A tissue-type-based system for establishing blood-brain barrier opening and its therapeutic parameters.

Abstract

A controller, communicatively coupled to an ultrasound transducer, acquires image data of one or more subregions of a target area, determines the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions based on the image data, determines acoustic therapy parameters for each of the one or more subregions based on the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions, and causes the ultrasound transducer to ultrasonically treat the one or more subregions according to the acoustic therapy parameters corresponding to each of the one or more subregions.

Description

Technical Field

[0001] Cross - reference to Related Applications This is related to U.S. Patent Application No. 18 / 176,978, filed on March 1, 2023, and International Patent Application No. PCT / IB2022 / 000747, filed on December 8, 2022, each of which is hereby incorporated by reference in its entirety.

[0002] The field of the present disclosure generally relates to ultrasonic systems, and more particularly, to systems and methods for selectively and targetedly opening the blood - brain barrier using ultrasonic treatment.

Background Art

[0003] The blood - brain barrier (BBB), formed by a layer of cells in the central nervous system (CNS), excludes large molecules from entering the brain parenchyma, thereby protecting the brain parenchyma from damage by toxic foreign substances. However, the BBB also represents one of the greatest obstacles to treating many brain diseases. Specifically, the BBB prevents many therapeutic agents, such as drugs and gene therapy vectors, from reaching the patient's brain tissue. For example, the treatment of CNS infections, neurodegenerative diseases, congenital enzyme deficiencies, and brain tumors are all hindered, among other things, by the ability of the BBB to block the passage of antibiotics, antiretroviral drugs, enzyme replacement therapies, gene preparations, and anti - tumor drugs. Therefore, it is desirable to "open" the BBB temporarily and locally to allow therapeutic amounts of these agents to access the affected brain tissue.

[0004] Focused ultrasound (FUS) is a technique that enables the mechanical opening of the blood-brain barrier (BBB), allowing drugs and other molecules to be introduced into the brain parenchyma. BBB opening is achieved by sonicating systemically circulating bubbles, thus applying localized mechanical strain to the endothelial cells. Currently, BBB opening surgery is limited to small brain regions or yields variable results due to the heterogeneous nature of brain tissue. Different brain regions differ in their physiological properties (e.g., tissue composition, mechanical properties, vascular density, vascular diameter distribution, vascular blood flow velocity, etc.). Furthermore, cancerous and benign tumors are known to have abnormal and deformed vascular systems, as well as their own heterogeneous microenvironments. Often, tumor vascular systems differ between the tumor core and its rim, and in certain regions, deformed vessels have their own unique mechanical properties. In some other conditions, such as Alzheimer's disease (AD), the vascular system is known to be more permeable and fragile compared to healthy tissue. Using FUS to open the BBB in such diverse regions and microenvironments can lead to overtreatment and damage, or tissue-dependent BBB opening. Therefore, there is a need for a FUS treatment system and method that can achieve safe and fused BBB openings in different brain regions and the microenvironment, thereby avoiding permanent damage to the BBB and its surrounding tissues.

[0005] Furthermore, the autonomic nervous system may alter blood flow characteristics between repeated ultrasound treatments due to accumulated blood-brain barrier opening effects and vasoconstriction. Therefore, there is a need for FUS treatment systems and methods that can achieve safe and fused BBB opening in brain regions where physiological properties are altered. [Overview of the Initiative] [Means for solving the problem]

[0006] This disclosure provides a system and method for adaptively treating a target area in a safe and effective manner by identifying the treatment-related properties of the target area while considering local microbubble concentration, blood flow pattern, and tissue type. This adaptive treatment plan enables safe and efficient blood-brain barrier (BBB) ​​opening in large heterogeneous brain regions. In addition, specific acoustic treatment parameters for optimal BBB opening with minimal treatment-related side effects are described in detail. The technique described herein estimates the optimal acoustic parameters for each different area or tissue to be treated and adjusts the treatment parameters to achieve optimal BBB opening for each specified treatment area or tissue. Furthermore, the technique described herein adaptively modifies the treatment parameters in real time in response to changes in blood flow patterns.

[0007] In some embodiments, the disclosure relates to a system and / or method for providing focused ultrasound to a target region. The controller is configured to acquire image data of one or more subregions of a target region and / or regions surrounding the target region, determine a tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions based on the image data, determine acoustic therapeutic parameters for each of the one or more subregions based on the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions, and cause an ultrasound transducer to ultrasonically treat the one or more subregions according to the acoustic therapeutic parameters corresponding to each of the one or more subregions.

[0008] In some embodiments, a first subregion of one or more subregions includes a first tissue type characterized by a first vascular density, and a second subregion of one or more subregions includes a second tissue type characterized by a second vascular density lower than the first vascular density, and determining acoustic therapy parameters for each of the one or more subregions includes, for the first subregion, determining a first acoustic therapy dose, therapy rate, and / or focal zone heterogeneity, and for the second subregion, determining a second acoustic therapy dose, therapy rate, and / or focal zone heterogeneity lower than the first acoustic therapy dose, therapy rate, and / or focal zone heterogeneity. In some embodiments, the target region includes a portion of the blood-brain barrier, including gray matter and white matter, where the first tissue type is gray matter and the second tissue type is white matter. In some embodiments, the first tissue type can tolerate a therapy rate 2 to 4 times higher than that of the second tissue type.

[0009] In some embodiments, a first subregion of one or more subregions includes a first tissue type characterized by a first tolerance level for treatment, and a second subregion of one or more subregions includes a second tissue type characterized by a second tolerance level for treatment lower than the first tolerance level for treatment, and determining acoustic therapy parameters for each of the one or more subregions includes, for the first subregion, determining a first acoustic therapy dose, treatment rate, and / or focal zone heterogeneity, and for the second subregion, determining a second acoustic therapy dose, treatment rate, and / or focal zone heterogeneity lower than the first acoustic therapy dose, treatment rate, and / or focal zone heterogeneity. In some embodiments, the target region includes a portion of the blood-brain barrier, including gray matter and white matter, where the first tissue type is gray matter and the second tissue type is white matter. In some other embodiments, the target region includes a portion of the blood-brain barrier containing healthier and unhealthier tissues, where the first tissue type is gray matter and the second tissue type is white matter. In some embodiments, the unhealthier tissue is tissue heavily affected by neurodegenerative diseases such as Alzheimer's disease.

[0010] In some embodiments, a first subregion of one or more subregions is characterized by a first vascular density, a second subregion of one or more subregions is characterized by a second vascular density lower than the first vascular density, and determining acoustic therapy parameters for each of the one or more subregions includes, for the first subregion, determining a first acoustic therapy dose, treatment rate, and / or focal zone heterogeneity, and for the second subregion, determining a second acoustic therapy dose, treatment rate, and / or focal zone heterogeneity lower than the first acoustic therapy dose, treatment rate, and / or focal zone heterogeneity.

[0011] In some embodiments, a first subregion of one or more subregions is characterized by a first microbubble concentration, a second subregion of one or more subregions is characterized by a second microbubble concentration lower than the first microbubble concentration, and determining the acoustic therapy parameters for each of the one or more subregions includes, for the first subregion, determining a first acoustic therapy dose, therapy rate, and / or focal band heterogeneity, and for the second subregion, determining a second acoustic therapy dose, therapy rate, and / or focal band heterogeneity lower than the first acoustic therapy dose, therapy rate, and / or focal band heterogeneity.

[0012] In some embodiments, the controller is configured to determine, based on image data, the tissue type associated with each of one or more subregions, and the acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or therapy duration, and determining the acoustic therapy parameters for each of one or more subregions includes determining a relatively low pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or therapy duration for subregions having tissue types characterized by relatively low therapy tolerance, bubble density, vascular density, or vascular flow velocity. In some embodiments, in those regions, the controller may select a lower acoustic frequency that generates more bubble activity. In other embodiments, in those regions, the controller may select an acoustic frequency that better matches the resonant frequency of the bubbles to maximize the bubble response. In some embodiments, the controller may manipulate the phase or time delay configuration to improve or defocus the focus to obtain less heterogeneous therapy in the focal area according to the tissue tolerance.

[0013] In some embodiments, the controller is configured to determine, based on image data, vascular properties associated with each of one or more subregions, where the vascular properties are vascular density or vascular flow velocity, and the acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or therapy duration, and determining the acoustic therapy parameters for each of one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low therapy duration for subregions having relatively low vascular density or vascular flow velocity.

[0014] In some embodiments, the controller is configured to determine the microbubble concentration associated with each of one or more subregions based on image data, and the acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or therapy duration, and determining the acoustic therapy parameters for each of one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low therapy duration for subregions having a relatively low microbubble concentration.

[0015] In some embodiments, the controller is further configured to cause an ultrasonic transducer to ultrasonically process one or more subregions, acquire subsequent image data of one or more subregions of the target region, determine updated vascular properties or microbubble concentrations associated with each of the one or more subregions based on the subsequent image data, determine updated acoustic therapy parameters for each of the one or more subregions based on the updated vascular properties or microbubble concentrations associated with each of the one or more subregions, and cause the ultrasonic transducer to ultrasonically process one or more subregions according to the updated acoustic therapy parameters corresponding to each of the one or more subregions.

[0016] In some embodiments, the controller is further configured to determine acoustic therapeutic parameters for each of the one or more subregions for each ultrasound treatment or pulse, based on the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions, along with acoustic information received during previous ultrasound treatments or pulses of the subregions, and to cause the ultrasound transducer to ultrasound the one or more subregions according to the updated acoustic therapeutic parameters corresponding to each of the one or more subregions.

[0017] In some embodiments, acquiring image data includes acquiring contrast-enhanced ultrasound (CEUS) data, ultrasound localization microscope (ULM) data for acquiring ultrasound super-resolution images, magnetic resonance imaging (MRI) data, or computed tomography (CT) data.

[0018] In some embodiments, sonicating one or more subregions with an ultrasonic transducer includes generating and / or activating microbubbles by applying ultrasound to a target region, or sonicating microbubbles administered by the system in the target region with the transducer. In some embodiments, acquiring image data includes imaging the target region. In some embodiments, acquiring image data includes identifying the target region and determining vascular properties associated with each of the one or more subregions using an atlas. In some embodiments, sonicating one or more subregions with an ultrasonic transducer includes controlling the acoustic output or energy emitted by the transducer elements of the ultrasonic transducer so that the acoustic output or energy exceeds a threshold level, thereby inducing microbubble generation or higher acoustic radiation. In some embodiments, acoustic therapeutic parameters are frequency, amplitude, or phase associated with multiple transducer elements of the ultrasonic transducer.

[0019] In some embodiments, the treatment controller has a separate algorithm for maintaining treatment safety based on acoustic feedback during treatment. Such implementations are sometimes called blind implementations because the controller is not aware of the tissue type. The blind controller may use one set of one or more bands of acoustic feedback in treatment for efficacy (e.g., calculation of treatment dose and treatment rate) and another independent set of one or more bands for maintaining safety (e.g., keeping the energy or power measured in the safety band below a threshold). In some embodiments, the bands for efficacy and the bands for safety may partially or completely overlap.

[0020] In some embodiments, safety information may be acquired by the controller using curve fitting or other types of preprocessing, which can separate narrowband signals indicating overtreatment from broadband efficacy indicators without prior knowledge of their specific frequencies. The bifurcation exhibits intense cavitation activity and appears in the PCD spectrum as a symmetrical peak around a quasi-harmonic peak, whose exact frequency could not be estimated beforehand. Comb filters can separate narrowband peaks (harmonics) from broadband signals when their frequencies are known (e.g., the harmonic sum method for improved narrowband and broadband signal quantification during passive monitoring of ultrasound therapy). A slightly different approach using curve fitting extends this to separate peaks with unknown frequencies from broadband signals.

[0021] In some embodiments, the safety algorithm can use the tissue type determined by the controller as input to the safety algorithm. In some embodiments, the safety algorithm selects a safety threshold based on the tissue type (e.g., white matter vs. gray matter, or any other tissue type characteristic). In some embodiments, the controller selects a lower safety threshold for tissues with lower vascular density, while in some other embodiments, if possible, the controller may prefer efficacy over safety and select a higher safety threshold for tissues characterized by lower vascular density, resulting in lower treatment rates.

[0022] Where used herein, the terms “about” and “substantially” mean ±20%, and in some embodiments, ±5%. Throughout this specification, any reference to “one example,” “an example,” “one embodiment,” or “an embodiment” means that a particular feature, structure, or characteristic described in relation to that example is included in at least one example of the Art. Thus, the appearance of the phrases “one example,” “an example,” “one embodiment,” or “an embodiment” in various places throughout this specification does not necessarily all refer to the same example. Furthermore, a particular feature, structure, routine, step, or characteristic may be combined in any preferred manner in one or more examples of the Art. The headings provided herein are for convenience only and are not intended to limit or imply any limitation or interpretation of the scope or meaning of the claimed Art.

[0023] In the drawings, similar reference letters generally refer to the same part throughout different drawings. Furthermore, the drawings are not necessarily to scale, and instead, the focus is generally on illustrating the principles of the invention. In the following description, various embodiments of the invention are described with reference to the following drawings. [Brief explanation of the drawing]

[0024] [Figure 1] This section schematically illustrates exemplary ultrasonic systems in various embodiments. [Figure 2] Shows the presence of microbubbles within a target tissue region according to various embodiments. [Figure 3] Shows exemplary image data of a target region according to some embodiments. [Figure 4] Shows exemplary adaptation plan data for one or more sub-regions within a target region according to some embodiments. [Figure 5] Shows an exemplary scenario in which acoustic treatment parameters can vary according to a combination of tissue type and vascular characteristics according to some embodiments. [Figure 6] Shows a flowchart of an exemplary method for providing focused ultrasound to a target region according to some embodiments. [Figure 7] Shows experimental results of BBB opening in Landrace pigs that were ultrasonically treated over a wide range of anatomical regions according to some embodiments. [Figure 8] Shows experimental results of BBB opening in Landrace pigs that were ultrasonically treated over a wide range of anatomical regions according to some embodiments. [Figure 9] Shows experimental results of BBB opening in Landrace pigs that were ultrasonically treated over a wide range of anatomical regions according to some embodiments. [Figure 10] Shows experimental results of BBB opening in Landrace pigs that were ultrasonically treated over a wide range of anatomical regions according to some embodiments. [Figure 11] Shows experimental results of BBB opening in Landrace pigs that were ultrasonically treated over a wide range of anatomical regions according to some embodiments. [Figure 12] Shows experimental results of BBB opening in Landrace pigs that were ultrasonically treated over a wide range of anatomical regions according to some embodiments. [Figure 13] Shows experimental results of BBB opening in Landrace pigs that were ultrasonically treated over a wide range of anatomical regions according to some embodiments. [Figure 14]Experimental results of BBB opening in landrace pigs sonicated over a wide range of anatomical regions, according to several embodiments, are shown. [Figure 15] Experimental results of BBB opening in landrace pigs sonicated over a wide range of anatomical regions, according to several embodiments, are shown. [Modes for carrying out the invention]

[0025] Figure 1 shows an exemplary ultrasound system 100 for generating a focused acoustic energy beam and delivering it to a target region 101 within the patient's body. The ultrasound treatment with the applied ultrasound may induce microbubble cavitation or acoustic radiation to disrupt the target BBB region in a controlled and reversible manner. The applied ultrasound may be reflected from the target region and / or non-target regions, and images of the target region and / or non-target regions may be generated based on the reflected waves. Additionally, microbubbles may be introduced into the target region 101 and / or non-target regions to increase ultrasound reflection, thereby improving the contrast of the ultrasound image. In some embodiments, the applied ultrasound may ablate tissue within the target region 101 and / or induce microbubble vibration and / or cavitation to improve the therapeutic effect.

[0026] In various embodiments, the system 100 includes a phase array 102 of transducer elements 104, a beamformer 106 that drives the phase array 102, a controller 108 that communicates with the beamformer 106 and is configured to operate the beamformer 106 according to an adaptive treatment plan 118, and a frequency generator 110 that provides input electronic signals to the beamformer 106.

[0027] In various embodiments, the ultrasound system 100 further includes an imaging device 112 for determining the anatomical properties (e.g., type, nature, structure, thickness, density, etc.) of the target region 101 and / or the surrounding tissue (referred to as the non-target region). For example, the imaging device 112 may be a contrast-enhanced ultrasound device (CEUS), an ultrasound localization microscope (ULM) for acquiring ultrasound super-resolution images, 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 ultrasound system 100 and / or the imaging device 112 may be used to detect the presence, type, and / or location associated with microbubble cavitation.

[0028] In various embodiments, the ultrasonic system 100 further includes an acoustic signal detector 114, also called a cavitation detection device, for detecting information associated with microbubble cavitation. For example, the acoustic signal detector 114 may be a passive cavitation detector (PCD), a hydrophone, or any suitable alternative.

[0029] The array 102 may have a curved shape (e.g., spherical or parabolic) suitable for placement on the surface of the skull, or it may include one or more planar or other shaped sections. Its dimensions may vary between a few millimeters and several tens of centimeters. The transducer elements 104 of the array 102 may be piezoelectric ceramic elements and may be mounted to silicone rubber or any other material suitable for attenuating the mechanical coupling between the elements 104. Piezoelectric composite materials, or any material in general that can convert electrical energy into acoustic energy, may also be used. To ensure maximum power transmission to the transducer elements 104, the elements 104 may be configured to resonate electrically at 50 Ω so as to match (or substantially match) the input connector impedance.

[0030] The transducer array 102 is coupled to a beamformer 106, which drives the individual transducer elements 104 so that they collectively generate a focused ultrasonic beam or field. For n transducer elements, the beamformer 106 may include n driver circuits, each driver circuit including or consisting of an amplifier, a phase shift circuit, and / or a time shift circuit. Each driver circuit drives one of the transducer elements 104. The beamformer 106 receives a radio frequency (RF) input signal from a frequency generator 110, typically in the range of 0.1 MHz to 1.0 MHz. The input signal may be split into n channels for the n amplifiers, phase shift circuits, and time shift circuits of the beamformer 106. In some embodiments, the frequency generator 110 is integrated with the beamformer 106. The frequency generator 110 and beamformer 106 are configured to drive the individual transducer elements 104 of the transducer array 102 at the same frequency, but with different amplification, different phase, and / or different time delays. The time delay shifts all frequencies by the same amount of time, while the phase delay shifts some frequencies longer than others.

[0031] The amplification or attenuation coefficients α1~αn, phase shifts Φ1~Φn, and / or time shifts t1~tn imposed by the beamformer 106 help to transmit and focus the ultrasonic energy through the patient's skull to a selected region 101 of the patient's BBB and to account for the distortion of the waves induced in the skull and soft brain tissue. The amplification coefficients, phase shifts, and time shifts are calculated using a controller 108, which may provide computational capabilities through software, hardware, firmware, wiring, or any combination thereof. For example, the controller 108 may utilize a software-programmed general-purpose or dedicated digital data processor in a conventional manner, without excessive experimentation, to determine the optimal values ​​of the ultrasonic parameters (e.g., frequency, amplification coefficients, phase shifts, and / or time shifts) associated with each element 104 to obtain a desired focus or any other desired spatial field pattern. The optimal values ​​of the ultrasound parameters may be experimentally refined one or more times before, after, and / or during the ultrasound treatment, based on, for example, the focus quality, the focal position relative to the target 101, and / or the microbubble response to the ultrasound treatment. The focus quality and position may be monitored using the imaging device 112, and the microbubble response may be detected using the transducer 102 and / or the acoustic signal detector 114.

[0032] In certain embodiments, the optimal values ​​of the ultrasound parameters are computationally estimated based on detailed information regarding the properties of the intervening tissue and their effects on the propagation of acoustic energy (e.g., reflection, refraction, and / or scattering). Such information may be obtained from the imaging device 112 and analyzed manually or computationally. Image acquisition may be three-dimensional, or alternatively, the imaging device 112 may provide a set of two-dimensional images suitable for reconstructing three-dimensional images of the target and / or non-target regions. Image manipulation functions may be implemented in the imaging device 112, in the controller 108, or in a separate device.

[0033] In certain treatment scenarios, ultrasound propagating toward the target region 101 from different directions may encounter highly variable anatomical structures such as different vascular densities, different vascular morphologies (e.g., diameter distribution), different vascular hemodynamics, different tissue layer thicknesses, and different acoustic impedances. As a result, the energy deposition in the target region 101 varies significantly with frequency, often non-monotonic, and the optimal frequency for a particular patient is typically unpredictable. Therefore, in some embodiments, the ultrasound frequency is optimized by sequentially ultrasound-treating the target region 101 with waves having different “test frequencies” within a test frequency range, and for each frequency tested, parameters indicating energy deposition within the target region 101 (e.g., temperature, acoustic force, tissue displacement, etc.) are measured. The test range may extend to the entire range of frequencies suitable for ultrasound treatment (e.g., 0.1 MHz to 10 MHz in various embodiments), but is typically a much smaller subrange within which the optimal frequency is expected. Such subranges may be determined, for example, based on calculated estimates of the optimal frequency, simulation results, or empirical data obtained for the same target in other patients. Further details regarding determining the optimal frequency for ultrasonic applications are provided, for example, in U.S. Patent Publication 2016 / 0008633, the entirety of which is incorporated herein by reference.

[0034] In some embodiments, optimizing the ultrasonic frequency involves iteratively setting a test frequency, ultrasonically treating the target region 101 at the selected frequency, and quantitatively evaluating the resulting focusing properties or energy deposition in the target region 101. This may be achieved, for example, by MRI thermometry to measure the temperature rise in the target region 101 due to the deposited energy, MR-ARFI to measure tissue displacement due to acoustic radiation forces in the target region 101, ultrasonic detection to measure the intensity of ultrasound reflected from the target region 101, or generally by any experimental technique to measure parameters correlated with energy deposition in the target region 101 in a known and predictable manner. Following frequency optimization, the amplitude, phase, and / or time settings of the phase array transducer 102 may be adjusted in the beamformer 106 to optimize focusing for the selected frequency. A strategy for evaluating the focusing properties in the target region 101 and adjusting the ultrasonic frequency, amplitude, and / or phase settings of the phase array transducer 102 based thereon is provided, for example, in International Patent Application PCT / IB2022 / 000747, filed on 8 December 2022, the entire disclosure of which is incorporated herein by reference.

[0035] Referring to Figure 2, in various embodiments, the acoustic energy emitted by the transducer element 104 may exceed a threshold, thereby generating a small cloud of bubbles (or "microbubbles") 202 in the liquid contained within the target BBB region 101. Microbubbles 202 can form when a heated liquid bursts and is filled with gas / vapor due to negative pressure generated by propagating ultrasound or pulses, or when a gentle acoustic field is applied to tissue containing cavitation nuclei. However, generally, at relatively low acoustic power (e.g., 1-2 watts above the microbubble generation threshold), the generated microbubbles 202 undergo vibrations with equal compression and dilution, and therefore the microbubbles generally remain unbursted. At higher acoustic power (e.g., more than 10 watts above the microbubble generation threshold), the generated microbubbles 202 undergo dilution greater than compression, which can cause cavitation of the microbubbles. Microbubble cavitation can result in transient disruption (or "opening") of the target BBB region 101, thereby allowing therapeutic or prophylactic agents present in the bloodstream to penetrate the "opened" BBB region 101 and effectively deliver the treatment to the target tissue (e.g., target brain cells).

[0036] In various embodiments, microbubbles and / or other therapeutic agents are introduced intravenously, or in some cases by injection in close proximity to the target area 101, using an administration system 116 (Figure 1) for enhancing ultrasound treatment of the target area. For example, microbubbles may be introduced into the patient's brain in the form of droplets that subsequently vaporize, or as gas-filled bubbles, or mixed with another suitable substance such as a conventional ultrasound contrast agent. Due to the encapsulation of their gases, microbubbles may act as scatterers / harmonic oscillators or reflectors of ultrasound. Reflections from microbubbles may be stronger than reflections from the body's soft tissues and / or blood. Thus, by using a microbubble-based contrast agent, the contrast level of the ultrasound image may be significantly increased.

[0037] To avoid undesirable damage to the target BBB region 101 and / or surrounding tissue caused by microbubble cavitation, in various embodiments, the formation and / or amount of induced microbubbles 202 within the target BBB region 101 is monitored by detecting the acoustic signals emitted therefrom using an acoustic signal detector 114 (Figure 1), and then transmitting the signal to a controller 108. Alternatively, the transducer elements 104 may have both transmitting and detecting capabilities. In some embodiments, each individual transducer element 104 may alternately transmit ultrasonic signals to and receive ultrasonic signals from the microbubbles. For example, all transducer elements 104 may transmit ultrasonic signals to the microbubbles 202 substantially simultaneously and then receive echo signals from the microbubbles 202. In some embodiments, the transducer array may be divided into a plurality of sub-regions, each containing an array of transducer elements 104. The sub-regions may be assigned different amplitudes, frequencies, phases, and / or time delays from one another, and may be activated one at a time to transmit ultrasound to the microbubbles 202 and receive echo signals from the microbubbles 202. For example, one sub-region may be operated as a receiving region, and another sub-region may be operated as a transmitting region. The transducer elements in the transmitting region transmit ultrasound / pulses, and the transducer elements in the receiving region receive echo signals from the microbubbles 202. The received signals are then sent to the controller 108 for analysis. The transmitting and receiving regions of the transducer array may be configured with different patterns and shapes at various locations on the transducer array.

[0038] Referring to Figure 3, target region 302 (corresponding to 101 in Figures 1-2) is depicted in a slice of the patient's brain. Target region 302 is relatively larger than the target region in conventional focused ultrasound treatment systems. As a result, target region 302 is inherently heterogeneous, containing one or more subregions with different physiological properties. For example, subregion 304 contains or is otherwise characterized by gray matter, and subregion 306 contains or is otherwise characterized by white matter. Gray matter contains nerve cell bodies, axon terminals, dendrites, and nerve synapses, and primarily functions to receive and regulate transmitted information. White matter contains bundles of axons and primarily helps transmit signals to the brain, spinal cord, and other areas of the body. Importantly, these different tissue types behave differently while attempting to open the BBB during focused ultrasound treatment because different tissue types have different vascular properties. For example, white matter is less vascularized and more delicate, so it tends to be overtreated when subjected to the same treatment parameters as gray matter, while gray matter is more vascularized and therefore contains a higher concentration of microbubbles. Thus, using the same acoustic treatment parameters (e.g., frequency, amplitude, phase, and / or timing) to treat the entire target area 302 may result in overtreatment of white matter 306, undertreatment of gray matter 304, or a combination of both.

[0039] Referring to Figure 4, the target region 304 is divided into subregions 311-315, each subregion corresponding to a tissue type, vascular characteristics, or microbubble concentration. The tissue types in subregions 311-314 correspond to gray matter and are therefore more vascular than the other tissue types in subregion 315, which correspond to white matter. Because the tissues in subregions 311-314 are more vascular, they require or accept higher microbubble concentrations to open the blood-brain barrier (BBB) ​​in those regions during focused ultrasound therapy. Similarly, the tissues in subregion 315 are less vascular and therefore require or accept lower microbubble concentrations to open the BBB in that subregion during focused ultrasound therapy. To address the different microbubble concentration requirements, different acoustic therapy parameters (e.g., frequency, amplitude, phase, and / or timing) may be used to open the BBB in each subregion.

[0040] In some embodiments, acoustic therapy parameters may vary according to a combination of tissue type and vascular characteristics. For example, referring to Figure 5, the combination of tissue type and relative distance from the interface affects the therapy parameters. Specifically, for a given distance from the interface, gray matter and white matter respond differently to a given acoustic therapy dose. In another embodiment, the same bubble density in normal and tumor vessels may have different implications due to the different mechanical properties of these vessels.

[0041] Figure 6 is a flowchart showing an exemplary process 600 for providing focused ultrasound to a target region in several implementation forms. The process may be managed by instructions stored in computer memory or a non-temporary computer-readable storage medium. The instructions may be contained in one or more programs stored in the non-temporary computer-readable storage medium. When executed by one or more processors (e.g., controller 108), the instructions cause the system to carry out the process. The non-temporary computer-readable storage medium may include one or more solid storage devices (e.g., flash memory), magnetic disks 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.

[0042] In operation 602, the controller (e.g., 108) acquires image data of one or more subregions of the target region (e.g., subregions 311-315 of the target region 302) and / or the region surrounding the target region. Depending on the embodiment and use case, the controller may acquire image data of only one subregion of the target region, or two or more subregions of the target region. Additionally, the controller may acquire image data of the region surrounding the target region, such as healthy tissue that is not intended to be treated. Such healthy tissue may still be subject to acoustic therapy dose and / or treatment rate limits to ensure that the healthy tissue is not damaged. Similar to subregions within the target region, subregions in the surrounding tissue (associated with healthy tissue) may be subject to variable acoustic dose and / or treatment rate limits or thresholds based on tissue type and / or vascular characteristics. Accordingly, any description in this disclosure regarding adaptive treatment of subregions of the target region applies equally to regions or subregions surrounding the target region, or otherwise outside the target region. In various embodiments, the image data may include contrast-enhanced ultrasound (CEUS) data, ultrasound localization microscopy (ULM) data for acquiring ultrasound super-resolution images, magnetic resonance imaging (MRI) data, computed tomography (CT) data, and / or anatomical information based on medical atlases.

[0043] In operation 604, the controller determines, based on the image data, a tissue type, vascular property, or microbubble concentration associated with each of one or more subregions (or, depending on the embodiment and use case, associated with only one subregion). Generally, these factors are sometimes referred to as the physiological properties of the subregion. Exemplary vascular properties include vascular density, vascular morphology, vascular flow velocity, and vascular flow pattern (including flow direction). Additionally or alternatively, the physiological properties determined by the controller for each subregion may be disease state or symptoms (e.g., presence and / or location of protein aggregates such as tumors or amyloid plaques), common cerebral anatomical structures taken from one or more anatomical atlases, or in vivo microbubble concentration. Additionally or alternatively, the physiological properties determined by the controller for each subregion may be one or more perfusion parameters that can be extracted from a perfusion MRI scan, including blood flow, blood volume, mean transition time, permeability, or any other perfusion parameters. In some embodiments, the MRI scan may allow the processor to characterize tissue types, including quantitative or qualitative MRI data such as T1, T2, MT, diffusion, sensitivity, and others. Such properties can also assist in registration to neuroanatomical structures.

[0044] In operation 606, the controller determines one or more acoustic therapy parameters for each of one or more subregions (or, depending on the embodiment and use case, for just one subregion) based on the tissue type, vascular characteristics, or microbubble concentration (or, generally, any physiological properties described above) associated with each of one or more subregions (e.g., determining acoustic therapy parameters associated with subregion 311, determining acoustic therapy parameters associated with region 312, etc.). In some embodiments, the acoustic therapy parameters are stored in data storage communicably coupled to the controller and include an adaptive treatment plan 118.

[0045] Acoustic therapy parameters are involved in achieving the overall therapeutic effect. The therapeutic effect may be expressed in terms of therapeutic dose and / or treatment rate.

[0046] The therapeutic dose (also called acoustic dose or acoustic therapeutic dose) represents the cumulative amount that expresses the overall effect of focused ultrasound therapy. The therapeutic dose may be measured by summing the total acoustic signals or energy or output measured by the acoustic signal detector 114 on selected spectral bands.

[0047] The treatment rate is related to the time it takes to reach the therapeutic dose. A higher treatment rate means the therapeutic dose is reached more quickly.

[0048] In some embodiments, determining acoustic therapy parameters involves determining the level of heterogeneity of tissue subregions within the focal zone (referred to as focal zone heterogeneity). Based on heterogeneity, the treatment rate and / or treatment dose may be determined. For example, the more heterogeneous the tissue within the focal zone, the greater the variation in treatment rate and / or treatment dose across the various subregions of tissue within the focal zone.

[0049] Some types of tissue are more sensitive to therapeutic dose, while others are more sensitive to treatment rate. For example, tissues more sensitive to therapeutic dose are more affected by the cumulative amount of acoustic energy absorbed, regardless of the absorption rate. On the other hand, tissues more sensitive to treatment rate are more affected by the rate of acoustic energy absorption, regardless of how much acoustic energy is absorbed. Therefore, the controller 108 may manage the therapeutic dose and treatment rate of various types of tissue in parallel.

[0050] Depending on the tissue type, vascular characteristics, or optimal therapeutic effect (therapeutic dose and / or treatment rate) associated with a given subregion of the target area, the controller 108 determines one or more therapeutic parameters (therapeutic dose and / or treatment rate) to achieve that therapeutic effect. For example, the controller 108 may determine a specific pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, and / or treatment duration to achieve a specific therapeutic dose and / or treatment rate for a given subregion.

[0051] In operation 608, the controller causes the ultrasonic transducer to ultrasonically treat one or more subregions (or, depending on the embodiment and use case, just one subregion) according to acoustic therapeutic parameters corresponding to each of the one or more subregions (for example, treating subregion 311 using acoustic therapeutic parameters specifically determined for that subregion, treating subregion 312 using acoustic therapeutic parameters specifically determined for that subregion, etc.). In embodiments in which the acoustic therapeutic parameters are stored as part of the adaptive treatment plan 118, the controller operates the ultrasonic transducer according to the acoustic therapeutic parameters currently stored in the adaptive treatment plan 118.

[0052] In some embodiments, the ultrasound treatment in operation 608 includes one treatment in a multi-treatment procedure. After (or during) a given treatment, the tissue within the treated subregion may respond to the treatment. To prevent overtreatment, it may be necessary to normalize the acoustic therapy parameters before proceeding with the next treatment in the procedure. Therefore, the acoustic therapy parameters (stored in the adaptive treatment plan 118) may be adaptively replanned and controlled for subsequent ultrasound treatments. In these embodiments, after performing the ultrasound treatment in operation 608, the process is repeated. Specifically, operation 602 is performed again to obtain updated image data (because the image data has changed due to the effects of the previous ultrasound treatment on the subregion). Then, operation 604 is performed again, during which updated vascular properties or microbubble concentrations may be determined (based on the updated image data). Next, operation 606 is performed again, during which the acoustic therapy parameters are updated for one or more subregions (thus updating the adaptive treatment plan 118). Then, the subsequent ultrasound treatment is performed in operation 608. Operations 602-608 may be repeated sequentially for each subsequent ultrasound treatment in a multi-treatment procedure.

[0053] The following description includes several examples of operations 602–606. Specifically, these examples involve distinguishing between tissue types of healthy brain states and pathological brain states (e.g., Alzheimer's disease, Parkinson's disease, cancer, Huntington's disease, etc.) for the purpose of establishing tissue-related acoustic therapy parameters in operation 606.

[0054] Example 1: One example involves the use of CEUS or ultrasound super-resolution imaging (e.g., using ultrasound localization microscopy or ULM) to calculate a vascular map before and during BBB opening treatment.

[0055] The ultrasound imaging-based analysis in operation 604 may include adjusting therapeutic parameters according to the estimated local microbubble concentration, vascular density, vascular morphology (e.g., diameter distribution), and vascular hemodynamics, using one or both of the calculations described below with reference to (I) and (II).

[0056] (I) CEUS or super-resolution ultrasound scan performed before treatment to estimate vascular density. Harmonics or time-varying echoes are known to originate from intravascular bubbles. After generating a spatial map of bubbles within each frame, tissue-related scattering may be removed from the desired bubble signal in a process known as beamforming. CEUS processing may include denoising the beamformed bubble image over time to produce a sharp, low-resolution image of the vascular system. ULM processing may include finding the precise location of resolvable bubbles and aggregating this information across many frames to produce a super-resolution image of the vascular system. High and / or low microbubble densities, long (ms) and / or short (ms) pulses, and long and / or short acquisitions may be used according to the specific implementation. These calculations may be aided by information from co-registered vascular maps obtained using different imaging modalities such as MRI and CT.

[0057] (II) Super-resolution acoustic map of therapeutic BBB opening dose calculated based on pre-treatment ULM map. Since microbubbles are purely intravascular, their possible locations may be constrained according to the calculated super-resolution vascular map. Because BBB pulses are typically long, short echoes can be generated to produce a super-resolution passive acoustic map by slightly modulating the transmission frequency (ultrasonic coding) and removing the desired frequency upon reception. By imposing constraints such as rarefiing and allowed reconstruction grids on the passive acoustic mapping calculations, reconstruction resolution can be improved beyond the diffraction limit to reveal details missing in classical passive acoustic maps. These rarefiing precursors may be determined according to the bubble density of each vascular region. These calculations may be aided by information from co-registered vascular maps obtained using different imaging modalities such as MRI and CT.

[0058] Ultrasound imaging-based analysis in operation 604 may include monitoring the treatment according to CEUS or super-resolution vascular changes (vascular integrity, changes in vascular diameter, vasoconstriction) by comparing the vascular map during treatment and the flow velocity and pattern with the vascular map before treatment (or a map acquired in a previous session of BBB opening treatment) to track functional vascular changes (functional vascular density, diameter histogram, integrity, and flow pattern), and updating the acoustic parameters of the treatment accordingly (in operation 606). Vascular map sampling may be (i) between repeated pulses, (ii) during ultrasound processing, and / or (iii) between treatment sessions.

[0059] Any or all of the above data analysis operations may rely on artificial intelligence (AI) or heuristic algorithms to achieve optimal results. For example, algorithms may be used to detect changes in the vascular system in real time from short scans and partial vascular information. Similarly, reconstruction may be based on the fitting of assumed bubble shapes or depend on the dilution of the underlying vascular system.

[0060] Example 2: Another example involves using MRI scans acquired during the planning phase of BBB treatment to adjust treatment parameters to match MRI-related tissue values.

[0061] In some embodiments, the MRI analysis may include T1 and T2-based treatment planning. In these embodiments, the method includes (in operation 604) reviewing T1 and T2 values ​​for the treatment area, and (in operation 606) adjusting acoustic therapy parameters according to the acquired values ​​using empirical formulas obtained from experimental results. The data analysis in these embodiments may include the use of AI for optimal results.

[0062] In some embodiments, MRI analysis may include MR angiography (MRA)-based treatment planning. In these embodiments, treatment parameters may be determined according to diffusion imaging (DTI) using empirical formulas obtained from experimental results. Data analysis in these embodiments may include the use of AI for optimal results.

[0063] Example 3: Another embodiment involves using CT angiography during the planning phase of BBB treatment to adjust treatment parameters to the properties of the tissue vascular system. In this technique, CT is performed using a contrast agent. Treatment parameters may be determined according to the tissue-dependent properties of the vascular system (determined in action 604) (in action 606) using empirical formulas obtained from experimental results. Data analysis in these embodiments may include the use of AI for optimal results.

[0064] Example 4: Another embodiment involves the use of anatomical, physiological, and neurophysiological brain atlases to modulate therapeutic parameters. In these embodiments, therapeutic parameters may be determined (in action 606) according to the properties of the atlas-based vascular system (determined in action 604) using empirical formulas obtained from experimental results.

[0065] In some embodiments, physiological properties may be determined in operation 604 using any combination of the usages described in Examples 1 to 4 above, and acoustic therapy parameters may be determined in operation 606 based on the determined physiological properties.

[0066] The following description provides examples of acoustic and auxiliary parameters that may be adjusted (in operation 606) according to the BBB treatment area / tissue type (determined in operation 604).

[0067] In one example, one or more acoustic therapy parameters include the total energy (therapeutic dose) and energy rate (therapeutic rate) of a specific spectral frequency band (all bands combined and each band separately). This may determine the pulse duration, acoustic output, maximum output level, therapeutic duration, pulse duty cycle, and / or acoustic frequency for each therapeutic area (e.g., each sub-region 311-315). For example, local microbubble concentration and vascular density may be taken into consideration when determining the acoustic therapy parameters (e.g., PCD output) in operation 606. In this way, the system aims for a lower therapeutic effect when treating areas of low vascular density rather than increasing the transmit output to achieve a uniform therapeutic effect. Similarly, the therapeutic effect may be normalized to the local microbubble concentration to account for variability in bubble production and administration.

[0068] In another example, adjusting one or more acoustic therapy parameters involves adaptively adjusting the microbubble concentration and / or flow rate while injecting microbubbles into a subregion. This ability allows the system to compensate for heterogeneous tumor vascular systems.

[0069] In another example, adjusting one or more acoustic therapy parameters involves adaptively adjusting blood flow velocity in the treatment area using different medications. For instance, microbubble concentration or injection rate can be increased by slowing down blood flow velocity when treating areas with insufficient perfusion.

[0070] In another example, adjusting one or more acoustic therapy parameters may involve generating acoustic holographic patterns to match vascular shapes and distinguish between different neurological regions. For instance, the beam direction may be adjusted to conform to the boundary between white matter and gray matter regions.

[0071] In another example, adjusting one or more acoustic therapy parameters may involve selecting a target that fits the expected efficiency and safety profile of the ultrasound therapy. For example, locations in tissue close to sensitive blood vessels may be avoided.

[0072] In another example, adjusting one or more acoustic therapy parameters involves planning a target sequence opposite to the direction of blood flow, so that the microbubbles do not become increasingly depleted as subsequent targets are treated.

[0073] In another example, adjusting one or more acoustic therapy parameters may involve planning longer ultrasound treatments at lower rates to achieve greater efficacy in subregions sensitive to higher treatment rates.

[0074] In another example, adjusting one or more acoustic therapy parameters may involve planning ultrasound treatment with a blurred focal spot for a more sensitive subregion (e.g., tissue with AD).

[0075] The following description outlines an exemplary implementation of Method 600.

[0076] In some implementations, one or more subregions are multiple subregions, where a first subregion of the multiple subregions (e.g., 311) includes a first tissue type characterized by a first vascular density (e.g., gray matter with a relatively high vascular density), and a second subregion of the multiple subregions (e.g., 315) includes a second tissue type characterized by a second vascular density lower than the first vascular density (e.g., white matter with a relatively low vascular density). In these implementations, determining the acoustic therapy parameters for each of the one or more subregions in operation 606 includes determining a first acoustic therapy dose, treatment rate, and / or focal zone heterogeneity for the first subregion, and determining a second acoustic therapy dose, treatment rate, and / or focal zone heterogeneity lower than the first acoustic therapy dose, treatment rate, and / or focal zone heterogeneity for the second subregion. This is because the lower the vascular density of a given tissue type, the lower the microbubble concentration (because there are fewer vessels to which microbubbles may be injected, or to which they may not otherwise form), and lower microbubble concentrations do not require the same high acoustic therapy dose, treatment rate, and / or focal zone heterogeneity as those used for subregions with higher microbubble concentrations. By adjusting the acoustic therapy dose, treatment rate, and / or focal zone heterogeneity to match the specific microbubble concentration of a given subregion, it is prevented that one subregion is overtreated at the expense of another. Conversely, if a second tissue type is characterized by a second vascular density higher than that of the first, then the acoustic therapy dose, treatment rate, and / or focal zone heterogeneity for the second subregion will be higher than that for the first subregion.

[0077] In some implementations, one or more subregions are multiple subregions, where a first subregion (e.g., 311) is characterized by a first vascular density, and a second subregion (e.g., 315) is characterized by a second vascular density lower than the first. In these implementations, determining the acoustic therapy parameters for each of the one or more subregions in operation 606 includes determining a first acoustic therapy dose, treatment rate, and / or focal band heterogeneity for the first subregion, and determining a second acoustic therapy dose, treatment rate, and / or focal band heterogeneity for the second subregion that is lower than the first acoustic therapy dose, treatment rate, and / or focal band heterogeneity. This is because a lower vascular density in a given subregion results in a lower microbubble concentration, and a lower microbubble concentration does not require the same high acoustic therapy dose, treatment rate, and / or focal band heterogeneity as used for higher microbubble concentrations. Conversely, if the second vascular density is higher than the first vascular density, the second acoustic therapy dose, treatment rate, and / or focal zone heterogeneity will be higher than the first acoustic dose and / or treatment rate in the second subregion.

[0078] In some implementations, one or more subregions are multiple subregions, where a first subregion (e.g., 311) is characterized by a first microbubble concentration, and a second subregion (e.g., 315) is characterized by a second microbubble concentration lower than the first. In these implementations, determining the acoustic therapy parameters for each of the one or more subregions in operation 606 includes determining a first acoustic therapy dose, treatment rate, and / or focal band heterogeneity for the first subregion, and determining a second acoustic therapy dose, treatment rate, and / or focal band heterogeneity lower than the first acoustic therapy dose, treatment rate, and / or focal band heterogeneity for the second subregion. This is because lower microbubble concentrations do not require acoustic therapy dose, treatment rate, and / or focal band heterogeneity as high as that used for subregions with higher microbubble concentrations. Conversely, if the second microbubble concentration is higher than the first microbubble concentration, the second acoustic therapy dose, therapy rate, and / or focal zone heterogeneity are higher than the first acoustic dose and / or therapy rate in the second subregion.

[0079] To achieve the overall therapeutic effect (therapeutic dose and / or treatment rate), the phase array 102 delivers a series of ultrasound pulses to the target sub-region at specific timings or energy levels, which can be varied by modifying the frequency, amplitude, phase, and / or timing used by the beamformer 106. Therefore, a lower therapeutic effect may be achieved with a higher frequency or lower amplitude, or with a modified phase or timing delay resulting in lower energy in a given target sub-region. Similarly, a higher therapeutic effect may be achieved with a lower frequency or higher amplitude, or with a modified phase or timing delay resulting in higher energy in a given target sub-region. It should be noted that further increasing the amplitude dose or dose rate beyond the optimal therapeutic dose and dose rate may result in overtreatment and, in some cases, a reduction in payload delivery.

[0080] Additionally or alternatively, the overall therapeutic effect (therapeutic dose and / or treatment rate) may be obtained by setting specific values ​​for acoustic therapy parameters, such as pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or treatment duration. Thus, in some implementations, the controller is configured to determine, based on image data (as in operation 604), the tissue type associated with each of one or more subregions, where the acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or treatment duration, and in operation 606, determining the acoustic therapy parameters for each of one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low treatment duration for subregions having a tissue type characterized by a relatively low vascular density or vascular flow velocity. Conversely, in operation 606, determining acoustic therapeutic parameters for each of one or more subregions includes determining a relatively high therapeutic duration for subregions having a tissue type characterized by a relatively low acoustic frequency, a relatively high pulse duration, a relatively high pulse duty cycle, a relatively high acoustic output level, or a relatively high vascular density or vascular flow velocity.

[0081] In some implementations, the controller is configured to determine, based on image data (as in operation 604), vascular properties associated with each of one or more subregions, where vascular properties are vascular density or vascular flow velocity, and acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or therapy duration, and determining acoustic therapy parameters for each of one or more subregions in operation 606 includes determining a relatively low therapy duration for subregions having a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low therapy duration for subregions having a relatively low vascular density or vascular flow velocity. Conversely, determining acoustic therapy parameters for each of one or more subregions in operation 606 includes determining a relatively low acoustic frequency, a relatively high pulse duration, a relatively high pulse duty cycle, a relatively high acoustic output level, or a relatively high therapy duration for subregions having a relatively high vascular density or vascular flow velocity.

[0082] In some implementations, the controller is configured to determine the microbubble concentration associated with each of one or more subregions based on image data (as in operation 604), where the acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or therapy duration, and determining the acoustic therapy parameters for each of one or more subregions in operation 606 includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low therapy duration for a subregion having a relatively low microbubble concentration. Conversely, determining the acoustic therapy parameters for each of one or more subregions in operation 606 includes determining a relatively high treatment duration for a subregion having a relatively low acoustic frequency, a relatively high pulse duration, a relatively high pulse duty cycle, a relatively high acoustic output level, or a relatively high microbubble concentration.

[0083] In some implementations, the controller is configured to determine the acoustic therapeutic parameters for each of one or more subregions for each ultrasound or pulse in which acoustic therapeutic parameters have been determined, based on acoustic information acquired during previous ultrasound or pulses in one or more subregions. In other words, in some scenarios, the adaptive treatment plan 118 determines the therapeutic parameters for the next ultrasound or pulse for each ultrasound or pulse in a series of ultrasound or pulses, taking into account both the tissue-based information described above (e.g., tissue type and / or vascular characteristics) and the acoustic feedback received during previous ultrasound or pulses. For example, if the acoustic feedback received during a previous ultrasound or pulse indicates that a particular tissue type has experienced a dose or dose rate that deviates from the plan corresponding to that particular tissue type or associated vascular characteristics, the controller takes this acoustic feedback into account when determining the therapeutic parameters for the next ultrasound or pulse (e.g., by increasing the acoustic frequency, decreasing the pulse duration, decreasing the pulse duty cycle, decreasing the acoustic output level, blurring the focus, and / or decreasing the therapeutic duration for the next ultrasound). Focus blurring can be achieved by changing the phase configuration of the elements (for example, by adding a random phase to each element from an arbitrary phase range). The larger the range and number of elements affected, the greater the blur.

[0084] In some implementations, the controller is further configured to cause an ultrasonic transducer to sonicate one or more subregions, then (by repeating operation 602) acquire subsequent (updated) image data of one or more subregions of the target region, (by repeating operation 604 using the updated image data) determine updated vascular characteristics or microbubble concentrations associated with each of the one or more subregions based on the subsequent image data, (by repeating operation 606) determine updated acoustic therapy parameters for each of the one or more subregions based on the updated vascular characteristics or microbubble concentrations associated with each of the one or more subregions, and (by repeating operation 608 using the updated acoustic therapy parameters) cause the ultrasonic transducer to sonicate one or more subregions according to the updated acoustic therapy parameters corresponding to each of the one or more subregions.

[0085] In some embodiments, the controller is configured to operate the ultrasound transducer according to a safety algorithm that maintains treatment safety based on acoustic feedback during treatment. Such implementations are sometimes called blind implementations because the controller does not recognize the tissue type. A blind controller may use one set of one or more bands of acoustic feedback in treatment for efficacy (e.g., calculation of treatment dose and treatment rate) and another independent set of one or more bands for maintaining safety (e.g., keeping the energy or power measured in the safety band below a threshold). In some embodiments, the bands for efficacy and the bands for safety may partially or completely overlap.

[0086] Thus, a system for providing focused ultrasound to a target region may comprise an ultrasound transducer and a controller. The controller may acquire acoustic feedback associated with an ultrasound operation involving the ultrasound transducer treating one or more subregions of the target region and / or regions surrounding the target region, determine the therapeutic dose and / or treatment rate of the ultrasound operation for each of the one or more subregions according to a first set of one or more frequency bands of the acoustic feedback, determine the energy level and / or output level of the ultrasound operation for each of the one or more subregions according to a second set of one or more frequency bands of the acoustic feedback, determine acoustic therapeutic parameters for each of the one or more subregions based on (i) the therapeutic dose and / or treatment rate associated with each of the one or more subregions and (ii) the energy level and / or output level associated with each of the one or more subregions, and cause the ultrasound transducer to ultrasound the one or more subregions according to the acoustic therapeutic parameters corresponding to each of the one or more subregions. The acoustic therapeutic parameters may be frequencies, amplitudes, or phases associated with multiple transducer elements of the ultrasound transducer.

[0087] In some embodiments, determining acoustic therapy parameters based on a therapeutic dose and / or treatment rate involves adjusting the acoustic therapy parameters to maintain the therapeutic dose and / or treatment rate relative to an efficacy threshold. For example, the acoustic therapy parameters may be adjusted to maintain a therapeutic dose in a first sub-region above an efficacy threshold (e.g., to treat a target region) and a therapeutic dose in a second sub-region below an efficacy threshold (e.g., to minimize damage outside the target region).

[0088] In some embodiments, determining acoustic treatment parameters based on energy levels and / or output levels involves adjusting the acoustic treatment parameters so that the energy levels and / or output levels are maintained relative to a safety threshold. For example, to minimize damage, the acoustic treatment parameters may be adjusted to keep the energy and / or output levels below a safety threshold.

[0089] In some embodiments, the controller may acquire safety information (acoustic feedback) using curve fitting or other types of preprocessing, which allows the controller to separate narrowband signals indicating overtreatment from broadband efficacy indicators without prior knowledge of their specific frequencies. The bifurcation exhibits intense cavitation activity and appears in the PCD spectrum as a symmetrical peak around a quasi-harmonic peak, whose exact frequency could not be estimated beforehand. Comb filters can separate narrowband peaks (harmonics) from broadband signals when their frequencies are known (e.g., the harmonic sum method for improved narrowband and broadband signal quantification during passive monitoring of ultrasound therapy). A slightly different approach using curve fitting extends this to separate peaks with unknown frequencies from broadband signals.

[0090] In some embodiments, the safety algorithm can use the tissue type determined by the controller as input to the safety algorithm. In some embodiments, the safety algorithm selects a safety threshold based on the tissue type (e.g., white matter vs. gray matter, or any other tissue type characteristic). In some embodiments, the controller selects a lower safety threshold for tissues with lower vascular density, while in some other embodiments, if possible, the controller may prefer efficacy over safety and select a higher safety threshold for tissues characterized by lower vascular density, resulting in lower treatment rates.

[0091] As described above, the function for providing focused ultrasound to a target region to disrupt the blood-brain barrier (BBB) ​​may be provided by one or more modules implemented in hardware, software, or a combination of both, whether integrated within the controller 108 of the ultrasound system 100, imaging device 112, and / or administration system 116, or provided by a separate external controller. Additionally, the imaging device 112 and / or administration system 116 may be controlled by the controller 108 or other separate processor(s). In embodiments where the function is provided as one or more software programs, the programs may be written in one of several high-level languages, such as PYTHON®, FORTRAN, PASCAL, JAVA®, C, C++, C#, BASIC, various scripting languages, and / or HTML. Additionally, the software may be implemented in assembly language directed to a microprocessor residing on the target computer; for example, if the software is configured to run on an IBM PC or PC clone, the software may be implemented in Intel 80x86 assembly language. The software may be implemented on products including, but not limited to, floppy disks, jump drives, hard disks, optical disks, magnetic tapes, PROMs, EPROMs, EEPROMs, field-programmable gate arrays, or CD-ROMs. Embodiments using hardware circuitry may be implemented, for example, using one or more FPGAs, CPLDs, or ASIC processors.

[0092] While the above discussion focused on microbubbles, they represent just one example of a therapeutic enhancer. Similar results can be expected with bubbles in different size ranges, such as submicron-range bubbles (called nanobubbles). Additionally or alternatively, nanoparticles such as nanodroplets or gold seeds may be used.

[0093] Figures 7–15 show experimental results of BBB opening in landrace pigs, ultrasound-treated across a wide anatomical region using an Exablate Neuro 220kHz transducer. Pre- and post-treatment MRI scans were performed using a SIGNA® 1.5T GE scanner and a 3T Siemens Lumina system. Anatomical SPGR(GE) or MPRAGE(Siemens) scans were used for tissue recognition treatment planning.

[0094] Figure 7 illustrates the need to consider vascular density in different tissues. White matter and gray matter respond differently to ultrasound-assisted blood-branch opening due to differences in vascular density and mechanical properties that characterize these tissues. As a result, a higher acoustic output is required for the same acoustic dose in the white matter region. Experiments have demonstrated that overtreatment can be observed when the same acoustic parameters (AD=0.7, without changing the treatment rate) are used in different tissues. The effect of overtreatment is shown as black spots in post-treatment GRE MRI scans. Here, treatment regions, including gray matter and white matter regions, were defined using anatomical SPGR MRI scans. In some embodiments, imaging is used to characterize the tissue type of subregions. In some embodiments, the controller selects a lower treatment dose and / or treatment rate for white matter to avoid overtreatment.

[0095] Figures 8–10 illustrate how differences between tissue type and vascular density can lead to a broad focal spot resulting in a heterogeneous blood-brain opening (BBB). Typically, the focal spot of an ultrasound system is much larger in axial dimensions. When using a large focal spot, for example by selecting a small aperture, the central lobe of the beam covers a large section of tissue that often contains different tissue types and vascular densities. Treatment planning is generally performed based on an intermediate imaging plane (Figure 8). Here, a post-treatment T1-weighted scan with gadolinium, showing a region with a high degree of BBB opening, is overlaid in red on the corresponding anatomical SPGR image in blue (left). The treatment plan shows the ultrasound-treated subspots in green on the anatomical SPGR image (right). Thus, if the tissue composition in adjacent axial planes differs from the tissue composition of the planned section, the BBB opening pattern depends on the local tissue composition in addition to the geometry of the treatment plan (Figures 9–10). Here, too, a T1-weighted scan after gadolinium treatment, showing a region with a high degree of BBB opening, is overlaid in red on the corresponding blue anatomical SPGR image (left). The anatomical SPGR image is also presented without excessive indication of the location of the lighter white and darker gray tissue areas (right).

[0096] In some embodiments, the controller selects a smallest focus in areas of mixed tissue types to minimize situations where multiple tissue types are treated within the same spot. In some embodiments, if tissue health outweighs all other considerations, the controller treats the mixed area based on the parameters of the weakest tissue type in the mixture. In some embodiments (e.g., oncological treatment), if therapeutic efficacy is critical and cannot be entirely sacrificed, the controller may treat the mixed tissue based on the dominant tissue type in the mixture, or based on parameters that are the average of the parameters that would have been applied to each tissue on their own. In some embodiments, the controller selects a mixed approach in which the treatment rate is selected based on the most sensitive tissue type in the mixture, and the treatment dose is higher than or equal to the desired treatment dose for the most sensitive tissue type in the mixture.

[0097] Figure 11 shows when an anatomical structure-based treatment plan leads to BBB opening in white and gray matter. Here, the treatment area, including gray matter (G) and white matter (W) regions, was defined using an anatomical SPGR MRI scan (left). The acoustic volume and dose rate in the white matter region were set to one-third of the acoustic volume and volume rates used in the gray matter region. This tissue-adaptive treatment plan led to a more uniform opening in the heterogeneous tissue, which was observed as a bright area on post-treatment T1-weighted MRI scans after gadolinium injection.

[0098] In some embodiments, uniform opening is key to successful treatment (e.g., when the treatment is used for the delivery of toxic drugs), and the controller attempts to make the opening as uniform as possible. In some embodiments, the controller may open the tissue as much as possible under the constraints of safety, treatment time, and bubble volume, and in those treatments, the controller's treatment plan prefers more opening than uniform opening. For example, the aim is to achieve higher payload delivery in gray matter areas with higher vascular density compared to gray matter areas.

[0099] Figure 12 illustrates how anatomical structure-based treatment planning enables more homogeneous opening of heterogeneous tissues. The methodology of the tissue-adaptive BBB opening treatment planning described above has repeatedly resulted in extensive opening of gray and white tissue areas. BBB opening is observed as a bright area on post-treatment T1-weighted MRI scans after gadolinium injection. The results have been consistent across numerous experiments using different animals.

[0100] Figure 13 illustrates a case where a treatment plan based on anatomical structure results in repeatable BBB opening. The reproducibility of the described methodology was quantified using multi-echo arrays and calculation of the R1 parameter at Hz. When calculating the success probability per area, treatment at a given pixel was considered successful if the maximum axial R1 value was above 0.1 Hz. When calculating the success probability per voxel, treatment at a given voxel was considered successful if its R1 value was above 0.1 Hz. Repeatable BBB opening was observed in gray matter, white matter, and grooved gray matter. Lower degrees of reproducibility were observed in the white matter of grooved areas. In some embodiments, the patient should undergo multiple treatments. Post-treatment images may be used to further characterize subregional tissue types based on the tissue response for actual treatment (efficacy - Figure 13, and safety - Figure 14).

[0101] Figure 14 illustrates how anatomical structure-based treatment planning can lead to safer opening with minimal signs of edema and microbleeds. High levels of BBB opening achieved using a tissue adaptation plan with lower acoustic doses for the white matter region indicated favorable treatment safety. Post-treatment GRE MRI scans showed several faint dark spots without significant evidence of microbleeds (center right). Post-treatment T2-weighted scans showed minimal signs of edema in the form of bright areas not present in pre-treatment scans. Upon observation, these signs of edema were concentrated around the tissue interface region (right).

[0102] Figure 15 illustrates the importance of precise treatment in the tissue interface region. This region is relatively sensitive and requires careful treatment monitoring to avoid overtreatment and insufficient therapeutic delivery. In the anatomical MPRAGE MRI image, a thin white matter area can be seen in the center of the gray / mixed matter (left, red arrow). If the controller did not provide adequate protection to this region, gadolinium delivery to this area was significantly lower in the post-treatment T1-weighted scan compared to the adjacent tissue area, suggesting overtreatment (middle). Similarly, signs of edema appeared around it in the T2-weighted follow-up scan one day after the procedure (right). Therefore, adaptive planning and high spatial resolution of the Exablate transducer are crucial for adaptive BBB opening.

[0103] The terms and expressions used herein are for illustrative purposes only, not limitation, and the use of such terms and expressions is not intended to exclude any equivalent of any of the features or parts thereof shown or described. In addition, while specific embodiments of this disclosure have been described, it will be apparent to those skilled in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of this disclosure. Accordingly, the embodiments described herein should be considered in all respects to be merely illustrative and not limiting.

[0104] The above description is based on reference to specific implementations. However, the above illustrative considerations are not intended to be exhaustive or to limit the claims to the exact form disclosed. Many variations are possible considering the above teachings. The implementations are selected and described to best illustrate the principle of operation and practical applications, thereby making them available to those skilled in the art.

[0105] Various diagrams show numerous elements in a specific order. However, elements that are not order-dependent can be rearranged, and other elements can be combined or separated. While some rearrangements or other groupings are specifically mentioned, other groupings will be obvious to those skilled in the art, so the rearrangements and groupings presented herein are not an exhaustive list of alternatives.

[0106] As used herein, the singular forms “a,” “an,” and “the” also include the plural unless the context clearly indicates otherwise; the term “and / or” encompasses all possible combinations of one or more of the related enumerated items (for example, A and / or B means A only, B only, or both A and B); terms such as “first,” “second,” etc., are used solely to distinguish one element from another and do not restrict the elements themselves; the term “if” may be interpreted as “when,” “at that time,” “in response to it,” or “according to it,” depending on the context; and the terms “include,” “including,” “comprise,” and “comprising” specify a particular feature or action but do not exclude any additional features or actions.

Claims

1. A system for providing focused ultrasound to a target area, Ultrasonic transducer and A controller is provided, and the controller is Image data of one or more sub-regions of the target region and / or regions surrounding the target region is acquired. Based on the aforementioned image data, the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions is determined. Based on the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions, acoustic therapy parameters are determined for each of the one or more subregions. A system configured to cause the ultrasonic transducer to ultrasonically treat one or more sub-regions according to the acoustic treatment parameters corresponding to each of the one or more sub-regions.

2. The one or more subregions are multiple subregions, The first subregion among the plurality of subregions includes a first tissue type characterized by a first vascular density, A second subregion among the plurality of subregions includes a second tissue type characterized by a second vascular density lower than the first vascular density, Determining the acoustic therapy parameters for each of the one or more sub-regions is With respect to the first subregion, the first acoustic therapy dose, therapy rate, or heterogeneity of the focal zone is determined, The system according to claim 1, comprising determining a second acoustic therapy dose, treatment rate, or focal band heterogeneity for the second subregion that is lower than the first acoustic therapy dose, treatment rate, or focal band heterogeneity.

3. The aforementioned target region includes a portion of the blood-brain barrier located within gray matter and white matter. The first tissue type is gray matter, The system according to claim 2, wherein the second tissue type is white matter.

4. The one or more subregions are multiple subregions, The first subregion among the plurality of subregions is characterized by a first vascular density, A second subregion among the aforementioned plurality of subregions is characterized by a second vascular density lower than that of the first vascular density. Determining the acoustic therapy parameters for each of the one or more sub-regions is With respect to the first subregion, the first acoustic therapy dose, therapy rate, or heterogeneity of the focal zone is determined, The system according to claim 1, comprising determining a second acoustic therapy dose, treatment rate, or focal band heterogeneity for the second subregion that is lower than the first acoustic therapy dose, treatment rate, or focal band heterogeneity.

5. The one or more subregions are multiple subregions, A first sub-region among the plurality of sub-regions is characterized by a first microbubble concentration, A second sub-region among the plurality of sub-regions is characterized by a second microbubble concentration lower than the first microbubble concentration. Determining the acoustic therapy parameters for each of the one or more sub-regions is With respect to the first subregion, the first acoustic therapy dose, therapy rate, or heterogeneity of the focal zone is determined, The system according to claim 1, comprising determining a second acoustic therapy dose, treatment rate, or focal band heterogeneity for the second subregion that is lower than the first acoustic therapy dose, treatment rate, or focal band heterogeneity.

6. The controller is configured to determine the tissue type associated with each of the one or more sub-regions based on the image data, The aforementioned acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or treatment duration. The system according to claim 1, wherein determining the acoustic therapy parameters for each of the one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low therapeutic duration for subregions having a tissue type characterized by a relatively low vascular density or vascular flow velocity.

7. The controller is configured to determine the vascular system characteristics associated with each of the one or more sub-regions based on the image data, wherein the vascular system characteristics are vascular density or vascular flow velocity. The aforementioned acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or treatment duration. The system according to claim 1, wherein determining the acoustic therapy parameters for each of the one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low treatment duration for subregions having a relatively low vascular density or vascular flow velocity.

8. The controller is configured to determine the microbubble concentration associated with each of the one or more sub-regions based on the image data. The aforementioned acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or treatment duration. The system according to claim 1, wherein determining the acoustic therapy parameters for each of the one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low treatment duration for a subregion having a relatively low microbubble concentration.

9. The system according to any one of claims 1 to 8, wherein, for each ultrasonic treatment or pulse in which acoustic therapeutic parameters have been determined, determining the acoustic therapeutic parameters for each of the one or more sub-regions is further based on acoustic information acquired during previous ultrasonic treatments or pulses of the one or more sub-regions.

10. After the controller has the ultrasonic transducer ultrasonically process one or more sub-regions, Obtain subsequent image data of one or more sub-regions of the target region, Based on the subsequent image data, updated vascular characteristics or microbubble concentrations associated with each of the one or more subregions are determined. Based on the updated vascular characteristics or microbubble concentration associated with each of the one or more subregions, updated acoustic therapy parameters are determined for each of the one or more subregions. The system according to any one of claims 1 to 9, wherein the ultrasonic transducer is further configured to ultrasonically treat one or more subregions according to the updated acoustic treatment parameters corresponding to each of the one or more subregions.

11. Acquiring the aforementioned image data Contrast-enhanced ultrasound (CEUS) device data, Ultrasound localization microscope (ULM) device data for acquiring ultrasound super-resolution images, Magnetic resonance imaging (MRI) data, Computed tomography (CT) data, and / or A system according to any one of claims 1 to 10, comprising obtaining anatomical information based on a medical atlas.

12. The system according to any one of claims 1 to 11, wherein the ultrasonic transducer ultrasonically processes one or more sub-regions, which includes generating and / or activating microbubbles by applying ultrasound to the target region, or ultrasonically processing microbubbles administered by the system in the target region.

13. The system according to any one of claims 1 to 12, wherein acquiring the image data includes imaging the target region.

14. The system according to any one of claims 1 to 13, wherein acquiring the image data includes identifying the target region and determining the vascular characteristics associated with each of the one or more subregions using either an atlas or a diagnosed pathology.

15. The system according to any one of claims 1 to 14, wherein the ultrasonic transducer ultrasonically processes one or more sub-regions, which includes controlling the acoustic output or energy emitted by the transducer element of the ultrasonic transducer so that the acoustic output or energy exceeds a threshold level, thereby inducing microbubble generation or a higher acoustic radiation force.

16. The system according to any one of claims 1 to 15, wherein the acoustic therapy parameter is a frequency, amplitude, or phase associated with a plurality of transducer elements of the ultrasonic transducer.

17. A method for providing focused ultrasound to a target region, A controller that is communicatively coupled to an ultrasonic transducer, Acquire image data of one or more sub-regions of the target region and / or regions surrounding the target region, Based on the aforementioned image data, determine the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions. To determine acoustic therapy parameters for each of the one or more subregions based on the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions, A method comprising: causing the ultrasonic transducer to ultrasonically treat one or more sub-regions according to the acoustic treatment parameters corresponding to each of the one or more sub-regions.

18. The one or more subregions are multiple subregions, The first subregion among the plurality of subregions includes a first tissue type characterized by a first vascular density, A second subregion among the plurality of subregions includes a second tissue type characterized by a second vascular density lower than the first vascular density, Determining the acoustic therapy parameters for each of the one or more sub-regions is With respect to the first subregion, the first acoustic therapy dose, therapy rate, or heterogeneity of the focal zone is determined, The method according to claim 17, comprising determining a second acoustic therapy dose, treatment rate, or focal band heterogeneity for the second subregion that is lower than the first acoustic therapy dose, treatment rate, or focal band heterogeneity.

19. The aforementioned target region includes a portion of the blood-brain barrier, including gray matter and white matter. The first tissue type is gray matter, The method according to claim 18, wherein the second tissue type is white matter.

20. The one or more subregions are multiple subregions, The first subregion among the plurality of subregions is characterized by a first vascular density, A second subregion among the aforementioned plurality of subregions is characterized by a second vascular density lower than that of the first vascular density. Determining the acoustic therapy parameters for each of the one or more sub-regions is With respect to the first subregion, the first acoustic therapy dose, therapy rate, or heterogeneity of the focal zone is determined, The method according to claim 17, comprising determining a second acoustic therapy dose, treatment rate, or focal band heterogeneity for the second subregion that is lower than the first acoustic therapy dose, treatment rate, or focal band heterogeneity.

21. The one or more subregions are multiple subregions, A first sub-region among the plurality of sub-regions is characterized by a first microbubble concentration, A second sub-region among the plurality of sub-regions is characterized by a second microbubble concentration lower than the first microbubble concentration. Determining the acoustic therapy parameters for each of the one or more sub-regions is With respect to the first subregion, the first acoustic therapy dose, therapy rate, or heterogeneity of the focal zone is determined, The method according to claim 17, comprising determining a second acoustic therapy dose, treatment rate, or focal band heterogeneity for the second subregion that is lower than the first acoustic therapy dose, treatment rate, or focal band heterogeneity.

22. Determining the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions includes determining the tissue type associated with each of the one or more subregions based on the image data. The aforementioned acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or treatment duration. The method according to claim 17, wherein determining the acoustic therapy parameters for each of the one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low therapeutic duration for subregions having a tissue type characterized by a relatively low vascular density or vascular flow velocity.

23. Determining the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions includes determining the vascular characteristics associated with each of the one or more subregions based on the image data, wherein the vascular characteristics are vascular density or vascular flow velocity. The aforementioned acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or treatment duration. The method according to claim 17, wherein determining the acoustic therapy parameters for each of the one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low treatment duration for subregions having a relatively low vascular density or vascular flow velocity.

24. Determining the tissue type, vascular characteristics, or microbubble concentration associated with each of the one or more subregions includes determining the microbubble concentration associated with each of the one or more subregions based on the image data, The aforementioned acoustic therapy parameters are pulse duration, pulse duty cycle, acoustic frequency, acoustic output level, or treatment duration. The method according to claim 17, wherein determining the acoustic therapy parameters for each of the one or more subregions includes determining a relatively high acoustic frequency, a relatively low pulse duration, a relatively low pulse duty cycle, a relatively low acoustic output level, or a relatively low treatment duration for a subregion having a relatively low microbubble concentration.

25. The method according to any one of claims 17 to 24, wherein, for each ultrasonic treatment or pulse in which acoustic therapy parameters have been determined, determining the acoustic therapy parameters for each of the one or more subregions is further based on acoustic information acquired during previous ultrasonic treatments or pulses of the one or more subregions.

26. After ultrasonically processing one or more sub-regions with the ultrasonic transducer, To acquire subsequent image data of one or more sub-regions of the target region, Based on the subsequent image data, the updated vascular characteristics or microbubble concentration associated with each of the one or more subregions is determined. Based on the updated vascular characteristics or microbubble concentration associated with each of the one or more subregions, updated acoustic therapy parameters are determined for each of the one or more subregions. The method according to any one of claims 17 to 25, further comprising causing the ultrasonic transducer to ultrasonically treat one or more subregions according to the updated acoustic treatment parameters corresponding to each of the one or more subregions.

27. Acquiring the aforementioned image data Contrast-enhanced ultrasound (CEUS) device data, Ultrasound localization microscope (ULM) device data for acquiring ultrasound super-resolution images, Magnetic resonance imaging (MRI) data, Computed tomography (CT) data, and / or The method according to any one of claims 17 to 26, comprising obtaining anatomical information based on a medical atlas.

28. The method according to any one of claims 17 to 27, wherein the ultrasonic transducer ultrasonically processes one or more sub-regions, the ultrasonic transducer generates microbubbles by applying ultrasound to the target region, or the transducer ultrasonically processes microbubbles administered by the system in the target region.

29. The method according to any one of claims 17 to 28, wherein acquiring the image data includes imaging the target region.

30. The method according to any one of claims 17 to 29, wherein acquiring the image data includes identifying the target region and determining the vascular characteristics associated with each of the one or more subregions using an atlas.

31. The method according to any one of claims 17 to 30, wherein the ultrasonic transducer ultrasonically processes one or more sub-regions, and controls the acoustic output or energy emitted by the transducer element of the ultrasonic transducer such that the acoustic output or energy exceeds a threshold level, thereby inducing the generation of microbubbles.

32. The method according to any one of claims 17 to 31, wherein the acoustic therapy parameter is a frequency, amplitude, or phase associated with a plurality of transducer elements of the ultrasonic transducer.

33. A system for providing focused ultrasound to a target area, Ultrasonic transducer and A controller is provided, and the controller is Acoustic feedback is obtained associated with an ultrasonic processing operation involving the ultrasonic transducer to treat one or more sub-regions of the target region and / or regions surrounding the target region. For each of the one or more sub-regions, the therapeutic dose and / or therapeutic rate of the ultrasonic processing operation is determined according to a first set of one or more frequency bands of the acoustic feedback. According to a second set of one or more frequency bands of the acoustic feedback, the energy level and / or output level of the ultrasonic processing operation is determined for each of the one or more sub-regions. (i) The therapeutic dose and / or therapeutic rate associated with each of the one or more subregions, and (ii) The energy level and / or output level associated with each of the one or more subregions, to determine acoustic therapeutic parameters for each of the one or more subregions. A system configured to cause the ultrasonic transducer to ultrasonically treat one or more sub-regions according to the acoustic treatment parameters corresponding to each of the one or more sub-regions.

34. Determining the acoustic therapy parameters based on the therapeutic dose and / or the therapeutic rate includes adjusting the acoustic therapy parameters so as to maintain the therapeutic dose and / or the therapeutic rate relative to an efficacy threshold. The system according to claim 33, wherein determining the acoustic therapy parameters based on the energy level and / or the output level includes adjusting the acoustic therapy parameters so as to maintain the energy level and / or the output level relative to a safety threshold.

35. The system according to claim 33 or 34, wherein the acoustic therapy parameter is a frequency, amplitude, or phase associated with a plurality of transducer elements of the ultrasonic transducer.

36. A method for providing focused ultrasound to a target region using an ultrasonic transducer, A controller that is communicatively coupled to the ultrasonic transducer, Acquiring acoustic feedback associated with ultrasonic processing operations involving the ultrasonic transducer to treat one or more sub-regions of the target region and / or regions surrounding the target region, Determining the therapeutic dose and / or therapeutic rate of the ultrasonic processing operation for each of the one or more sub-regions according to a first set of one or more frequency bands of the acoustic feedback, Determining the energy level and / or output level of the ultrasonic processing operation for each of the one or more sub-regions according to a second set of one or more frequency bands of the acoustic feedback, (i) determining acoustic therapeutic parameters for each of the one or more subregions based on the therapeutic dose and / or therapeutic rate associated with each of the one or more subregions, and (ii) the energy level and / or output level associated with each of the one or more subregions. A method comprising: causing the ultrasonic transducer to ultrasonically treat one or more sub-regions according to the acoustic treatment parameters corresponding to each of the one or more sub-regions.

37. Determining the acoustic therapy parameters based on the therapeutic dose and / or the therapeutic rate includes adjusting the acoustic therapy parameters so as to maintain the therapeutic dose and / or the therapeutic rate relative to an efficacy threshold. The method according to claim 37, wherein determining the acoustic therapy parameters based on the energy level and / or the output level includes adjusting the acoustic therapy parameters so as to maintain the energy level and / or the output level relative to a safety threshold.

38. The method according to claim 36 or 37, wherein the acoustic therapy parameter is a frequency, amplitude, or phase associated with a plurality of transducer elements of the ultrasonic transducer.

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