Targeted therapeutic tissue death by induced vascular disruption

Abstract

A system controllably causes tissue death in a target internal anatomic region. The system includes an ultrasound transducer for sonicating a target region in the presence of a contrast agent therein to cause sufficient damage to blood vessels to kill or change functionality of the tissue supplied by the damaged blood vessels; an acoustic detection system comprising at least one detector for detecting ultrasound reflection signals from the target region following each acoustic pulse; and a controller configured to: (i) control the ultrasound transducer to deliver a series of acoustic pulses to the target region; (ii) receive data from the acoustic detection system characterizing the detected reflection signals; and (iii) based at least in part on the received data from the acoustic detection system, determine a degree of damage to vascular tissue within the target region.

Description

TARGETED THERAPEUTIC TISSUE DEATH BY INDUCED VASCULAR DISRUPTIONTECHNICAL FIELD

[0001] The present disclosure relates to systems and methods for targeting therapeutic tissue death by induced vascular disruption.BACKGROUND

[0002] Various surgical techniques and pharmaceutical treatments have been developed to advance the state of the art for treating brain diseases. Among these, focused ultrasound (FUS) has proven to be a very effective noninvasive modality that can exert various effects on tissue, ranging from transient excitatory or inhibitory neural modulation to generation of lesions, depending on the intensity and pulse regime of the acoustic insonation. Indeed, today, thermal ablation is the primary method for therapeutically generating lesions in the brain. Highly focused acoustic energy causes rapid temperature elevation in target tissues, resulting in tissue death in seconds, while sparing healthy non-target tissues.

[0003] Due to the significant acoustic energy necessary to generate thermal lesions, a substantial portion of which is absorbed by the skull (especially when targeting off brain center targets), treatment protocols are generally limited to targets near the center of the brain. Even so, the absorbed energy in the skull can cause a significant temperature increase, risking unwanted lesion generation near the skull.

[0004] Another treatment modality currently under development is histotripsy. In this modality the focused ultrasound beam mechanically destroys tissue through cavitation, transforming the target into acellular debris. The ultrasonic pulses used in histotripsy are significantly shorter (a few tens of microseconds) than those used for thermal ablation, so the total energy used to generate a typical lesion is significantly less, resulting in less unwanted skull heating. The required pulse intensity for cavitation generation, however, is very high (>20 MPa), imposing stringent system requirements.

[0005] Existing ultrasound-based treatment modalities for the brain, therefore, are limited in use due to the need to avoid excessive skull heating or limited in practical application due to demanding performance criteria.SUMMARY

[0006] The present disclosure describes systems and methods that improve upon existing ultrasound-based treatment modalities by solving the aforementioned limitations as described below.

[0007] In one aspect, a system controllably causes tissue death in a target internal anatomic region. The system includes: an ultrasound transducer for sonicating a target region in the presence of a contrast agent therein to cause sufficient damage to blood vessels to kill or change functionality of the tissue supplied by the damaged blood vessels; an acoustic detection system comprising at least one detector for detecting ultrasound reflection signals from the target region following each acoustic pulse; and a controller configured to: (i) control the ultrasound transducer to deliver a series of acoustic pulses to the target region; (ii) receive data from the acoustic detection system characterizing the detected reflection signals; and (iii) based at least in part on the received data from the acoustic detection system, determine a degree of damage to vascular tissue within the target region. In some implementations, the controller is further configured to estimate a level of contrast agent activity at the target region based at least in part on the received data from the acoustic detection system; and determine the degree of damage to the vascular tissue based on the estimated level of contrast agent activity at the target region. In some implementations, the controller is further configured to repeat (i)-(iii) until a clinically significant degree of damage to vascular tissue within the target region is observed.

[0008] In another aspect, a method is described for controllably causing tissue death in a target internal anatomic region. The method includes: (i) delivering a series of acoustic pulses to the target region; (ii) receiving, at a plurality of spatially distributed detectors, reflection signals from the target region following each acoustic pulse; and (iii) based at least on the received signals, locations of the detectors, and a speed of sound between the detectors and the target region, determining a degree of damage to vascular tissue within the target region. In some implementations, the method further includes estimating a level of contrast agent activity at a plurality of locations at least spatially spanning the target region; and determining the degree of damage to the vascular tissue based on the estimated level of contrast agent activity at the plurality of locations. In some implementations, the method further includes repeating (i)-(iii) until a clinically significant degree of damage to vascular tissue within the target region is observed.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, with an emphasis instead generally being placed upon illustrating the principles of this disclosure. In the following description, various embodiments of the present disclosure are described with reference to the following drawings, in which:

[0010] Figure 1A schematically depicts an exemplary ultrasound system in accordance with various embodiments of the current disclosure.

[0011] Figure IB schematically depicts an exemplary MRI system in accordance with various embodiments of the current disclosure.

[0012] Figure 2 depicts an implementation of an acoustic reflector substantially close to a target region in accordance with some embodiments.

[0013] Figure 3 is a graph depicting observed and actual concentrations of contrast agent during a focused ultrasound procedure, in accordance with some embodiments.

[0014] Figures 4-9 are graphs depicting indications of cavitation during a focused ultrasound procedure comprising a plurality of sonications, in accordance with some embodiments.

[0015] Figure 10 depicts subtraction images that reflect microbubble cavitation, in accordance with some embodiments.

[0016] Figure 11 is a flow chart illustrating an exemplary approach for controllably causing tissue death during a focused ultrasound procedure, in accordance with some embodiments.DETAILED DESCRIPTION

[0017] Figure 1 A illustrates an exemplary ultrasound system 100 for generating and delivering a focused acoustic energy beam to a target region 101 within a patient’s body. The illustrated system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 driving the phased array 102, a controller 108 in communication with the beamformer 106, and a frequency generator 110 providing an input electronic signal to the beamformer 106.

[0018] The array 102 may have a curved (e.g., spherical or parabolic) or other contoured shape suitable for placement on the surface of the patient’s body, or may include one or more planar or otherwise shaped sections. Its dimensions may vary between millimeters and tens of centimeters. The transducer elements 104 of the array 102 may be piezoelectric ceramic elements, and may be mounted in silicone rubber or any other material suitable for damping the mechanical coupling between the elements 104. Piezo-composite materials, or generally any materials capable of converting electrical energy to acoustic energy, may also be used. To assure maximum power transfer to the transducer elements 104, the elements 104 may be configured for electrical resonance at 50 Q, matching input connector impedance.

[0019] The transducer array 102 is coupled to the beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasonic beam or field. For n transducer elements, the beamformer 106 may contain n driver circuits, each 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, typically in the range from 0.1 MHz to 10 MHz, from the frequency generator 110, which may, for example, be a Model DS345 generator available from Stanford Research Systems. The input signal may 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.

[0020] The amplification or attenuation factors cq-om and the phase shifts ai-an imposed by the beamformer 106 serve to transmit and focus ultrasonic energy through the intervening tissue located between the transducer elements 104 and the target region onto the target region 101, and account for wave distortions induced in the intervening tissue. The amplification factors and phase shifts are computed using the controller 108, which may provide the computational functions through software, hardware, firmware, hardwiring, or any combination thereof. In various embodiments, the controller 108 utilizes a general- purpose or special-purpose digital data processor programmed with software in a conventional manner, and without undue experimentation, to determine the frequency, phase shifts and / or amplification factors necessary to obtain a desired focus or any other desired spatial field patterns at the target region 101. In certain embodiments, the computation isbased on detailed information about the characteristics (e.g., the type, size, location, property, structure, thickness, density, structure, etc.) of the intervening tissue located between the transducer element 104 and the target and their effects on propagation of acoustic energy. Such information may be obtained from an imager 112. The imager 112 may be, for example, a magnetic resonance imaging (MRI) device, a computer tomography (CT) device, a positron emission tomography (PET) device, a single-photon emission computed tomography (SPECT) device, or an ultrasonography device. Image acquisition may be three-dimensional (3D) or, alternatively, the imager 112 may 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., the region surrounding the target 101 or another target region). Imagemanipulation functionality may be implemented in the imager 112, in the controller 108, or in a separate device. In addition, the ultrasound system 100 and / or imager 112 may be utilized to detect signals from an acoustic reflector (e.g., microbubbles 202, see Figure 2) located substantially close to the target region 101 as further described below. Additionally or alternatively, the system 100 may include an acoustic-signal detection device (such as a hydrophone or suitable alternative) 124 that detects transmitted or reflected ultrasound from the acoustic reflector, and which may provide the signals it receives to the controller 108 for further processing. In addition, the ultrasound system 100 may include an administration system 126 for parenterally introducing the acoustic reflector into the patient’s body. The imager 112, the acoustic-signal detection device 124, and / or the administration system 126 may be operated using the same controller 108 that facilitates the transducer operation; alternatively, they may be separately controlled by one or more separate controllers intercommunicating with one another.

[0021] Figure IB illustrates an exemplary imager - namely, an MRI apparatus 112. The apparatus 112 may include a cylindrical electromagnet 134, which generates the requisite static magnetic field within a bore 136 of the electromagnet 134. During medical procedures, a patient is placed inside the bore 136 on a movable support table 138. A region of interest 140 within the patient (e.g., the patient’s head) may be positioned within an imaging region 142 wherein the electromagnet 134 generates a substantially homogeneous field. A set of cylindrical magnetic field gradient coils 144 may also be provided within the bore 136 and surrounding the patient. The gradient coils 144 generate magnetic field gradients of predetermined magnitudes, at predetermined times, and in three mutually orthogonal directions. With the field gradients, different spatial locations can be associated with differentprecession frequencies, thereby giving a magnetic-resonance (MR) image its spatial resolution. An RF transmitter coil 146 surrounding the imaging region 142 emits RF pulses into the imaging region 142 to cause the patient’s tissues to emit MR response signals. Raw MR response signals are sensed by the RF coil 146 and passed to an MR controller 148 that then computes an MR image, which may be displayed to the user. Alternatively, separate MR transmitter and receiver coils may be used. Images acquired using the MRI apparatus 112 may provide radiologists and physicians with a visual contrast between different tissues and detailed internal views of a patient’s anatomy that cannot be visualized with conventional x- ray technology.

[0022] The MRI controller 148 may control the pulse sequence, i.e., the relative timing and strengths of the magnetic field gradients and the RF excitation pulses and response detection periods. The MR response signals are amplified, conditioned, and digitized into raw data using a conventional image-processing system, and further transformed into arrays of image data by methods known to those of ordinary skill in the art. Based on the image data, the target region (e.g., a tumor or a target BBB) can be identified.

[0023] To perform targeted drug delivery or tumor ablation, it is necessary to determine the location of the target region 101 with high precision. Accordingly, in various embodiments, the imager 112 is first activated to acquire images of the target region 101 and / or non-target region (e.g., the healthy tissue surrounding the target region, the intervening tissue located between the transducer array 102 and the target region 101 and / or any regions located near the target) and, based thereon, determine anatomical characteristics (e.g., the tissue type, location, size, thickness, density, structure, shape, vascularization) associated therewith. For example, a tissue volume may be represented as a 3D set of voxels based on a 3D image or a series of 2D image slices and may include the target region 101 and / or nontarget region.

[0024] To create a high-quality focus at the target region 101, it may be necessary to calibrate the transducer elements 104 and take into account transducer geometric imperfections resulting from, for example, movement, shifts and / or deformation of the transducer elements 104 from their expected locations. In addition, because the ultrasound waves may be scattered, absorbed, reflected and / or refracted when traveling through inhomogeneous intervening tissues located between the transducer elements 104 and the target region 101, accounting for these wave distortions may also be necessary in order to improve the focusing properties at the target region 101.

[0025] Referring to Figure 2, ultrasound waves transmitted from all (or at least some) transducer elements 104 are reflected by the acoustic reflectors 202. The acoustic reflectors 202 may consist essentially of microbubbles generated by the ultrasound waves and / or introduced parenterally by an administration system. In some embodiments, the administration system 126 introduces a seed microbubble into the target region 101; the transducer 102 is then activated to transmit ultrasound waves to the seed microbubble for generating a cloud of microbubbles. Approaches to generating the microbubbles and / or introducing the microbubbles to the target region 101 are provided, for example, in PCT Publication No. WO 2018 / 020315, PCT Application Nos. PCT / US2018 / 064058 (filed on December 5, 2018), PCT / IB2018 / 001103 (filed on August 14, 2018), PCT / US2018 / 064892 (filed on December 11, 2018), PCT / IB2018 / 000841 (filed on June 29, 2018), and PCT / US2018 / 064066 (filed on December 5, 2018), U.S. Patent Publication No. 2019 / 0083065, and U.S. Patent Application No. 15 / 837,392 (filed on December 11, 2017), the contents of which are incorporated herein by reference.

[0026] In FUS systems, increasing acoustic power intensifies the interaction between microbubbles undergoing cavitation and the surrounding tissue. At a high enough intensity level, perivascular extravasations with hemorrhagic nature occur in the sonicated region. Further increasing FUS intensity results in neuron loss through an ischemic process. We have found this effect may be exploited beneficially, disrupting blood flow to a specific region of the brain by destruction of the microvasculature and thereby inducing ischemic stress on the parenchymal cells, eventually resulting in their death and the generation of local lesions. In contrast to thermal ablation, which as noted is generally restricted to centrally located brain targets, the combination of FUS and a microbubble-based ultrasound contrast agent greatly reduces the ultrasound exposure level needed to ablate brain tissue, and may broaden the range of brain treatments achievable using FUS. At the same time, these benefits are achieved without high pulse intensities.

[0027] To summarize, in accordance with embodiments of this invention, microbubbles and activity initiated by interaction of ultrasound and bubbles cause damage to blood vessels, which in turn causes ischemic damage to the tissue. The target brain cells die from lack of oxygen / lack of blood flow - that is, tissue death is an indirect result of FUS. To minimize the ultrasound intensity necessary to produce this effect and ensure treatment safety by avoiding clinically significant damage outside of the target tissue, it is necessary to control pulse shape, pulse length, pulse sequence and pulse intensity in the target region. Typically thetreatment is performed in the presence of a conventional contrast agent (also referred to as an acoustic reflector) containing a suspension of microbubbles. The contrast agent is usually administered parenterally, although in some cases it may be injected at or near the target site. The contrast agent typically range in size from 150 nm to 20 pm, and are either gas-filled bubbles (microbubbles or nanobubbles) or phase-shifting droplets.

[0028] In accordance with various embodiments, a train of short acoustic pulses is applied to the target region, and cavitation within and surrounding the target region is monitored. The amplitude of the acoustic pulses is held constant or gradually increased until cavitation is achieved, and sonication continues until cavitation is detected throughout the target region. At this point sonication stops but the sequence may be repeated after sufficient time has passed for the circulation to replenish, at least to some degree, the supply of microbubbles in the target region. For example, experiments may be carried out over many patients to determine, for a particular target region, the optimal pulse period and amplitude as well as the average elapsed time before cavitation is first observed. These parameters may provide the basis for treating a new patient, and if cavitation is not observed when expected, the pulse amplitude can be increased and / or the pulse period altered. The sonication sequence may be repeated until vascular damage in the target zone is recognized using, for example, MRI scans, CT scans, or monitoring blood perfusion by measuring the reflected acoustic signal from the microbubbles.

[0029] The latter technique may be understood with reference to FIG. 3. As shown therein, an initial insonation destroys some of the microbubbles of the contrast agent by cavitation. The intensity of the reflected signal from the second insonation depends on the extent of this destruction and the delay between insonations, during which the microbubbles’ concentration is replenished through blood perfusion. By fitting reflection intensities of successive insonations to a model, one can extract the blood perfusion coefficient.

[0030] In FIG. 3, the “observed concentration” curve corresponds to the magnitude of the reflection signal at each insonation. The “actual concentration” curve shows how the insonation pulse destroys a fraction of the microbubbles, and the concentration partially recovers as a result of the circulation; as a result, this cycle of destruction and recovery reflects and can be used to estimate the perfusion rate. When the FUS intensity is not sufficient to generate microbubble cavitation, a flat (steady) reflected signal from all the pulses in the pulse train is obtained.

[0031] In accordance with embodiments described herein, the reflection measurements of such a pulse sequence may be used to detect the onset of microbubble dynamic cavitation and to estimate the extent of this cavitation activity. Such measurements can be used to monitor and control the extent of controlled ischemic damage at a target region. In particular, detected variations in the reflected signals from pulses in the pulse sequence may be used to identify the onset of microbubble cavitation. Moreover, it is possible to quantify this difference to deduce a quantitative value for cavitation activity, which in turn relates to the probability and degree of BBB disruption.

[0032] In various embodiments, the analysis is performed using the first harmonic of the transmission signal (i.e., using the reflected signal at the same frequency as the transmitted signal). It should be understood, however, that it is possible to use any other frequency band of the reflected signal. For the measurement itself, a single hydrophone or an array of them may be employed. Without loss of generality, the following description assumes that the signal is detected using a hydrophone array. As the difference between two reflected signals through the skull is monitored, effects due to aberration and attenuation are eliminated, and system calibration is generally unnecessary to obtain quantitative results.

[0033] There are several mathematical methods that can be used to analyze the measured data. One approach is to compare the reflected signal intensities of two successive pulses. If there are more than two pulses in a pulse sequence, the intensity variance in the sequence may be used as a measure. Statistical analysis methods such as analysis of variance (ANOVA) and analysis of means (ANOM) may be employed to obtain more quantitative results. These approaches can be used for data from a single hydrophone or a hydrophone array.

[0034] When using a hydrophone array, there is a significant advantage in using ANOVA or ANOM to monitor cavitation. In these approaches, the ensembles of amplitude measurements for each pulse are compared. Due to the large number of readings, the analysis tends to be more sensitive to variations and quantifies the difference between pulses, resulting in a quantitative estimate of cavitation level.

[0035] The reflected signal has two components: amplitude and phase. Statistical analysis can be applied to the phase part as well as the amplitude, and differences between phase ensembles can be used to identify the onset of cavitation as well. A combination of resultsusing a plurality of analysis techniques on different components of the measured data can contribute to the statistical confidence level of the obtained result.

[0036] When using an ultrasound frequency of 100 kHz to 1000 kHz, typical pulses in a pulse train are 10 psec to 100 psec long. Different pulse lengths may be used, especially when using different FUS frequencies. A typical delay between pulses in the pulse sequence is 0.5 to 5 msec. To increase measurement sensitivity, it may be preferred to use a shorter delay time (~1 msec).

[0037] Using such short pulses with a hydrophone array enables generation of 3D acoustic activity maps of the target area, a procedure also known as passive acoustic mapping or PAM. This may be accomplished by constructing a 3D image of the spatial acoustic field using 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; accordingly, based on the time of flight and by aggregating measurements from all sensing transducer elements to resolve degeneracies, the response to an event at each voxel can be computed. As a result, the analysis methods described above can be implemented on a per-voxel basis in the target region, providing spatial information relating to treatment progress, efficacy, and safety.

[0038] Specifically, generating a cavitation activity map for each pulse in the sequence facilitates comparison between two pulses (e.g., the first and second pulses in the sequence) and thus generation of a 3D map of the effective dynamic cavitation and BBB disruption probability. These probability maps can be overlayed on MRI maps to estimate ischemic effects and coverage.

[0039] Another approach to 3D spatial reconstruction is to reconstruct a single 2D plane within the target and use the well-known angular spectrum method to create adjacent planes and, hence, a 3D spatial map. The angular spectrum method involves expanding a complex wave field into a summation of plane waves of the same frequency and different directions. The technique can predict an acoustic pressure field distribution over a plane, based upon knowledge of the pressure field distribution at a parallel plane.

[0040] The following paragraphs present the results of a typical experiment involving 10 sonication cycles, where each cycle is a sequence of 10 insonations. The driving voltage is increased by 0.05 V in each successive sonication, which in turn increases FUS power. FIG. 4 illustrates the averaged signal from all hydrophones in the array as a function of individualinsonation; there were 1024 hydrophones in the array. The driving voltage and sonication number are indicated as well. As FUS power is increased, the total reflected signal increases. The plot shows that dynamic cavitation starts at sonication 5 (S5). This is better represented in FIG. 5, in which the data is normalized to the maximum value per sonication.

[0041] Applying ANOVA to the normalized data allows the onset of dynamic cavitation to be detected earlier. FIG. 6 illustrates the Fisher ratio (F) and the probability that the new set of data is equivalent to the previous sets. This evaluation is performed successively after each sonication cycle. The dashed upper and lower lines represent, respectively, 95% and 99% confidence levels. Dynamic cavitation is detected in sonication 4 (S4) with 99% confidence.

[0042] FIG. 7 shows the result of applying ANOM to the same data set. In this case the data mean per sonication is compared with the 95% lower decision line (LDL). Once the result crosses the zero line, it can be stated with 95% confidence level that the set of data is not equivalent to the previous sets. In the illustrated case, the sensitivity of the method is inferior to that of ANOVA.

[0043] To obtain quantitative information regarding dynamic cavitation activity and estimate the probability of BBB disruption, it may be preferred to evaluate differences between repetitions within a sonication sequence (FIG. 8). ANOVA exhibits less sensitivity to the onset of cavitation on this data set (FIG. 9), so it is preferable to use the normalized average for cavitation detection and amplitude differences to quantify cavitation activity once detected.

[0044] The computed degree of cavitation may be used in a control loop whereby FUS power is progressively increased until, first, cavitation is detected, and then until the difference in mean amplitude between successive pulses reaches a level indicating a degree of cavitation corresponding to a desired degree of vascular damage (or a high probability thereof). The specific degree of desired damage can change from patient to patient based on target tissue parameters such as tissue type, shape, location, volume, and so forth. In general, however, the degree of desired damage meets a balance between efficacy (killing target tissue) and safety (preserving as much healthy tissue outside the target tissue as possible). Stated another way, a desired degree of damage is high enough to kill target tissue, and low enough to preserve as much healthy tissue outside the target tissue as possible. Stated in yet another way, a desired degree of damage corresponds to clinically significant damage (anamount of damage causing injury) confined to the target region, thereby preventing the healthy tissue surrounding the target region from being damaged.

[0045] The foregoing approach enables a simple 3D reconstruction of the acoustic activity following each pulse. This may be accomplished by constructing a 3D image of the spatial acoustic field using 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; accordingly, based on the time of flight and by aggregating measurements from all sensing transducer elements to resolve degeneracies, the response to an event at each voxel can be computed. As a result, the analysis methods described above can be implemented on a per-voxel basis in the target region, providing spatial information relating to treatment progress, efficacy, and safety.

[0046] FIG. 10 illustrates subtraction images that reflect microbubble cavitation (axis dimensions are millimeters). As insonation power reaches the cavitation threshold, acoustic activity that deviates slightly from the target (0,0,0) is observed (FIGS. 8a and 8b). As power increases (FIGS. 8c and 8d), the cavitation level increases as does the volume in which this activity occurs. Once calibrated, the measured values can be used to express the probability of ischemic effects in specific regions of the targeted volume.

[0047] Figure 11 is a flow diagram illustrating an example process 1100 for controllably causing tissue death during a focused ultrasound procedure, in accordance with some implementations. The process may be governed by instructions that are stored in a computer memory or non-transitory computer readable storage medium. The instructions may 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 may include one or more solid state storage devices (e.g., Flash memory), magnetic or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that can be interpreted by one or more processors. Some operations in the process may be combined, and the order of some operations may be changed.

[0048] In operation 1102, an ultrasound transducer (e.g., 102) delivers a sequence of acoustic pulses to a target volume.

[0049] In operation 1104, a plurality of spatially distributed detectors (e.g., elements 104 or a hydrophone array) receives ultrasound reflection signals from the target volume following each acoustic pulse.

[0050] In operation 1106, based at least on the received signals, locations of the detectors, and a speed of sound between the detectors and the target region, a controller (e.g., 108 and / or 148) determines a degree of damage to vascular tissue within the target region.

[0051] In some implementations, the method further includes estimating a level of contrast agent activity at a plurality of locations at least spatially spanning the target region; and determining the degree of damage to the vascular tissue based on the estimated level of contrast agent activity at the plurality of locations.

[0052] In some implementations, the method further includes repeating (i)-(iii) until a clinically significant degree of damage to vascular tissue within the target region is observed.

[0053] A representative hardware platform for implementation of the present invention is described in U.S. Patent Publ. No. 2020 / 0139158, the entire disclosure of which is hereby incorporated by reference. The hardware system may include an imaging device (e.g., a magnetic resonance imaging (MRI) device) to characterize tissue types and / or properties of the target BBB region and / or its surrounding tissue; each type and location of tissue, depending on its properties, may have corresponding tolerances for cavitation; accordingly, the imaging device may be used to spatially characterize tissue tolerance, and this spatial representation may be used for comparison to a spatial map of cavitation effects generated and updated as described above. The ’9158 application also describes suitable ultrasound transducer arrangements and driver circuitry.

[0054] More generally, functionality for performing controlled ischemic damage at a target region may be structured in one or more modules implemented in hardware, software, or a combination of both. For embodiments in which the functions are provided as one or more software programs, the programs may 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 a target computer; for example, the software may be implemented in Intel 80x86 assembly language if it is configured to run on an IBM PC or PC clone. The software may be embodied on an article of manufacture including, but not limited to, a floppy disk, a jump drive, a hard disk, an optical disk, amagnetic tape, a PROM, an EPROM, EEPROM, field-programmable gate array, or CD- ROM. Embodiments using hardware circuitry may be implemented using, for example, one or more FPGA, CPLD or ASIC processors.

[0055] As used herein, the term “substantially” refers to ± 10% of the tissue volume, in some embodiments, ± 5% of the tissue volume. The term “clinically significant” refers to an undesirable (sometimes less desirable) effect on tissue that a clinician would classify as significant (e.g., causing injury).

[0056] The term “tissue death” refers to any type of cell death, including, for example, accidental cell death (ACD), anoikis, autophagy-dependent cell death, autosis, cellular senescence, efferocytosis, entotic cell death, extrinsic apoptosis, ferroptosis, immunogenic cell death, intrinsic apoptosis, lysosome-dependent cell death, mitochondrial permeability transition (MPT)-driven necrosis, mitotic catastrophe, mitotic death, necroptosis, necrosis, NET otic cell death, parthanatos, programmed cell death (PCD), pyroptosis, regulated cell death (RCD), and so forth.

[0057] Reference have been made in detail to various implementations, examples of which are illustrated in the accompanying drawings. In the above detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention and the described implementations. However, the invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the implementations.

[0058] It will be understood that, although the terms “first,” “second,” etc. may 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.

[0059] The terminology used herein is for the purpose of describing particular implementations only and is not intended to be limiting of the claims. As used in the description of the implementations 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 will also 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: A only; B only; C only; A and B; A and C; B and C; or A, B, and C. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0060] As used herein, the term “if’ may be construed to mean “when” or “upon” or “in response to determining” or “in accordance with a determination” or “in response to detecting,” that a stated condition precedent is true, depending on the context. Similarly, the phrase “if it is determined [that a stated condition precedent is true]” or “if [a stated condition precedent is true]” or “when [a stated condition precedent is true]” may be construed to mean “upon determining” or “in response to determining” or “in accordance with a determination” or “upon detecting” or “in response to detecting” that the stated condition precedent is true, depending on the context.

[0061] The foregoing description, for purpose of explanation, has been described with reference to specific implementations. However, the illustrative discussions above are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The implementations were chosen and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various implementations with various modifications as are suited to the particular use contemplated.

Claims

CLAIMS1. A system for controllably causing tissue death in a target internal anatomic region, the system comprising: an ultrasound transducer for sonicating a target region in the presence of a contrast agent therein to cause sufficient damage to blood vessels to kill or change functionality of the tissue supplied by the damaged blood vessels; an acoustic detection system comprising at least one detector for detecting ultrasound reflection signals from the target region following each acoustic pulse; and a controller configured to:(i) control the ultrasound transducer to deliver a series of acoustic pulses to the target region;(ii) receive data from the acoustic detection system characterizing the detected reflection signals; and(iii) based at least in part on the received data from the acoustic detection system, determine a degree of damage to vascular tissue within the target region.

2. The system of claim 1, wherein the controller is further configured to: estimate a level of contrast agent activity at the target region based at least in part on the received data from the acoustic detection system; determine the degree of damage to the vascular tissue based on the estimated level of contrast agent activity at the target region.

3. The system of claim 1, wherein the controller is further configured to repeat (i)-(iii) until a clinically significant degree of damage to vascular tissue within the target region is observed.

4. The system of claim 1, wherein the ultrasound transducer comprises an array of elements for sonicating the target region, and the at least one detector of the acoustic detection system is physically the same as all or part of the elements of the array.

5. The system of claim 1, wherein the ultrasound transducer comprises an array of elements for sonicating the target region, and the at least one detector of the acoustic detection system is physically different from all or part of the elements of the array.

6. The system of claim 1, wherein the acoustic detection system comprises a plurality of spatially distributed acoustic detectors.

7. The system of claim 6, wherein the level of contrast agent activity is determined at least in part based on locations of the acoustic detectors with respect to the target region.

8. The system of claim 7, wherein the level of contrast agent activity is determined at a plurality of spatially distributed locations.

9. The system of claim 1, wherein the degree of damage to vascular tissue within the target region is determined by estimating a blood perfusion rate in the target region based on the detected reflection signals.

10. The system of claim 1, wherein: the degree of damage to vascular tissue within the target region is determined using at least one image; and the system further comprises an MRI device for generating the at least one image or a CT device for generating the at least one image.

11. The system of claim 1, wherein the acoustic pulses have a period in a range of 20ps to 70ps.

12. The system of claim 1, wherein the contrast agent activity is at least one of onset of cavitation and an extent of cavitation.

13. The system of claim 1, wherein contrast agent activity outside the target region is detected using local maxima analysis.

14. The system of claim 1, wherein contrast agent activity outside the target region is detected by summing contrast agent activity around the target region up to a predetermined radius and comparing it to a total microbubble activity level.

15. A method of controllably causing tissue death in a target internal anatomic region, the method comprising:(i) delivering a series of acoustic pulses to the target region;(ii) receiving, at a plurality of spatially distributed detectors, reflection signals from the target region following each acoustic pulse; and(iii) based at least on the received signals, locations of the detectors, and a speed of sound between the detectors and the target region, determining a degree of damage to vascular tissue within the target region.

16. The method of claim 15, further comprising: estimating a level of contrast agent activity at a plurality of locations at least spatially spanning the target region; and determining the degree of damage to the vascular tissue based on the estimated level of contrast agent activity at the plurality of locations.

17. The method of claim 15, further comprising repeating (i)-(iii) until a clinically significant degree of damage to vascular tissue within the target region is observed.

18. A method of controllably causing tissue death in a target internal anatomic region, the method comprising: controllably destroying a blood supply to the target internal anatomic region based on contrast agent activity level at the target internal anatomic region, and spatial distribution characteristics used with estimating contrast agent activity level.

19. The method of claim 18, wherein controllably destroying the blood supply to the target internal anatomic region includes:(i) delivering a series of acoustic pulses to the target internal anatomic region;(ii) determining a degree of damage to vascular tissue within the target internal anatomic region.

20. The method of claim 19, further comprising: receiving, at a plurality of spatially distributed detectors, reflection signals from the target internal anatomic region following each acoustic pulse; and based at least on the received signals, locations of the spatially distributed detectors, and a speed of sound between the spatially distributed detectors and the target internal anatomic region, estimating a level of microbubble activity at a plurality of locations at least spatially spanning the target internal anatomic region.

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