians with visual contrasts between different tissues and internal detail views of patient anatomy that cannot be visualized using conventional X-ray techniques.

[0018] The MRI controller 148 can control the pulse sequence, i.e., the relative timing and strength of the magnetic field gradients and RF excitation pulses and response detection periods. The MR response signals are amplified, conditioned, and digitized into raw data using conventional image processing systems and further converted into an image data array by methods known to those of ordinary skill in the art. Based on the image data, a target region (e.g., a tumor or a target BBB) can be identified.

[0019] To perform targeted drug delivery or tumor ablation, the location of the target region 101 needs to be determined with high precision. Thus, in various embodiments, the imager 112 is first activated to acquire images of the target region 101 and / or non-target regions (e.g., healthy tissue encircling the target region, intervening tissue between the transducer array 102 and the target region 101, and / or any region located in the vicinity of the target) and determine anatomical properties (e.g., tissue type, location, size, thickness, density, structure, shape, vascularization) associated therewith based thereon. For example, a tissue volume can be represented as a set of 3D voxels based on a 3D image or a series of 2D image slices and can include the target region 101 and / or non-target regions.

[0020] To produce high quality focusing at the target region 101, it can be desirable to calibrate the transducer elements 104 and account for transducer geometric imperfections resulting from, for example, movement, displacement, and / or deformation of the transducer elements 104 from their intended positions. In addition, because scattering, absorption, reflection, and / or refraction of the ultrasound waves can occur as the waves travel through non-uniform intervening tissue located between the transducer elements 104 and the target region 101, it can also be desirable to account for these wave distortions in order to improve the focusing properties at the target region 101.

[0021] Referring to FIG. 2, the ultrasound waves emitted from all (or at least some) of the transducer elements 104 are reflected by an acoustic reflector 202. The acoustic reflector 202 can consist essentially of microbubbles introduced through ultrasound generation and / or through parenteral administration by the administration system. In some embodiments, the administration system 126 introduces seed microbubbles into the target region 101; the transducer 102 is then activated to transmit ultrasound waves to the seed microbubbles to produce a microbubble cloud. Methods of generating microbubbles and / or introducing microbubbles into a target region 101 are provided, for example, in PCT Publication No. WO 2018 / 020315, PCT Application No. PCT / US2018 / 064058 (filed December 5, 2018), PCT / IB2018 / 001103 (filed August 14, 2018), PCT / US2018 / 064892 (filed December 11, 2018), PCT / IB2018 / 000841 (filed June 29, 2018), and PCT / US2018 / 064066 (filed December 5, 2018), U.S. Patent Publication No. 2019 / 0083065, and U.S. Patent Application No. 15 / 837,392 (filed December 11, 2017), the contents of which are incorporated herein by reference.

[0022] According to various embodiments, control of the tissue ablation procedure is based on spatial acoustic imaging of the target region 101. This essentially provides a 3D picture of the acoustic energy distribution, enabling detection of high energy events, such as cavitation, that stand out from the background. The acoustic energy is either produced by the tissue ablation event (e.g., acoustic waves emitted by a cavitation bubble) or is initiated by the transducer transmission and reflected by the product of the tissue ablation event (e.g., acoustic waves transmitted from the transducer and reflected by a cavitation bubble) during or after the event. As used herein, the acoustic imaging terms "reflected signal" and "reflected signals" refer to signals generated by acoustic energy, regardless of the source of this energy. Control of the applied acoustic power can be based on multiple successive cavitation level estimates, which can result in complete stopping of the delivery of acoustic pulses, continuing the pulse sequence at a constant power level, or increasing the delivered power at a rate at least partially determined by successive cavitation level estimates. For example, the delivered power can be increased until observed acoustic events (i.e., significant confined reflected signals) are observed at the focal zone within the target region, which can indicate cavitation. At this point, the power can be slowly increased, typically by 2% to 5% relative to the previous acoustic power. After several events are observed at the focal zone, typically one to four events per focal spot, the treatment power can be held constant until several more (e.g., one to ten) events are observed, at which point the treatment of the focal zone is complete. The power can now be increased or decreased by a factor (e.g., 40%), the focal zone is shifted to a new portion of the target region, and the foregoing process is repeated. If no events are detected after the power has been increased to a maximum safe level, the focal spot can be shifted to another target region, or the treatment can be stopped completely. Reflected signals received from the current focal zone can also be used to improve focusing of nearby points.

[0023] In various embodiments, a particular frequency or band of frequencies of the reflected signal is selected for analysis. The reflected signal can be analyzed using the first harmonic of the transmitted signal (i.e., the same frequency as the transmitted signal). Additionally or alternatively, the reflected signal can be analyzed using any other frequency band (e.g., second harmonic frequencies, sub-harmonic frequencies, and / or super-harmonic frequencies). In some embodiments, a broadband signal is used for analysis. For the measurement itself, either a single hydrophone or an array of hydrophones can be employed. Without loss of generality, the following description assumes the use of an array of hydrophones to detect the reflected signal. Since what is being monitored is the difference between two reflected signals that pass through the skull, the effects of aberrations and attenuation are eliminated, and quantitative results are typically obtained without the need for system calibration.

[0024] The use of short pulses representing tissue ablation with an array of hydrophones enables the generation of 3D acoustic activity maps of the target region, a process also known as passive acoustic mapping or PAM. This can be achieved by constructing a 3D image of the spatial acoustic field using the reflected signals from the spatially distributed transducer elements. The distance between each transducer element and each voxel in the spatial region of interest is known, as is the speed of sound through the relevant tissue; therefore, based on the time-of-flight and / or phase delay and by aggregating the measurements from multiple sensing transducer elements to resolve the degeneracy, the response to an event at each voxel of interest can be calculated. Thus, the analysis methods described above can be implemented on a per-voxel basis in the region of interest, providing spatial information relating to treatment progress, efficacy, and safety. For example, excessive activity can be identified at an undesired location (e.g., a main beam effect from an unintended displacement of the target region).

[0025] Typically, the signals reflected from tissue ablation events are mixed with signals from other reflectors in the body (e.g., bone). In some embodiments, generating cavitation activity maps for each pulse in a sequence facilitates comparison between two pulses (e.g., the first and second pulses in a sequence), generating a 3D map of the acoustic field generated as a response to the transmitted pulses in the region of interest. These maps can be superimposed on MRI maps to estimate treatment outcomes with respect to efficacy and safety.

[0026] In some embodiments, a general pipeline for generating acoustic maps for a controller includes: (a) generating a tissue ablation event (e.g., a cavitation bubble), (b) receiving a signal (e.g., emitted by or reflected from a cavitation bubble), (c) optionally removing undesired portions of the signal (e.g., reflections of the transmitted therapy signal reflected by static anatomy such as the skull), (d) correcting aberrations of the signal, and (e) summing the signal (e.g., field reconstruction).

[0027] Producing tissue ablation in a treatment region can require a pulse, each pulse comprising as little as one cycle. Even so, in some scenarios, the pulse used to generate acoustic maps can be longer (e.g., longer than 3 cycles), which results in reduced resolution. To overcome this challenge, the reflected signal can be processed as follows: First, for each receiver, subtract two consecutive received signals to remove the background. Then, filter the important part of the signal (comparable to the pulse length) for a specific frequency (typically the transmission frequency, or other frequency as described above), and obtain the phase and amplitude of this signal part at the selected frequency. Using a relatively long signal part utilizes more energy for the measurement, and improves the SNR by sacrificing resolution (assuming sparsity effects). This produces a complex signal value (containing phase, amplitude, or both) for the selected frequency for each receiver.

[0028] To correct for wave propagation time and / or aberrations, phase delay corrections are applied to the complex signals based on (i) the distance from the receiver to each reconstructed spatial point and / or (ii) an anatomically related aberration.

[0029] Wave propagation time is the time of flight of the acoustic wave from the tissue ablation event to each receiver based on the speed of sound in water and in the water-containing tissue. Correction for wave propagation time is achieved by a simple calculation of length and velocity.

[0030] Correction for aberrations is the correction for aberrations caused by more complex tissue such as the skull. Correction for aberrations can be done using (i) physical models such as described in U.S. Patent No. 10,765,892, the entire disclosure of which is hereby incorporated by reference; (ii) intraoperative measurements such as those described in U.S. Patent Publication No. 2019 / 0308038, the entire disclosure of which is hereby incorporated by reference; and / or (iii) other models such as those described in U.S. Patent No. 11,291,430, the entire disclosure of which is hereby incorporated by reference.

[0031] The corrected complex signal values from all receivers are summed to obtain the amplitude at each reconstructed point (corresponding to the magnitude of the acoustic field). The phase of each point is also obtained. The phase and amplitude values on all reconstructed points make up the 3D PAM.

[0032] Another method of 3D spatial reconstruction is to reconstruct individual 2D planes point-by-point within the target and use an angular spectrum method to create adjacent planes, thus creating a 3D spatial map. Specifically, the angular spectrum method can include expanding the complex wavefield into a sum of plane waves of the same frequency and different directions. The technique can predict the pressure field distribution above a plane based on knowledge of the pressure field distribution at parallel planes.

[0033] The following paragraphs give the results of a typical tissue ablation experiment using the tissue ablation controller. In each trigger initiated by the controller, the transducer ultrasound processes a sequence of two consecutive pulses, each of length ~50 us. Each ultrasound processing sequence triggers the acquisition system to acquire acoustic signals from the treatment region of interest. The acoustic signals are then analyzed as described above (with reference to the reflected signals) and a 3D acoustic map is delivered to the tissue ablation controller to decide the next trigger parameters. For this treatment, the tissue ablation activity is monitored via the maximum intensity of the reconstructed acoustic map.

[0034] The left axis in FIG. 3 plots the maximum intensity in the treatment region measured in arbitrary units, labeled as “Signal.” According to previous experiments, a Signal above 0.015 is identified as evidence of tissue ablation; therefore, Signal = 0.015 is set as the tissue ablation treatment threshold.

[0035] The spatial distribution of the field in the 3D acoustic map can be analyzed. When the power is below the tissue ablation event generation threshold, the measured acoustic field has a wide distribution. When the power bar exceeds the tissue ablation threshold level, local tissue ablation event generation has a narrow distribution of strong field (e.g., >50% of the energy within 3 mm radius). Additionally, if the power level is above the safety threshold, the tissue ablation effect can be greater or can affect a larger area, and thus the reconstructed acoustic field can have a wider distribution. In some embodiments, the acoustic field distribution is used to determine the treatment threshold and / or the safety threshold.

[0036] In this experiment, the basic tool management treatment was used. Specifically, the measured maximum acoustic intensity (Signal in Fig. 3) was the input, and the output voltage (RPout in Fig. 3) was controlled as the output, which in turn increased the FUS power. The initial output voltage was 30% of the maximum voltage allowed by the user. If Signal was above the threshold, the counter of “tissue ablation events” was increased by 1, i.e., events = events + 1. If “events” was 0, the next trigger was set to increase its voltage by 5%. If “events” was greater than 0 and less than 3, the next trigger was set to increase its voltage by 2%. If “events” was greater than 2 but less than 20, the next trigger was set to the previous voltage until the desired cumulative events, which was set to equal to 20 “events” in this experiment, was reached. If “events” was higher than 20, the next trigger was set to zero, or in other words, the treatment was ended. The right axis in Fig. 3 plots the voltage (corresponding to the delivered power) applied according to the foregoing controller algorithm.

[0037] In addition to or as an alternative to the hardware platforms described above with reference to Figs. 1A-2, a representative hardware platform for implementing the present application is described in U.S. Patent No. 11,918,832, the entire disclosure of which is hereby incorporated by reference. The hardware system can include an imaging device (e.g., a magnetic resonance imaging (MRI) device) to characterize the tissue types and / or properties of the target region and / or its surrounding tissue; each type of tissue and location (depending on its properties) can have a corresponding tolerance for tissue ablation; thus, the imaging device can be used to spatially characterize the tissue tolerances, and this spatial representation can be used for comparison with the spatial acoustic map. The ’832 patent also describes suitable ultrasound transducer arrangements and driver circuitry (similar to those described above with reference to Figs. 1A-2).

[0038] A controlled tissue ablation treatment of a single point can cover a volume of 0.001 to 1 cubic centimeter (cc), and a typical ablation volume can be about 0.1 cc. The target to be treated by tissue ablation treatment is typically 0.5 cc to (but not limited to) 125 cc. Careful treatment control starting at a power below the treatment threshold and gradually increasing (as described above with reference to FIG. 3) is a good starting point for volume treatment. In addition, this careful threshold detection gives a high safety margin. However, since the target can consist of thousands of points that need to be ablated, repeating this process for each point to be ablated within the target can take too long.

[0039] Therefore, a strategy for quickly ablating each point in a target while maintaining efficacy and safety of the treatment is needed. In experiments, it was determined that the variation of tissue ablation thresholds is very high; however, the threshold difference between two proximate points within a single tissue type is not large (up to 50% difference). Therefore, in some embodiments, once the threshold of a particular point is measured by the controller, the controller can set the working power level for a region and treat the entire region at the same power level. The working power for a region can be slightly higher (10% to 100%) than the threshold found for the points in the region. In some embodiments, a region is defined as all points that are less than a pre-defined radius away from the point for which the threshold was measured. A typical pre-defined radius can be 10 to 20 mm. In some embodiments, a medical image of the treatment region is used to segment the region by tissue type, and the working power selection can be limited to tissue from the same type. In some embodiments, tissue ablation events in the treatment region are used for focused gradual correction. In some embodiments, the controller monitors the treatment of points around the point for which the threshold was measured in the same way that the treatment of the first point was monitored to ensure efficacy and safety. If the signal of cavitation events is lost, the controller can start increasing the treatment power. If the reflection from the tissue ablation events causes safety issues, the controller can decrease the power. In some embodiments, the treatment region for which the working power applies is not limited to a specific radius. As long as efficacy and safety are tolerable, the treatment can continue, and the power level can be adjusted as needed.

[0040] In some embodiments, the system also has an imaging device for guiding targeting. In some embodiments, the imaging device is an MRI, CT, and / or ultrasound scanner. To ensure treatment at the desired location, an image can be taken, and the location of the actual interaction of the acoustic beam and tissue (the actual location of the treatment) can be located on the image. The image can be taken before, during, and / or between tissue ablation events. In some embodiments, the image is a thermal image of the acoustic heating by the acoustic beam. The thermal image can be produced using MRI thermometry or ultrasound thermometry. The heating is typically mild, temporary heating that does not produce a significant clinical effect. In some embodiments, the image shows the extravasation of microscopic blood cells caused by the explosion of the acoustic contrast agent or the (typically small, weak) tissue ablation event. The extravasation of blood cells can be imaged by MRI (T2* or the like) or CT imaging. In some embodiments, ultrasound imaging is used to detect the bubbles produced by tissue ablation. In some embodiments, the controller automatically locates the actual location of the treatment on the image. In some embodiments, the controller adjusts the treatment parameters to shift the actual location of the treatment toward the desired location of the treatment. In some embodiments, the controller configures or triggers the imaging at the right location and / or time.

[0041] FIG. 4 is a flowchart showing an example process 400 for controllably causing tissue disruption in an internal anatomical region of a target, according to some embodiments. The process can be controlled by instructions stored in a computer memory or a non-transitory computer-readable storage medium. The instructions can be included in one or more programs stored in the non-transitory computer-readable storage medium. When executed by one or more processors (e.g., 108 and / or 148), the instructions cause the system to perform the process. The non-transitory computer-readable storage medium can include one or more solid state storage devices (e.g., flash memory), disk or optical storage devices, or other non-volatile memory devices. The instructions can include source code, assembly language code, object code, or any other format that can be understood by one or more processors. Some operations in the process can be combined and the order of some operations can be changed.

[0042] In operation 402, the ultrasound system (e.g., 100) performs ultrasound treatment of a target region (e.g., 101) with a series of acoustic pulses.

[0043] In operation 404, the system detects (e.g., 112) ultrasound reflection signals from the target region after at least some of the acoustic pulses.

[0044] In operation 406, the system controls the ultrasound transducer (e.g., 102) to deliver a series of acoustic pulses with sufficient amplitude to the target region to induce sufficient cavitation in the target region to mechanically disrupt tissue therein, each acoustic pulse having a duration of no more than 70 µsec or no more than 100 µsec (or a duration outside of these ranges depending on the application).

[0045] In operation 408, the system receives data (e.g., 124) characterizing the detected reflected signals.

[0046] In operation 410, based at least on the data characterizing the detected reflected signals, the system computes an estimate of the acoustic activity level or location or acoustic field distribution at the target region.

[0047] In operation 412, based on the multiple acoustic activity level estimates or acoustic field distribution estimates, the system stops delivering acoustic pulses (e.g., after pulse 39 in FIG. 3), continues delivering acoustic pulses at a constant power level (e.g., between pulses 21 and 39 in FIG. 3), increases the power level used to deliver acoustic pulses (e.g., between pulses 1 and 20 in FIG. 3); or decreases the power level used to deliver acoustic pulses. In some embodiments, the multiple acoustic activity level estimates or acoustic field distribution estimates include multiple successive acoustic activity level estimates or acoustic field distribution estimates.

[0048] In some embodiments, detecting the ultrasound reflected signals includes using multiple spatially distributed acoustic detectors.

[0049] In some embodiments, the acoustic activity level or acoustic field distribution is determined based at least in part on the locations of the acoustic detectors relative to the target region.

[0050] In some embodiments, the acoustic activity level or acoustic field distribution is determined at multiple spatially distributed locations.

[0051] In some embodiments, the process further includes computing a volumetric acoustic field in the target region by field reconstruction.

[0052] In some embodiments, the acoustic pulses have a period in the range of 10 µs to 100 µs.

[0053] In some embodiments, the process further includes estimating the acoustic field distribution for a transmitted frequency field, a second harmonic field, a subharmonic field, and / or a superharmonic field.

[0054] In some embodiments, the process further includes determining a treatment threshold and / or a safety threshold based at least in part on the acoustic field distribution.

[0055] In some embodiments, the process further includes increasing the power level for delivering the acoustic pulses based on the plurality of acoustic activity level estimates, including increasing the power level at a rate determined at least in part by the acoustic activity level estimates.

[0056] In some embodiments, the process further includes setting the constant power level, the increased power level, or the decreased power level as an operating power level for a plurality of points within the target region; and continuing to deliver the acoustic pulses to the plurality of points within the target region at the operating power level without re-estimating the acoustic activity level or the acoustic field distribution.

[0057] In some embodiments, the process further includes defining the region including the plurality of points as: all points at a distance less than a predefined radius from an initial point at which the acoustic activity level or the acoustic field distribution was estimated; or all points in a segment of the target region having a tissue type corresponding to a tissue type at an initial point at which the acoustic activity level or the acoustic field distribution was estimated.

[0058] In some embodiments, the process further includes: acquiring an image using an imaging device, the imaging device including a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, or an ultrasound device; determining a location of the interaction using the image acquired by the imaging device; and adjusting one or more treatment parameters to shift the location of the interaction to a desired location in the target region.

[0059] In some embodiments, the image is a thermal image of acoustic heating caused by the acoustic pulses, or the image is an image sensitive to blood cell extravasation.

[0060] In some embodiments, determining the location of the interaction includes locating blood cell extravasation in the image, or otherwise determining the location of the interaction in the image.

[0061] More generally, the functionality for performing controlled tissue resection at a target region can be structured in one or more modules implemented in hardware, software, or a combination of both. For embodiments in which the functionality is provided as one or more software programs, the programs can be written in any of a number of high level languages such as PYTHON, FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and / or HTML. Additionally, the software can be implemented in an assembly language directed to the microprocessor resident on the target computer; for example, if the software is configured to run on an IBM PC or PC clone, the Intel 80x86 assembly language can be used for implementation. The software can be embodied on an article of manufacture including, but not limited to, a floppy disk, a flash memory disk, a hard disk, an optical disk, a magnetic tape, a PROM, an EPROM, an EEPROM, a field programmable gate array, or a CD-ROM. Embodiments using hardware circuitry can be implemented using, for example, one or more FPGA, CPLD, or ASIC processors.

[0062] Reference has been made throughout this detailed description to various embodiments, examples of which are illustrated in the accompanying drawings. While the application has been described in some detail, the detailed description is considered to be illustrative of the application only. Numerous other modifications or changes can be undertaken by others skilled in the art without departing from the true spirit and scope of the application. Accordingly, it is intended that all such modifications and changes be considered as within the scope of the application as claimed.

[0063] It should be understood that, although the terms “first,” “second,” etc. can be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first device could be termed a second device, and, similarly, a second device could be termed a first device, without changing the meaning of the description, so long as all occurrences of the first device are renamed consistently and all occurrences of the second device are renamed consistently. The first device and the second device are both devices, but they are not the same device.

[0064] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the scope of the claims. As used in the description of the embodiments and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It also will be understood that the term "and / or," as used herein, refers to and encompasses any and all possible combinations of one or more of the associated listed items. For example, "A, B, and / or C" means any

[0065] As used herein, the term "if' can be construed to mean "when" or "once" or "in response to determining" or "in response to detecting" that the stated condition or event has been met, depending on the context. Similarly, the phrase "if it is determined [that a stated condition is true]" or "if [a stated condition is true]" or "when [a stated condition is true]" can be construed to mean "once it is determined" or "in response to determining" or "in response to detecting" that the stated condition is true, depending on the context.

[0066] The foregoing description, for purposes of explanation, has been described with reference to specific embodiments. However, the illustrative discussions above are not intended to be exhaustive or to limit the scope of the application to the precise forms presented. Many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the application and its practical applications, thereby enabling others skilled in the art to best utilize the application and various embodiments with various modifications as are suited to the particular use contemplated.

Claims

1. A system for controllably causing tissue disruption in an internal anatomical region of a target, the system comprising: an ultrasound transducer for ultrasonically treating a target region with a series of acoustic pulses; an acoustic detection system comprising at least one detector for detecting ultrasonic reflection signals from the target region after at least some of the acoustic pulses; and a controller configured to: control the ultrasound transducer to deliver a series of acoustic pulses having sufficient amplitude to the target region to induce sufficient cavitation in the target region to mechanically disrupt tissue therein, each acoustic pulse having a duration of no more than 100 µsec; receive data characterizing the detected reflection signals from the acoustic detection system; estimate a level or location of acoustic activity or a distribution of acoustic field at the target region based at least on the data characterizing the detected reflection signals; and based on a plurality of acoustic activity level estimates or acoustic field distribution estimates: stop delivering the acoustic pulses; continue delivering the acoustic pulses at a constant power level; increase a power level used to deliver the acoustic pulses; or decrease a power level used to deliver the acoustic pulses.

2. The system of claim 1, wherein: the acoustic detection system comprises a plurality of spatially distributed acoustic detectors; and the acoustic activity level or the acoustic field distribution is determined based at least in part on locations of the acoustic detectors relative to the target region.

3. The system of claim 1, wherein the acoustic activity level or the acoustic field distribution is determined at a plurality of spatially distributed locations.

4. The system of claim 1, wherein: the controller is configured to compute a volumetric acoustic field in the target region by field reconstruction; and the acoustic pulses have a period in a range of 10 µs to 100 µs.

5. The system of claim 1, wherein the controller is configured to: estimate the acoustic field distribution for a transmission frequency field, a second harmonic field, a subharmonic field, and / or a superharmonic field; and determine a treatment threshold and / or a safety threshold based at least in part on the acoustic field distribution.

6. The system of claim 1, wherein the controller is configured to increase the power level used to deliver the acoustic pulses based on the plurality of acoustic activity level estimates, including increasing the power level at a rate determined at least in part by the acoustic activity level estimates.

7. The system of claim 1, wherein the controller is configured to: set the constant power level, the increased power level, or the decreased power level as an operating power level for a plurality of points within the target region; and continue delivering the acoustic pulses to the plurality of points within the target region at the operating power level without re-estimating the acoustic activity level or the acoustic field distribution.

8. The system of claim 7, wherein the controller is configured to define a region including the plurality of points as: all points at a distance less than a predefined radius from an initial point at which the acoustic activity level or the acoustic field distribution was estimated; or a region including all points within a predefined distance from a point at which the acoustic activity level or the acoustic field distribution was estimated. ​ all points in a segment of the target region having a tissue type corresponding to a tissue type estimated at the initial point at which the acoustic activity level or the acoustic field distribution is located.

9. The system of claim 1, further comprising an imaging device, the imaging device comprising a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, or an ultrasound device; wherein the controller is further configured to: determine a location of an interaction of the acoustic pulses using images acquired by the imaging device; and adjust one or more treatment parameters to shift the location of the interaction to a desired location in the target region.

10. The system of claim 9, wherein: the images are thermal images of acoustic heating caused by the acoustic pulses, or the images are images sensitive to blood cell extravasation; and the controller is configured to determine the location of the interaction in the images.

11. A method of controllably causing tissue disruption in a target internal anatomical region, the method comprising: ultrasonically treating a target region with a series of acoustic pulses; detecting ultrasonic reflection signals from the target region after at least some of the acoustic pulses; controlling an ultrasonic transducer to deliver a series of acoustic pulses having sufficient amplitude to the target region to induce sufficient cavitation in the target region to mechanically disrupt tissue therein, each acoustic pulse having a duration of no more than 100 µsec; receiving data characterizing the detected reflection signals; based at least on the data characterizing the detected reflection signals, computing an estimate of an acoustic activity level or location or acoustic field distribution at the target region; and based on a plurality of acoustic activity level estimates or acoustic field distribution estimates: stopping delivery of the acoustic pulses; continuing to deliver the acoustic pulses at a constant power level; increasing a power level used to deliver the acoustic pulses; or decreasing a power level used to deliver the acoustic pulses.

12. The method of claim 11, wherein: detecting the ultrasonic reflection signals includes using a plurality of spatially distributed acoustic detectors; and the acoustic activity level or the acoustic field distribution is determined based at least in part on locations of the acoustic detectors relative to the target region.

13. The method of claim 11, wherein the acoustic activity level or the acoustic field distribution is determined at a plurality of spatially distributed locations.

14. The method of claim 11, wherein: the method further comprises computing a volumetric acoustic field in the target region by field reconstruction; and the acoustic pulses have a period in a range of 10 µs to 100 µs.

15. The method of claim 11, further comprising: estimating the acoustic field distribution for a transmission frequency field, a second harmonic field, a subharmonic field, and / or a superharmonic field; and determining a treatment threshold and / or a safety threshold based at least in part on the acoustic field distribution.

16. The method of claim 11, further comprising increasing the power level used to deliver the acoustic pulses based on a plurality of acoustic activity level estimates, including increasing the power level at a rate determined at least in part by the acoustic activity level estimates.

17. The method of claim 11, further comprising: setting the constant power level, increased power level, or decreased power level as an operating power level for a plurality of points within the target region; and continuing to deliver the acoustic pulses to the plurality of points within the target region at the operating power level without re-estimating the acoustic activity level or the acoustic field distribution.

18. The method of claim 17, further comprising defining a region including the plurality of points as: all points at a distance less than a predefined radius from an initial point at which the acoustic activity level or the acoustic field distribution was estimated; or all points in a segment of the target region having a tissue type corresponding to a tissue type at the initial point at which the acoustic activity level or the acoustic field distribution was estimated.

19. The method of claim 11, further comprising: acquiring an image using an imaging device, the imaging device including a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, or an ultrasound device; determining a location of an interaction of the acoustic pulses using the image acquired by the imaging device; and adjusting one or more treatment parameters to shift the location of the interaction to a desired location in the target region.

20. The method of claim 19, wherein: the image is a thermal image of acoustic heating caused by the acoustic pulses, or the image is an image sensitive to blood cell extravasation; and determining the location of the interaction includes determining the location of the interaction in the image.

Images