Adaptive autofocus and power adjustment based on single bubble in ultrasound programming

Abstract

A method for focusing an ultrasonic transducer having multiple transducer elements includes: generating a first ultrasonic treatment on one or more target regions and measuring a first set of reflected signals generated by the first ultrasonic treatment; determining, based on the first set of reflected signals, whether a target number or target occurrence rate of focusing events has been reached; if not, generating a second ultrasonic treatment at adjusted acoustic power to the target regions and measuring a second set of reflected signals generated by the second ultrasonic treatment; and adjusting parameter values ​​associated with one or more transducer elements, at least in part, based on the second set of reflected signals, to improve ultrasonic focus at the target regions.

Description

[0001] Related applications

[0002] This application claims the benefit and priority of U.S. Provisional Patent Applications Nos. 62 / 949,593 and 62 / 949,595 (both filed on December 18, 2019), the entire disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention generally relates to systems and methods for ultrasonic focusing, and more specifically, to automatic focusing using microbubbles and adjusting the acoustic power of the ultrasonic beam after focusing. Background Technology

[0004] Focused ultrasound (i.e., sound waves with frequencies greater than approximately 20 kHz) can be used to image or treat tissues within a patient's body. For example, ultrasound can be used in ablation applications involving tumors, eliminating the need for invasive surgery, targeted drug delivery, blood-brain barrier (BBB) ​​control, clot lysis, and other surgical procedures. During tumor ablation, a piezoelectric ceramic transducer is placed outside the patient but very close to the tissue to be ablated (i.e., the target). The transducer converts an electronically driven signal into mechanical vibrations, resulting in the emission of sound waves. The transducer can be geometrically shaped and positioned together with other such transducers so that the ultrasound energy emitted by them collectively forms a focused beam in a "focal region" corresponding to (or within) the target tissue area. Alternatively or additionally, a single transducer can be formed from multiple individually driven transducer elements, the phase of which can be independently controlled. This "phased array" transducer facilitates the manipulation of the focal region to different locations by adjusting the relative phase between the transducers. As used herein, the term "element" refers to an individual transducer in an array or an independently drivable portion of a single transducer. Magnetic resonance imaging (MRI) is used to visualize patients and targets, and in turn to guide ultrasound beams.

[0005] During a focused ultrasound procedure, a series of ultrasound treatments are applied to cause coagulation necrosis of the target tissue (e.g., a tumor) without damaging surrounding tissue. If used in the central nervous system, these treatments can cause microbubble cavitation, which may interfere with blood vessels and create “openings” in the BBB to enhance targeted drug delivery. To achieve these goals, the ultrasound energy emitted from the transducer must be accurately and reliably shaped and focused onto the desired target location. Incorrectly configured transducer elements can result in inadequate or suboptimal focus quality, leading to ineffective treatment and / or unwanted damage to non-target tissues. Additionally, an improperly shaped ultrasound beam may generate unexpected secondary hot spots outside the intended focal region; such hot spots can cause unwanted fever, pain, and / or potential necrosis of non-target tissues.

[0006] One source of transducer output errors is the inhomogeneity of the interventional tissue (e.g., human skull) through which ultrasound waves travel before reaching the focal region. Ultrasound waves interact with the interventional tissue through multiple processes, including propagation, scattering, absorption, reflection, and refraction. For example, tissue inhomogeneity can cause refraction of acoustic energy at the boundaries of areas with different sound velocities. Refraction can reduce constructive interference and thus reduce the intensity of acoustic energy at the focal region. Therefore, inhomogeneous tissue can generate beam distortion and refraction, distorting the focal point and reducing its intensity, thereby affecting treatment efficiency.

[0007] Various calibration methods have been proposed to account for beam distortion caused by the interventional tissue. For example, a common method measures the phase shift caused by the ultrasound beam traveling through the interventional tissue and then adjusts the ultrasound parameters to account for distortion at least partially caused by the tissue. Typically, this method uses a receiving probe designed for catheter insertion into the brain to measure the amplitude and phase distortion caused by the human skull. However, catheter insertion still requires surgery, which can be painful and carries the risk of infection.

[0008] Alternative, entirely non-invasive methods use X-ray computed tomography (CT) images, rather than receiving probes, to predict wave distortion caused by the skull. However, in practice, calculating the relative phase alone can also be inaccurate and fail to achieve high-quality focusing. For example, when ultrasound is focused into the brain to treat a tumor, the skull in the acoustic path can cause distortions that are not easily determined. In such cases, a focusing procedure is typically performed before treatment, in which an ultrasound focus is generated at or near the target location, the quality of the focus is measured (using, for example, thermal imaging or acoustic radiation force imaging (ARFI)), and experimental feedback is used to adjust the phase of the transducer elements to achieve sufficient focus quality.

[0009] However, the preceding focusing procedures can be time-consuming, which may render them impractical or at least inconvenient for patients. Furthermore, ultrasound energy inevitably deposits into the tissue surrounding the target during the procedure, potentially damaging healthy tissue. While the impact of pre-treatment ultrasound treatment can be minimized by employing imaging techniques that require only low sound intensity (e.g., ARFI), the number of ultrasound treatments prior to treatment generally needs to be limited.

[0010] Another method for estimating wave distortion caused by interventional tissue involves using acoustic reflectors (e.g., small clouds of microbubbles) in the focal region. By transmitting ultrasound waves to the microbubbles and receiving the reflections from them, the amplitude and / or phase associated with the reflected ultrasound can be determined; based on this, the distortion caused by the interventional tissue can be learned, and transducer parameters (e.g., phase shift and / or amplitude) can be adjusted to compensate for distortion at least partially caused by the interventional tissue. While this method can effectively improve focusing properties at the target site, various challenges exist. For example, the microbubble concentration at the target site should be within the range that provides significant interaction with the ultrasound waves and also produces a reflected signal that can be directly analyzed. Additionally, the acoustic power of the ultrasound waves must be sufficiently high to create interaction with the microbubbles without generating unwanted artifacts again in the reflected signal. Furthermore, because the anatomical properties of the interventional tissue and / or the pharmacokinetics of each patient differ, different microbubble concentrations and different acoustic powers may be required to perform autofocusing procedures for different patients. Therefore, a method is needed to determine the optimal patient-specific microbubble concentration and acoustic power for performing ultrasound autofocusing to achieve high-quality ultrasound focus at the target site.

[0011] In some cases, microbubbles can cause undesirable damage to target and / or non-target tissues. For example, after adjusting transducer parameters to improve focusing properties, the maximum acoustic energy deposited in the focal region may increase significantly, potentially leading to permanent damage to BBB tissues. By the time damage to target / non-target tissues due to excessive energy exposure is detected during an actual ultrasound procedure, it is often too late to avoid the problem. Therefore, methods are needed to generate high-quality ultrasound focus in the target area while avoiding excessive acoustic energy exposure in the target / non-target areas. Summary of the Invention

[0012] This invention relates to a method for automatically focusing an ultrasound beam at a target area using one or more transient reflectors (e.g., one or more microbubbles) through a non-uniform medium. The transient reflectors can be generated and / or introduced near (e.g., less than 5 mm away) the target area or at one or more ultrasound treatment locations within the target area. Furthermore, optimization methods are implemented to determine one or more optimal values ​​for one or more parameters (e.g., acoustic power, microbubble concentration, etc.) associated with the ultrasound transducer and / or acoustic reflector to facilitate the autofocusing procedure. Because optimization can be performed for each patient, the obtained optimal values ​​are patient-specific; therefore, adjusting ultrasound parameters (e.g., amplitude, phase, etc.) using the autofocusing procedure can be more accurate, thereby advantageously improving focusing properties and treatment efficiency at the target area. It should be understood that the method of this invention can be used with any type of transient acoustic reflector, i.e., an acoustic reflector that moves, evolves, and / or dissipates during a cycle between two measurements. Although this specification focuses on microbubbles, this is for illustrative purposes only, and the reference to microbubbles should be understood as being interchangeable with other forms of transient acoustic reflectors (e.g., phase-shifting droplets, red blood cells, etc.).

[0013] In various embodiments, the method is optimized by generating and / or introducing an initial concentration of microbubbles at an ultrasound treatment location near or within the target area. Preferably, the initial microbubble concentration is sufficiently high to cause significant interaction between the microbubbles and ultrasound waves, and sufficiently low such that acoustic reflections appear to originate from a point target (e.g., having a size less than one-quarter the wavelength of the ultrasound treatment), such as a single microbubble (rather than a cloud of microbubbles). The initial microbubble concentration can be determined based on, for example, preclinical studies, pre-treatment procedures, and / or from known literature.

[0014] Subsequently, at least some of the transducer elements can be activated to emit a series of low-power (e.g., 7 watts) ultrasonic treatments onto the microbubble; reflected signals from the microbubble can be measured. In one embodiment, a signal selection method is implemented to select reflected signals from individual microbubbles based on the consistency between reflected signals. In one embodiment, a consistency function is defined for the travel time and / or phase delay associated with the reflected signal, and a reflected signal is considered sufficiently consistent only if the value of the consistency function is maximized or exceeds a predetermined threshold. In various embodiments, the acoustic power of the emitted ultrasonic treatments is gradually increased until there is a significant (e.g., greater than 50% or 100%) change in parameters (e.g., amplitude, phase, etc.) associated with the selected reflected signal between two measurements; such reflected signals are referred to as “focusing events”. Additionally, the acoustic power of the emitted ultrasonic treatments is continuously increased until a sufficient number (e.g., 10, or greater than 30 in some embodiments) of focusing events are measured. The power used to generate a sufficient number of focusing events is called the optimal power and can be used during the automatic focusing procedure. In some embodiments, the occurrence rate of focusing events (e.g., the number of focusing events detected in a second time period of the most recent measurement) is calculated, and the power level is adjusted based on the occurrence rate. For example, the power level can be increased when the occurrence rate is too low (e.g., more than 50% or 100% below the target occurrence rate) and decreased when the occurrence rate is too high (e.g., more than 50% or 100% above the target occurrence rate). The target occurrence rate may be one event per second, or in some embodiments, more than 10 events per second.

[0015] However, in some cases, the acoustic power of the ultrasound treatment may have reached a threshold before a sufficient number (or sufficient frequency) of focusing events are detected, where the nonlinear response of the microbubbles (and consequently artifacts in the reflected signal) is detected. Therefore, in various embodiments, after determining that artifacts exist in the reflected signal or that the number of reflected signals with artifacts is unacceptably high (e.g., two, five, or ten times) relative to the number of focusing events, the optimization method can immediately adjust another parameter, such as the microbubble concentration, to determine the optimal configuration to facilitate the autofocusing procedure. For example, the microbubble concentration may be increased by 10% or, in some embodiments, by 20%; and the applied ultrasound treatment may then be restarted at low power and gradually increased until the optimal power is reached. Again, if the acoustic power reaches a threshold causing artifacts in the reflected signal before a sufficient number of focusing events are detected, the microbubble concentration can be further increased. The acoustic power at which a sufficient number of focusing events are detected indicates the ultrasound power level required to generate a sufficient therapeutic sound field in the target area. Therefore, a sufficient number (or sufficient occurrence rate) of acoustic power values ​​corresponding to the focused events can be used to adjust and / or scale the power level during ultrasound treatment (or diagnostic) procedures.

[0016] Conversely, in other cases, the initial or adjusted microbubble concentration may result in too many focusing events (e.g., greater than 50, or in some embodiments greater than 80) when the acoustic power is still low (e.g., less than 8 watts). To conserve microbubbles and reduce the computational complexity of analyzing reflected signals, the microbubble concentration is reduced in some embodiments (e.g., 5%, or in some embodiments 10%). Again, ultrasound processing can be performed at low power, which is gradually increased until an optimal acoustic power is reached. These steps can also be performed iteratively until an optimal microbubble concentration and optimal acoustic power are obtained. Subsequently, an autofocusing procedure can be initiated using the determined optimal acoustic power and optimal microbubble concentration. Based on the focusing events measured during the autofocusing procedure, ultrasound parameters (e.g., amplitude and / or phase) can then be adjusted to compensate for tissue distortion, thereby optimizing the focusing properties at each ultrasound processing location near or within the target area.

[0017] Therefore, various embodiments provide methods for determining optimal values ​​of one or more parameters (e.g., acoustic power, microbubble concentration, etc.) associated with an ultrasound transducer and / or acoustic reflector for performing an accurate and reliable ultrasound autofocusing procedure. Because optimization can be performed for each patient, the optimal values ​​obtained can be patient-specific. Thus, the autofocusing procedure can be used to compensate for distortions caused by patient-specific interventional tissues and thereby obtain optimal manipulation parameters (e.g., ultrasound amplitude, phase) to focus acoustic energy at the target area.

[0018] Additionally, various embodiments predict changes in the temperature or peak power of the ultrasound focal point resulting from optimization (or at least improvement) of focusing properties (due to changes in transducer parameters), and based on these predictions, adjust the emitted acoustic power level during the ultrasound procedure to avoid overheating of target and / or non-target tissues. In one embodiment, the prediction of the peak power / temperature change at each ultrasound treatment location is based on a phase adjustment determined using a sufficiently consistent reflected signal. For example, a physical model and / or imager (e.g., MRI equipment) or other suitable means may be implemented first to predict and / or measure the peak power / temperature change in a first ultrasound treatment location resulting from an amplitude / phase adjustment determined using a sufficiently consistent reflected signal from the reflector. Subsequently, based on the measured peak power / temperature change in the first ultrasound treatment location and a comparison of the phase adjustment associated with the reflected signal from the first ultrasound treatment location and the phase adjustment associated with the reflected signal from other ultrasound treatment locations (determined using a sufficiently consistent reflected signal from other reflectors in the other ultrasound treatment locations), the peak power / temperature changes in other ultrasound treatment locations can be estimated. This discussion focuses on temperature changes as exemplary therapeutic and / or acoustic effects; however, it should be understood that other such effects can be predicted using the techniques described herein and are within the scope of this invention. These other effects may include changes in pressure, mechanical properties, cavitation activity, tissue sensitivity, blood-brain barrier disruption, acoustic radiation, and / or speckle shape.

[0019] Alternatively, the peak power / temperature changes at other ultrasound treatment locations can be estimated using a consistency function based on the measured peak power / temperature change at the first ultrasound treatment location and the phase adjustment associated with the reflected signals from the first and other ultrasound treatment locations.

[0020] In various embodiments, the reflections are determined to be sufficiently consistent. All (or at least some) transient acoustic reflectors can be computationally shifted to coincide at a single location, and the phase associated with the shifted and / or unshifted reflected signals at the coincident location can be determined. Additionally, the increase in acoustic power / temperature at the coincident location resulting from each of the shifted and / or unshifted reflected signals can be determined (e.g., using a consistency function). Based on this, the phase associated with the transducer element measuring the reflected signals can be calculated as an average or weighted average of the phases associated with the shifted and / or unshifted reflected signals at the coincident location; and the temperature increase at the coincident location can be estimated as an average or weighted average of the temperature increase resulting from phase adjustments to the shifted and / or unshifted reflected signals at the coincident location.

[0021] In various embodiments, a physical model is used to computationally establish or empirically determine, prior to the ultrasound procedure, a relationship between one or more ultrasound parameter values ​​(e.g., acoustic power level, ultrasound frequency, or acoustic energy level) and the resulting peak power / temperature change at the target location. Based on this relationship and the predicted peak power / temperature change at each ultrasound treatment location, adjustments to the ultrasound parameter values ​​required to compensate for the peak power / temperature change at the target location can be determined. Subsequently, the adjusted phase, power level, frequency, and / or energy level can be used to operate the transducer elements to generate optimal focus at the ultrasound treatment location while avoiding overheating of the target / non-target tissue. In one embodiment, the ultrasound parameter values ​​are adjusted only when the predicted change in peak power / temperature at the target location exceeds a maximum permissible change (e.g., 3°C per second) or when the predicted change causes the peak power / temperature at the target location to exceed a target value (e.g., 60°C).

[0022] Therefore, in one aspect, the present invention relates to a system for focusing an ultrasonic transducer. In various embodiments, the system comprises: an ultrasonic transducer having a plurality of transducer elements for providing a series of ultrasonic treatments to one or more target regions; and a controller configured to: (a) cause the transducer to generate a first ultrasonic treatment in the series of ultrasonic treatments on the target region, and measure a first set of reflected signals generated by the first ultrasonic treatment; (b) determine, based on the first set of reflected signals, whether a target number or target occurrence rate of focusing events has been reached; and (c) if not, then (i) cause the transducer to generate a second ultrasonic treatment on the target region at an adjusted acoustic power, and measure a second set of reflected signals generated by the second ultrasonic treatment; and (ii) adjust parameter values ​​(e.g., phase or amplitude) associated with one or more of the transducer elements, at least in part, based on the second set of reflected signals, to improve ultrasonic focus at the target region. In one embodiment, the focusing events are reflected signals from one or more transient acoustic reflectors located near or at the target region.

[0023] The controller may also be configured to determine the focusing event at least in part based on a change in a parameter (e.g., phase or amplitude) associated with the first set of reflected signals. Additionally, the controller may be further configured to: computationally reconstruct the sound field at the target region at least in part based on the first set of reflected signals; and identify the focusing event at least in part based on the reconstructed sound field. In one embodiment, the focusing event is identified only when the reconstructed sound field converges to the target region. In some embodiments, the controller is further configured to: select the second set of reflected signals at least in part based on the consistency among the second set of reflected signals; and determine the parameter value associated with the transducer element at least in part based on the selected second set of reflected signals. Additionally, the controller may be configured to, before adjusting the parameter values ​​associated with the transducer element, repeatedly (i) determine whether the target number or target occurrence rate of the focusing events has been reached, and (ii) if not, cause the transducer to generate the second ultrasonic treatment of the target region at the adjusted acoustic power, and measure the second set of reflected signals of the second ultrasonic treatment, until the target number or target occurrence rate of the focusing events has been reached. The controller may also be configured to adjust the parameter values ​​associated with the transducer element at least in part based on the adjusted acoustic power.

[0024] In various embodiments, the system further includes an application device for approaching or introducing a transient acoustic reflector at the target area; the first set of reflected signals and / or the second set of reflected signals are from the transient acoustic reflector. The application device may be an automatic application device or a manual application device. Additionally, the controller may be configured to: determine whether an artifact exists in the first set of reflected signals and / or the second set of reflected signals; and immediately after determining that the number of targets or the target incidence rate has not yet reached the focusing event and that an artifact exists in the first set of reflected signals and / or the second set of reflected signals, adjust the parameters (e.g., concentration, size, and / or reagent type) associated with the transient acoustic reflector. In some embodiments, the controller is further configured to determine whether the artifact exists in the first set of reflected signals before causing the transducer to generate the second ultrasound treatment. In one embodiment, the controller is further configured to immediately increase the concentration of the acoustic reflector after determining that the number of targets or the target incidence rate has not yet reached the focusing event and that an artifact exists in the first set of reflected signals and / or the second set of reflected signals.

[0025] The controller is further configured to, before adjusting the parameter values ​​associated with the transducer elements: determine whether the target number or target incidence of the focusing event has been reached based on the second set of reflected signals; determine whether the adjusted acoustic power associated with the second ultrasound treatment is below a target power level; and immediately reduce the concentration of the transient acoustic reflector by the application device after determining that the target number or target incidence of the focusing event has been reached and the adjusted acoustic power associated with the second ultrasound treatment is below the target power level. Additionally, the controller may also be configured to cause the transducer to generate acoustic energy for approaching the target area or creating a transient acoustic reflector at the target area; the first set of reflected signals and / or the second set of reflected signals are from the transient acoustic reflector. The controller may also be configured to cause at least some of the transducer elements to measure the first set of reflected signals and / or the second set of reflected signals. Alternatively or additionally, the system may also include an acoustic signal detector for measuring the first set of reflected signals and / or the second set of reflected signals. In some embodiments, the controller is further configured to: (e) predict a therapeutic or acoustic change in the target area resulting from an adjustment of the parameter value; (f) if the predicted change exceeds a maximum permissible change or causes the therapeutic or acoustic change in the target area to exceed a target value, then determine a power level, ultrasonic frequency, and / or energy level associated with the first and / or the second of the transducer elements to reduce the predicted therapeutic or acoustic change; and (g) activate the ultrasonic transducer at least in part based on the parameter value determined in step (d) and the power level, ultrasonic frequency, or energy level determined in step (f).

[0026] In another aspect, the present invention relates to a method for focusing an ultrasonic transducer having a plurality of transducer elements. In various embodiments, the method comprises: (a) generating a first ultrasonic treatment on one or more target regions and measuring a first set of reflected signals generated by the first ultrasonic treatment; (b) determining, based on the first set of reflected signals, whether a target number or target occurrence rate of focusing events has been reached; and (c) if not reached, then (i) generating a second ultrasonic treatment on the target regions at adjusted acoustic power and measuring a second set of reflected signals generated by the second ultrasonic treatment; and (ii) adjusting parameter values ​​(e.g., phase or amplitude) associated with one or more of the transducer elements, at least in part, based on the second set of reflected signals, to improve ultrasonic focus at the at least one target region. In one embodiment, the focusing events are reflected signals from one or more transient acoustic reflectors located near or at the target region.

[0027] The method may further include determining the focusing event based at least in part on a change in a parameter (e.g., phase or amplitude) associated with the first set of reflected signals. Additionally, the method may further include: computationally reconstructing the sound field at the target region based at least in part on the first set of reflected signals; and identifying the focusing event based at least in part on the reconstructed sound field. In one embodiment, the focusing event is identified only when the reconstructed sound field converges to the target region. In some embodiments, the method further includes selecting the second set of reflected signals based at least in part on the consistency between the second set of reflected signals, and determining the parameter value associated with the transducer element based at least in part on the selected second set of reflected signals. Additionally, the method may further include: repeating (i) determining whether the target number or target occurrence rate of the focusing event has been reached before adjusting the parameter value associated with the transducer element, and (ii) if not, causing the transducer to generate a second ultrasonic treatment of the target region at the adjusted acoustic power, and measuring the second set of reflected signals of the second ultrasonic treatment until the target number or target occurrence rate of the focusing event has been reached. The method may further include adjusting the parameter values ​​associated with the transducer element based at least in part on the adjusted acoustic power.

[0028] In various embodiments, the method further includes introducing a transient acoustic reflector near or at the target region; the first set of reflected signals and / or the second set of reflected signals originating from the transient acoustic reflector. Additionally, the method may further include: determining whether an artifact exists in the first set of reflected signals and / or the second set of reflected signals; and immediately adjusting the application device (e.g., concentration, size, and / or reagent type) associated with the transient acoustic reflector after determining that the number of targets or the target incidence rate has not yet reached the focusing event and that the artifact exists in the first set of reflected signals and / or the second set of reflected signals. In some embodiments, the presence of the artifact in the first set of reflected signals is determined before generating the second ultrasound treatment. In one embodiment, the method further includes immediately increasing the concentration of the acoustic reflector after determining that the number of targets or the target incidence rate has not yet reached the focusing event and that the artifact exists in the first set of reflected signals and / or the second set of reflected signals.

[0029] The method may further include, before adjusting the parameter values ​​associated with the transducer element: determining whether the target number or target incidence of the focusing event has been reached based on the second set of reflected signals; determining whether the adjusted acoustic power associated with the second ultrasonic processing is below a target power level; and immediately reducing the concentration of the transient acoustic reflector after determining that the target number or target incidence of the focusing event has been reached and the adjusted acoustic power associated with the second ultrasonic processing is below the target power level. Additionally, the method may further include generating acoustic energy for approaching the target area or creating a transient acoustic reflector at the target area; the first set of reflected signals and / or the second set of reflected signals are from the transient acoustic reflector. The method may further include: (e) predicting a therapeutic or acoustic change in the target area resulting from the adjustment of the parameter value; (f) if the predicted change exceeds a maximum permissible change or causes the therapeutic or acoustic change in the target area to exceed a target value, then determining a power level, ultrasonic frequency, and / or energy level associated with the first and / or the second of the transducer elements to reduce the predicted therapeutic or acoustic change; and (g) activating the ultrasonic transducer at least in part based on the parameter value determined in step (d) and the power level, ultrasonic frequency, and / or energy level determined in step (f).

[0030] Another aspect of the invention relates to a system for applying acoustic energy. In various embodiments, the system comprises: an ultrasonic transducer having a plurality of transducer elements for providing a series of ultrasonic treatments to one or more target areas; and a controller configured to: determine a phase value associated with a first of the transducer elements to be adjusted for generating a focal point at the target area; predict therapeutic or acoustic changes in the target area resulting from the adjustment of the phase value (e.g., temperature change, pressure change, mechanical index change, cavitation activity change, tissue sensitivity change, blood-brain barrier disruption change, acoustic radiation force change, and / or speckle shape change); and if the predicted change exceeds a maximum permissible change or causes the therapeutic or acoustic change in the target area to exceed a target value, then (i) determine a power level, ultrasonic frequency, and / or energy level associated with the first and / or the second of the transducer elements to reduce the predicted therapeutic or acoustic change, and (ii) activate the ultrasonic transducer at least in part based on the determined phase value, power level, ultrasonic frequency, and / or energy level. In one implementation, the controller is further configured to predict the treatment or acoustic changes based at least in part on tissue distortions caused by the interventional tissue located between the ultrasound transducer and the target area.

[0031] The controller may also be configured to establish a relationship between (i) the change in the target region and (ii) the power level, the ultrasonic frequency, and / or the energy level associated with the first and / or the second of the transducer elements. This relationship may be established empirically or using a physical model. Additionally, the system may include a transient acoustic reflector located near or at the target region. The controller may also be configured to: cause the transducer to generate a first ultrasonic treatment in a series of ultrasonic treatments for the target region; measure the reflected signal of the first ultrasonic treatment from the transient acoustic reflector; select the measured reflected signal at least in part based on the consistency between the measured reflected signals; and determine the phase value associated with the first of the transducer elements at least in part based on the selected reflected signal. Alternatively, the controller may also be configured to: cause the transducer to generate a first ultrasonic treatment in the ultrasonic treatment series for the target region; measure the reflected signal of the first ultrasonic treatment from the transient acoustic reflector; computationally reconstruct the sound field at the target region based at least in part on the measured reflected signal; select the measured reflected signal based at least in part on the reconstructed sound field; and determine the phase value associated with the first of the transducer elements based at least in part on the selected reflected signal.

[0032] In various embodiments, the system further includes a plurality of transient acoustic reflectors, each of the transient acoustic reflectors located near one of the target regions or at one of the target regions, and the controller is further configured to: sequentially generate a plurality of ultrasound processes to each of the transient acoustic reflectors and measure the reflected signals from each of the transient acoustic reflectors; and select the reflected signals at least in part based on the consistency among the reflected signals from the transient acoustic reflectors associated with the plurality of ultrasound processes. Additionally, the controller may also be configured to: determine the phase value at least in part based on a first set of the selected reflected signals from the first of the target regions; and determine a second phase value associated with the first of the transducer elements at least in part based on a second set of the selected reflected signals from the second of the target regions. In one embodiment, the controller is further configured to predict a second therapeutic or acoustic change in the second of the target regions resulting from an adjustment of the second phase value, at least in part based on the determined phase value, the second phase value, and the predicted therapeutic or acoustic change.

[0033] In some embodiments, the system further includes a measurement system for measuring the therapeutic or acoustic change in the first target region due to the adjustment of the determined phase value. The controller is also configured to predict, at least in part, a second therapeutic or acoustic change in the second target region resulting from the adjustment of the second phase value, based on the determined phase value, the second phase value, and the measured therapeutic or acoustic change in the first target region. Additionally, the controller may be further configured to: computationally shift the position of the first transient acoustic reflector to coincide with the position of the second transient acoustic reflector; computationally determine an updated phase value associated with the reflected signal from the shifted position of the first transient acoustic reflector; and predict, at least in part, the therapeutic or acoustic change in the coincident position resulting from the adjustment of the updated phase value and the determined phase value, based on the determined phase value, the updated phase value, and the predicted therapeutic or acoustic change.

[0034] In various embodiments, the system further includes an imaging system, such as a computed tomography (CT) device, a magnetic resonance imaging (MRI) device, a positron emission tomography (PET) device, a single-photon emission computed tomography (SPECT) device, or an ultrasound examination device, for acquiring images of the target area and / or a non-target area located between the transducer and the target area. The controller may also be configured to determine, at least in part, the spatial configuration of the target area relative to the transducer and tissue characteristics associated with the target area and the non-target area based on the acquired images. In one embodiment, the controller is further configured to implement a physical model for (i) predicting the treatment or acoustic changes in the target area, and / or (ii) determining the power level, the ultrasound frequency, and / or the energy level, at least in part, based on the phase value, the spatial configuration of the target area relative to the transducer, and / or the tissue characteristics associated with the target area and the non-target area.

[0035] In another aspect, the present invention relates to a method for applying acoustic energy to one or more target regions from an ultrasonic transducer having a plurality of transducer elements. In various embodiments, the method comprises: (a) determining a phase value associated with a first of the transducer elements to be adjusted for generating an ultrasonic focus at the target region; (b) predicting a therapeutic or acoustic change in the target region resulting from the adjustment of the phase value (e.g., temperature change, pressure change, mechanical index change, cavitation activity change, tissue sensitivity change, blood-brain barrier disruption change, acoustic radiation force change, and / or speckle shape change); and (c) if the predicted therapeutic or acoustic change exceeds a maximum permissible change or causes the therapeutic or acoustic change in the target region to exceed a target value, then (i) determining a power level, ultrasonic frequency, and / or energy level associated with the first and / or the second of the transducer elements to reduce the predicted therapeutic or acoustic change, and (ii) activating the ultrasonic transducer at least in part based on the determined phase value, power level, ultrasonic frequency, and / or energy level. In one implementation, the therapeutic or acoustic change is predicted at least in part based on tissue distortion caused by the interventional tissue located between the ultrasound transducer and the target area. Additionally, the power level, ultrasound frequency, and / or energy level determined in step (c) can reduce the predicted therapeutic or acoustic change to no more than the target or maximum permissible value.

[0036] The method may further include establishing a relationship between (i) the change in the target region and (ii) the power level, the ultrasonic frequency, and / or the energy level associated with the first and / or the second of the transducer elements. This relationship may be established empirically or using a physical model. Additionally, the method may further include: approaching or introducing a transient acoustic reflector at the target region; generating a first ultrasonic treatment on the target region; measuring the reflected signal from the first ultrasonic treatment from the transient acoustic reflector; selecting the measured reflected signal at least in part based on the consistency between the measured reflected signals; and determining the phase value associated with the first of the transducer elements at least in part based on the selected reflected signal. Alternatively, the method may further include: approaching or introducing a transient acoustic reflector at the target area; generating a first ultrasonic treatment of the target area; measuring a reflected signal from the first ultrasonic treatment of the transient acoustic reflector; computationally reconstructing a sound field at the target area based at least in part on the measured reflected signal; selecting the measured reflected signal based at least in part on the reconstructed sound field; and determining the phase value associated with the first transducer element based at least in part on the selected reflected signal.

[0037] In various embodiments, the method further includes: sequentially generating a plurality of ultrasonic processes to one or more transient acoustic reflectors located near or at one or more target regions, and measuring the reflected signals from the one or more transient acoustic reflectors; and selecting the reflected signals at least in part based on the consistency among the reflected signals associated with the plurality of ultrasonic processes from the transient acoustic reflectors. Additionally, the method may further include: determining the phase value in step (a) at least in part based on a first set of selected reflected signals from a first of the target regions; and determining a second phase value associated with the first of the transducer elements at least in part based on a second set of selected reflected signals from a second of the target regions.

[0038] In one embodiment, the method further includes predicting, at least in part, a second therapeutic or acoustic change in the second target region resulting from an adjustment of the second phase value, based on the determined phase value, the second phase value, and the predicted therapeutic or acoustic change. The method may further include measuring the therapeutic or acoustic change in the first target region due to the adjustment of the determined phase value. In one embodiment, the method further includes predicting, at least in part, a second therapeutic or acoustic change in the second target region resulting from an adjustment of the second phase value, based on the determined phase value, the second phase value, and the measured therapeutic or acoustic change in the first target region. In some embodiments, the method further comprises: computationally shifting the position of a first transient acoustic reflector to coincide with the position of a second transient acoustic reflector; computationally determining an updated phase value associated with the reflected signal from the shifted position of the first transient acoustic reflector; and predicting, at least in part, a therapeutic or acoustic change in the coincided position resulting from an adjustment to the updated phase value and the determined phase value, based on the determined phase value, the updated phase value, and the predicted therapeutic or acoustic change.

[0039] The method may further include acquiring images of the target region and / or a non-target region located between the transducer and the target region. Additionally, the method may further include determining, at least in part, the spatial configuration of the target region relative to the transducer and tissue characteristics associated with the target region and the non-target region based on the acquired images. In one embodiment, the method further includes implementing a physical model to (i) predict the therapeutic or acoustic changes in the target region, and / or (ii) determine the power level, the ultrasound frequency, and / or the energy level, at least in part, based on the phase value, the spatial configuration of the target region relative to the transducer, and / or the tissue characteristics associated with the target region and the non-target region.

[0040] Another aspect of the invention relates to a system for applying acoustic energy. In various embodiments, the system includes: an ultrasound transducer having a plurality of transducer elements; an imager; and a controller configured to: (a) populate a treatment profile specifying a plurality of treatment parameters associated with the ultrasound transducer and one or more target areas; (b) cause the imager to acquire images of a new target area and / or interventional tissue located between the transducer and the new target area; (c) determine new treatment parameters associated with the new target area based at least in part on the acquired images; (d) identify treatment parameters in the treatment profile that best match the determined new treatment parameters; and (e) determine (i) treatment parameters for the new target area based at least in part on the identified best-matching treatment parameters. (i) adjusting the phase value associated with one or more of the transducer elements to generate the optimal focus in the target area, and (ii) the therapeutic or acoustic change in the new target area resulting from the adjustment of the phase value; and (f) if the determined therapeutic or acoustic change exceeds the maximum permissible change or causes the therapeutic or acoustic change in the target area to exceed a target value, then determining an adjustment of the power level, frequency, and / or energy level associated with one or more of the transducer elements to reduce the therapeutic or acoustic change, and activating the ultrasonic transducer at least in part based on the adjustment of the phase value determined in step (e) and the determined adjustment of the power level, frequency, and / or energy level.

[0041] The treatment parameters may include: (i) the geometry of the transducer elements and their position and orientation relative to the target area; (ii) the tissue characteristics (e.g., location, thickness, density, or material properties) of the target area and the interventional tissue; (iii) adjustments to the phase values ​​associated with at least some of the transducer elements for generating optimal focus at the target area; (iv) the therapeutic or acoustic change at the target area resulting from the phase value adjustments; and / or (v) adjustments to the acoustic power, frequency, and / or energy level associated with at least some of the transducer elements for reducing the therapeutic or acoustic change. Additionally, the controller may also be configured to empirically determine the phase value adjustments in step (iii), the therapeutic or acoustic change at the target area in step (iv), and the acoustic power, frequency, and / or energy level adjustments in step (v). In one embodiment, the controller is further configured to implement a physical model to determine, at least in part, the adjustment of the phase value in step (iii), the treatment or acoustic change at the target area in step (iv), and the adjustment of the acoustic power, frequency, and / or energy level in step (v), based on the geometry of the transducer element and its position and orientation relative to the target area and the tissue characteristics of the target area and the interventional tissue.

[0042] In another aspect, the present invention relates to a method for applying acoustic energy using an ultrasonic transducer having a plurality of transducer elements. In various embodiments, the method comprises: (a) filling a treatment profile specifying a plurality of treatment parameters associated with the ultrasonic transducer and one or more target areas; (b) acquiring images of a new target area and / or interventional tissue located between the transducer and the new target area; (c) determining new treatment parameters associated with the new target area, at least in part based on the acquired images; (d) identifying treatment parameters in the treatment profile that best match the determined new treatment parameters; and (e) determining, at least in part based on the identified best-matching treatment parameters, (i) one or more of the transducer elements for generating optimal focus at the new target area. (i) adjustment of an associated phase value, and (ii) therapeutic or acoustic change at the new target area resulting from the adjustment of the phase value; and (f) if the determined therapeutic or acoustic change exceeds the maximum permissible change or causes the therapeutic or acoustic change in the target area to exceed a target value, then (i) an adjustment of the power level, frequency and / or energy level associated with one or more of the transducer elements is determined to reduce the therapeutic or acoustic change, and (ii) the ultrasonic transducer is activated at least in part based on the adjustment of the phase value determined in step (e) and the determined adjustment of the power level, frequency and / or energy level.

[0043] The treatment parameters may include: (i) the geometry of the transducer elements and their position and orientation relative to the target region; (ii) the tissue characteristics (e.g., location, thickness, density, or material properties) of the target region and the interventional tissue; (iii) adjustments to the phase values ​​associated with at least some of the transducer elements for generating optimal focus at the target region; (iv) the therapeutic or acoustic change at the target region resulting from the phase value adjustments; and / or (v) adjustments to the acoustic power, frequency, and / or energy level associated with at least some of the transducer elements for reducing the therapeutic or acoustic change. Additionally, the method may further include empirically determining the phase value adjustments in step (iii), the therapeutic or acoustic change at the target region in step (iv), and the acoustic power, frequency, and / or energy level adjustments in step (v). In one embodiment, the method further comprises implementing a physical model to determine, at least in part, the adjustment of the phase value in step (iii), the treatment or acoustic change at the target area in step (iv), and the adjustment of the acoustic power, frequency, and / or energy level in step (v), based on the geometry of the transducer element and its position and orientation relative to the target area and the tissue characteristics of the target area and the interventional tissue.

[0044] In another aspect, the present invention relates to a system for focusing an ultrasonic transducer. In various embodiments, the system comprises: an ultrasonic transducer having a plurality of transducer elements for providing a series of ultrasonic treatments to one or more target regions; and a controller configured to: (a) cause the transducer to generate a first ultrasonic treatment in the series of ultrasonic treatments on the target region, and measure a first set of reflected signals generated by the first ultrasonic treatment; (b) determine, based on the first set of reflected signals, whether a target number or target occurrence rate of focusing events has been reached; (i) if not, cause the transducer to generate a second ultrasonic treatment on the target region at an adjusted acoustic power, and measure a second set of reflected signals generated by the second ultrasonic treatment; (d) at least partially based on the second set of reflected signals... (i) adjusting the phase value associated with one or more of the transducer elements to improve the ultrasound focus at the target region; (e) predicting the therapeutic or acoustic change in the target region resulting from the adjustment of the parameter values; and (f) if the predicted change exceeds the maximum permissible change or causes the therapeutic or acoustic change in the target region to exceed a target value, then (i) determining the power level, ultrasound frequency, and / or energy level associated with the first and / or the second of the transducer elements to reduce the predicted therapeutic or acoustic change, and (ii) activating the ultrasound transducer at least in part based on the determined parameter values, power level, ultrasound frequency, and / or energy level.

[0045] In another aspect, the present invention relates to a method for focusing an ultrasonic transducer having a plurality of transducer elements. In various embodiments, the method includes: (a) generating a first ultrasonic treatment on one or more target regions and measuring a first set of reflected signals generated by the first ultrasonic treatment; (b) determining, based on the first set of reflected signals, whether a target number or target occurrence rate of focusing events has been reached; (c) if not, generating a second ultrasonic treatment on the target regions at adjusted acoustic power and measuring a second set of reflected signals generated by the second ultrasonic treatment; and (d) adjusting parameter values ​​associated with one or more of the transducer elements, at least in part, based on the second set of reflected signals, to improve the focusing effect. (e) predicting therapeutic or acoustic changes in the target area resulting from adjustments to the parameter values; and (f) if the predicted change exceeds the maximum permissible change or causes the therapeutic or acoustic change in the target area to exceed a target value, then (i) determining a power level, ultrasonic frequency, and / or energy level associated with the first and / or second of the transducer elements to reduce the predicted therapeutic or acoustic changes, and (ii) activating the ultrasonic transducer at least in part based on the determined parameter values, power level, ultrasonic frequency, and / or energy level.

[0046] As used herein, the term "substantially" means ±10%, and in some embodiments ±5%. Throughout this specification, the references to "an example," "example," "an embodiment," or "embodiment" mean that a particular feature, structure, or characteristic described in connection with the example is included in at least one instance of the invention. Therefore, the phrases "in an example," "in a particular example," "an embodiment," or "embodiment" appearing in various places throughout this specification do not necessarily all refer to the same example. Furthermore, particular features, structures, routines, steps, or characteristics may be combined in any suitable manner in one or more instances of the technology. The headings provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology. Attached Figure Description

[0047] In the drawings, the same reference characters typically refer to the same parts in different views. Furthermore, the drawings are not necessarily drawn to scale, but generally focus on illustrating the principles of the invention. In the following description, various embodiments of the invention will be described with reference to the following drawings, in which:

[0048] Figure 1 An exemplary ultrasound system according to various embodiments is schematically depicted;

[0049] Figure 2A Depicts one or more transient acoustic reflectors located near one or more target areas according to various embodiments;

[0050] Figure 2B The application of ultrasonic processing at multiple locations near a target area according to various embodiments is described;

[0051] Figure 3A The reflection signal measured from the transient reflector and the differential signal determined based on the measured reflection signal are depicted according to various embodiments.

[0052] Figure 3B The maximum amplitude associated with the differential signal of the measured reflected signal according to various embodiments is schematically depicted.

[0053] Figure 4A and 4B The restricted and unrestricted sound fields at the ultrasonic processing location are shown respectively according to various embodiments;

[0054] Figure 5 The relationship between the acoustic power of the applied ultrasonic treatment and the change in the reflected signal is schematically depicted according to various embodiments;

[0055] Figure 6This is a flowchart illustrating a method for automatically focusing an ultrasonic beam at a target area according to various embodiments;

[0056] Figure 7A The reflected signals measured by transient reflectors according to various embodiments are schematically shown;

[0057] Figure 7B The illustration schematically depicts, according to various embodiments, the calculated position of one transient acoustic reflector being shifted to coincide with the position of another transient acoustic reflector;

[0058] Figure 8 The diagram schematically depicts the relationship between the acoustic power level of the applied ultrasonic treatment according to various embodiments and the resulting temperature change at the target region; and

[0059] Figures 9A-9C This is a flowchart illustrating, according to various embodiments, a method for predicting changes in the temperature or peak power of an ultrasound focal point resulting from optimization / improvement of focusing properties, and adjusting one or more ultrasound parameters accordingly to avoid overheating of target and / or non-target tissues. Detailed Implementation

[0060] Figure 1 An exemplary ultrasound system 100 is shown for focusing an ultrasound beam through the skull onto a target area 101 within a patient's brain. However, those skilled in the art will understand that the ultrasound system 100 described herein can be applied to any part of the human body. In various embodiments, system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 driving the phased array 102, a controller 108 communicating with the beamformer 106, and a frequency generator 110 providing input electronic signals to the beamformer 106.

[0061] Array 102 may have a curved (e.g., spherical or parabolic) shape suitable for placement on a surface of the skull or other body parts, or may comprise one or more planar or otherwise shaped segments. Depending on the application, its size can vary from millimeters to tens of centimeters. The transducer elements 104 of array 102 may be piezoelectric ceramic elements and may be mounted in silicone rubber or any other material suitable for mechanical coupling between the attenuating elements 104. Piezoelectric composite materials, or any material generally capable of converting electrical energy into acoustic energy, may also be used. To ensure maximum power delivery to the transducer elements 104, elements 104 may be configured for electrical resonance at 50 Ω to match the input connector impedance.

[0062] Transducer array 102 is coupled to beamformer 106, which drives individual transducer elements 104 such that they collectively generate a focused ultrasonic beam or field. For n transducer elements, beamformer 106 may contain n driver circuits, each circuit comprising an amplifier 118 and a phase delay circuit 120 or thereof; each driver circuit drives one of the transducer elements 104. Beamformer 106 receives a radio frequency (RF) input signal, typically in the range of 0.1 MHz to 1.0 MHz, from frequency generator 110, which may be, for example, a DS345 generator purchased from Stanford Research Systems. The input signal may be split into n channels for the n amplifiers 118 and delay circuits 120 of beamformer 106. In some embodiments, frequency generator 110 is integrated with beamformer 106. The radio frequency generator 110 and the beamformer 106 are configured to drive the individual transducer elements 104 of the transducer array 102 at the same frequency but with different phases and / or different amplitudes.

[0063] The amplification or attenuation factor α1-α applied by the beamformer 106 n and phase shift a1-a n It is used to project ultrasound energy through non-uniform tissue (e.g., a patient's skull) and focus it onto a target area (e.g., a region in the patient's brain). By adjusting the amplification factor and / or phase shift, the desired shape and intensity of the focal region can be produced in the target area.

[0064] The amplification factor and phase shift can be calculated using controller 108, which can provide the calculation functionality through software, hardware, firmware, hardwiring, or any combination thereof. For example, controller 108 can utilize a general-purpose or special-purpose digital data processor programmed in software in a conventional manner without improper experimentation to determine the frequency, phase shift, and / or amplification factor of transducer element 104. In some embodiments, the controller calculations are based on information about the characteristics of the skull (e.g., structure, thickness, density, etc.) and their impact on sound energy propagation. In various embodiments, such information is obtained from imager 122, such as 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 examination device. Imager 122 can provide a set of two-dimensional images suitable for reconstructing a three-dimensional image of the skull from which thickness and density can be inferred; alternatively, image acquisition can be three-dimensional. Furthermore, image manipulation functionality can be implemented in imager 122, controller 108, or a separate device.

[0065] System 100 can be modified in various ways within the scope of this invention. For example, the system may further include an acoustic signal detector (e.g., a hydrophone) 124 that measures transmitted or reflected ultrasound and can provide the received signals to controller 108 for further processing. Reflected and transmitted signals may also provide alternative or additional sources of feedback for determining phase shift and / or amplification factors or for phase and amplitude adjustments of beamformer 106, as further described below. System 100 may include a locator for positioning an array 102 of transducer elements 104 relative to the patient's skull. The transducer array 102 may take different (e.g., cylindrical) shapes for applying ultrasound therapy to body parts other than the brain. In some embodiments, transducer elements 104 are movably and rotatably mounted, thereby providing mechanical degrees of freedom that can be used to improve focusing properties. Such movable transducers can be adjusted by conventional actuators, which may be driven by components of controller 108 or by a separate mechanical controller.

[0066] See Figure 2A In various embodiments, one or more transient reflectors 202 are introduced near (e.g., less than 5 mm away from) one or more ultrasonic processing locations close to or within the target area 101 to facilitate autofocusing of the ultrasound. Microbubbles 202 can be generated by applying acoustic energy from transducer element 104 to the target 101. Microbubbles 202 can be formed due to negative pressure generated by propagating ultrasound or when a heated liquid ruptures and is filled with gas / vapor. Due to their encapsulated gas, microbubbles 202 can act as reflectors of ultrasound and emit coherent omnidirectional signals 204-208 toward transducer 102; reflected signals 204-208 can be detected substantially simultaneously by their associated transducer element 104 and / or acoustic signal detector 124, as further described below. Based on the analysis of the reflected signal, the controller 108 can obtain information on the focusing properties at the target region 101, and subsequently adjust the transducer configuration (e.g., phase shift and / or amplitude) to compensate for the distortion caused by the interventional tissue 210 located between the transducer element 104 and the target 101, thereby optimizing (or at least improving) the focusing properties at the target region. Methods for generating microbubbles using ultrasound are illustrated, for example, in U.S. Patent Publication No. 2019 / 0308038, the entire contents of which are incorporated herein by reference; and methods for optimizing / improving the focusing properties of an acoustic beam using microbubbles are illustrated, for example, in PCT Publication No. WO 2020 / 128615, the entire contents of which are incorporated herein by reference.

[0067] Alternatively, the acoustic reflector 202 can be introduced into the patient's body intravenously; the transient reflector can be administered systemically into the patient or locally into the target area 101 using the application system 126. For example, the transient reflector 202 may comprise or consist of one or more microbubbles introduced into the patient's brain in the form of liquid droplets, which subsequently vaporize to form microbubbles; or as an inflatable bubble enclosed in a liquid carrier, such as a conventional ultrasound contrast agent. Alternatively, other substances suitable for cavitation nucleation can be administered instead of bubbles (see, for example, https: / / www.springer.com / cda / content / document / cda_downloaddocument / 9783642153426-c1.pdf? SGWID=0-0-45-998046-p174031757).

[0068] Typically, an automated application system can be operated by controller 108 or a dedicated controller associated with the application system. For example, analysis of the reflected signals can cause controller 108 to operate application device 126 to increase or decrease the amount of acoustic reflector introduced transvenously and / or adjust the type of microbubbles. Alternatively or additionally, analysis of the reflected signals can cause controller 108 to operate transducer 102 to increase or decrease the amount of circulating or localized microbubbles via induced cavitation; for example, increased acoustic power can reduce the number of microbubbles by causing microbubble collapse. Alternatively, application system 126 can be manual, such as a simple syringe. In the case of manual application, analysis of the reflected signals can cause controller 108 to determine the adjustment of the amount of acoustic reflector introduced transvenously and / or the type of microbubbles, and based on this, determine the operation of transducer 102. Methods for delivering acoustic reflectors to a target area using a suitable application system are illustrated, for example, PCT Publication WO 2019 / 116095, the entire disclosure of which is hereby incorporated herein by reference.

[0069] In one embodiment, the application system 126 introduces a relatively low concentration (e.g., 5% of the concentration used for standard imaging) of microbubbles into the target 101, such that the acoustic reflections appear to originate from a point target (e.g., having a size less than a quarter of the wavelength of the ultrasound processing), such as a single microbubble (rather than a cloud of microbubbles). This is because the reflected signal from a cloud of microbubbles can be incoherent and / or exhibit artifacts due to low SNR and / or vibrations from multiple microbubbles; therefore, analysis of the reflected signal from the cloud of microbubbles may be inaccurate, and adjustments to the transducer parameters based thereon may be insufficient to account for distortions caused by the interventional tissue. Furthermore, analysis of the reflected signal from the cloud of microbubbles can be computationally expensive and time-consuming. On the other hand, the microbubble concentration is preferably sufficiently high to create significant interaction with ultrasound, thereby providing detectable reflections for performing an autofocusing procedure. Therefore, in one embodiment, the initial microbubble concentration to be introduced into the target area is first determined empirically based on preclinical studies, pretreatment procedures, and / or from known literature prior to the autofocusing procedure. Subsequently, optimization methods are performed to determine the optimal concentration, acoustic power, and / or other parameters associated with the ultrasonic transducer and / or microbubbles to facilitate the autofocusing procedure, as further described below.

[0070] In an exemplary case, the initial microbubble concentration consists of 1.3 mL of microbubble suspension diluted in 500 mL of water (obtained from, for example, DEFINITY); the infusion is then introduced into the patient at a drip rate of 1 mL / min. See also Figure 2B After the microbubbles 202 are introduced, the controller 108 can activate at least some of the transducer elements 104 to sequentially generate multiple focal points at various ultrasonic processing locations 222-230 near the target area 101 (e.g., less than 5 mm apart) or within the target area 101, and each location may have one or more transient reflectors 202 associated with it. For example, the transducer elements 104 can generate one or more series of ultrasonic processing at a first ultrasonic processing location 222 and measure reflections from transient reflectors 232 near it. Subsequently, the transducer elements 104 can generate another one or more series of ultrasonic processing at a second ultrasonic processing location 224 and measure reflections from transient reflectors 234 associated with it. This process can continue until a desired number of reflection signals (e.g., at least 10) from all (or at least some) ultrasonic processing locations near the target 101 are measured.

[0071] In various embodiments, the ultrasonic processing locations 222-230 are determined based on images acquired by imager 122 and / or ultrasonic transducer 102. For example, imager 122 may acquire images of target and / or non-target areas; and ultrasonic transducer 102 may acquire images of these areas based on reflected signals from transient reflectors 202 in the target / non-target areas. Based on the acquired images of the target / non-target areas and the associated transient reflectors, controller 108 may select ultrasonic processing locations 222-230 near the target area (e.g., less than 5 mm away) and / or at the target area and having one or more transient reflectors close to it (e.g., less than 5 mm away). A method for acquiring images of transient reflectors using reflected signals from them is described, for example, in U.S. Patent Application No. 62 / 949,597 (filed December 18, 2019), the entire disclosure of which is hereby incorporated by reference.

[0072] In various embodiments, ultrasonic treatment is first performed with low acoustic power (e.g., in the range of 2 to 50 watts); then, reflections from tissue and microbubbles are measured and analyzed, as further described below. Typically, the reflected signals generated by the low-power emission may not differ significantly from one another. Therefore, in one embodiment, the acoustic power of the emitted ultrasonic treatment is gradually increased until a significant change is observed in the parameters (e.g., amplitude, phase, etc.) associated with the reflected signals between two consecutive measurements. For example, Figure 3A Five reflected signals 312-320 from the first ultrasonic processing position 222 measured by transducer element E are shown. Upon receiving the reflected signals, controller 108 can implement an initial signal processing method to obtain the reflected signal from transient acoustic reflector 232 (instead of the background reflector). In one embodiment, controller 108 first calculates a differential signal 322 (e.g., obtained by subtracting signal 312 from signal 314) representing the difference between reflected signals 314 and 312, a differential signal 324 representing the difference between reflected signals 314 and 316, a differential signal 326 representing the difference between reflected signals 316 and 318, and a differential signal 328 representing the difference between reflected signals 318 and 320. In this example, signals 312, 314, 318, and 320 are essentially background signals, and signal 316 is a combination of reflections from the transient signal and the background signal. Therefore, differential signals 324 and 326 are approximately clean reflected signals from transient reflector 232. It should be understood that reflected signals can be analyzed as they are received, i.e., without waiting for subsequent signals or sets of signals.

[0073] See Figure 3BSubsequently, controller 108 can compare the values ​​of the maximum amplitudes associated with the differential signals 322, 324, 326, and 328. As depicted, because there is a significant change in amplitude between signals 322 and 324 (e.g., greater than 50% or 100%), signal 324 can be selected to determine the focusing properties at the first ultrasound processing location 222. As used herein, signal 324 is referred to as the “focusing event,” and the acoustic power of the emitted wave that initiates the focusing event is referred to as the first threshold power P1.

[0074] In some embodiments, the focusing event is identified or selected based on the sound field at the location of the ultrasonic processing. For example, see again Figure 2B The controller can computationally reconstruct the sound field at the ultrasonic processing position 222 based on the measured reflected signal from the transient reflector 232 located nearby. See also Figure 4A In one embodiment, when the reconstructed sound field is confined (e.g., spanning less than 10 mm) 3 Or 20mm in some embodiments 3 When the volume of the confined sound field is such that the reconstructed reflected signal is identified as a focusing event, the confined sound field is used to reconstruct the reflected signal. See also Figure 4B When the reconstructed sound field is unrestricted (e.g., spanning less than 50mm) 3 Or 80mm in some embodiments 3 When the volume is large enough, the measurement signal can be discarded. Alternatively or additionally, the controller 108 can computationally reconstruct the sound field based on information about tissue distortion at the target / non-target area. Methods for computationally reconstructing a sound field based on tissue distortion are, for example, found in U.S. Patent Application No. 62 / 949,597 (filed December 18, 2019) and PCT Patent Application No. 62 / 949,597, filed on the same date, entitled “System and Method for Providing Tissue Information in Anatomically Targeted Areas Using Acoustic Reflectors,” the entire contents of which are incorporated herein by reference.

[0075] The identification and selection of focusing events can advantageously allow for the selection of reflected signals from transient reflectors (e.g., microbubbles) rather than background reflectors for further analysis. This is because reflected signals from background reflectors are typically relatively constant between two consecutive measurements, while reflected signals from transient reflector 202 can exhibit relatively significant changes between two consecutive measurements as the transient reflector moves, evolves, or dissipates during the measurement interval. Therefore, differential signals with relatively small amplitude changes are more likely to originate from background reflectors; in contrast, reflected signals with relatively large amplitude changes are more likely to originate from transient reflectors. As used herein, the term "transient reflector" refers to an acoustic reflector (e.g., microbubble) that dissipates or evolves over time during ultrasound processing, and the term "background reflector" refers to an acoustic reflector (e.g., skull) that does not significantly dissipate or evolve during ultrasound processing.

[0076] Alternatively, a signal selection method can be implemented to select reflected signals from individual microbubbles. In one embodiment, the signal selection method selects reflected signals based on the consistency between them. For example, a reflected signal is considered sufficiently consistent when the value of the consistency function of the phase delay (or travel time) associated with the reflected signal is maximized or exceeds a predetermined threshold (e.g., 40%). By using reflected signals with sufficient consistency, artifacts exhibited in the signal due to low SNR and / or vibrations from multiple microbubbles can be advantageously eliminated (or at least reduced); this, in turn, provides more accurate information about the focusing properties at the target region. Furthermore, the computational complexity of analyzing reflected signals can be significantly reduced. Further details regarding signal selection can be found, for example, in PCT Publication WO 2020 / 128615, the entire contents of which are incorporated herein by reference.

[0077] Generally, the greater the acoustic power applied during ultrasonic processing, the greater the number of focused events generated in the target area. Therefore, see [link to relevant documentation]. Figure 5 In various embodiments, the optimization method begins as follows: gradually increasing the acoustic power of the ultrasonic treatment to generate more focused events until a sufficient number of focused events (e.g., 10, or greater than 30 in some embodiments) or a sufficient occurrence rate (e.g., one event per second, or greater than 10 events per second in some embodiments) is measured to determine the focusing properties at the ultrasonic treatment location with the desired level of accuracy and reliability; to a certain extent (e.g., before the nonlinear response of the microbubbles occurs), more measurements yield greater accuracy. The power used to generate a sufficient number (or sufficient occurrence rate) of focused events is referred to as the optimal power P. F And it can be used during the autofocus process, that is, at the determined power level P. F Ultrasonic waves are emitted to induce sufficient interaction with the microbubbles near or at the ultrasonic processing location within the target area. However, in some cases, the acoustic power may reach a second threshold P2 before a sufficient number or occurrence rate of focusing events are detected, where a nonlinear response of the microbubbles is detected (and consequently, artifacts in the reflected signals). Artifacts can significantly reduce the coherence between reflected signals, leading to inaccurate determination of the focusing properties at the target area. Therefore, once it is determined that artifacts exist in the reflected signals or that the number of reflected signals with artifacts exceeds the number of focusing events (i.e., the number of non-coherent reflected signals exceeds the number of sufficiently coherent reflected signals), the optimization method can immediately adjust another parameter, different from the acoustic power of the emitted wave, to improve autofocus performance.

[0078] For example, the concentration of microbubbles introduced into the patient's body can be adjusted (e.g., increased by 10% or 20% in some embodiments). The applied ultrasound treatment can then be restarted at a low power (e.g., 7 watts), and the power can be gradually increased until the optimal power P is reached. F Then, if the acoustic power reaches the second threshold P2 before a sufficient number of focusing events are detected, the microbubble concentration can be further increased. These processes can be performed alternately and iteratively until a sufficient number of focusing events are detected before the acoustic power reaches the second threshold P2.

[0079] Conversely, in other cases, when the acoustic power is still low (e.g., less than 8 watts), the initial or adjusted microbubble concentration may result in too many focusing events (e.g., greater than 50, or greater than 80 in some embodiments); this indicates the presence of too many microbubbles at the ultrasonic processing location, thereby increasing the computational complexity of analyzing the reflected signals and / or wasting microbubbles. Therefore, the microbubble concentration can be reduced (e.g., 5%, or 10% in some embodiments) and ultrasonic processing can be resumed at a low power (e.g., 7 watts), where the power is gradually increased until the optimal acoustic power P is reached. F This process continues until autofocusing is performed. These processes can also be performed alternately and iteratively until an optimal concentration of microbubbles is introduced to achieve a sufficiently high (e.g., 10 watts) acoustic power P. F Provide a sufficient quantity (or a sufficient occurrence rate) of detectable focused events.

[0080] It should be noted that the above-described optimization methods for determining optimal acoustic power and / or microbubble concentration to facilitate an ultrasound focusing procedure are merely exemplary; any suitable method can be used to optimize the values ​​of any parameters associated with ultrasound and microbubbles to perform an automated focusing procedure, and therefore all such methods are within the scope of this invention. For example, the optimization method may adjust the emission mode of the ultrasound treatment, the reagent type, and / or the size of the microbubbles to generate a sufficient quantity (or a sufficient frequency) of focusing events to determine the focusing properties at the target region.

[0081] After determining the optimal acoustic power and / or optimal microbubble concentration, in various embodiments, the ultrasonic autofocusing procedure may begin as follows: introducing microbubbles at the determined concentration and activating transducer 102 to project the microbubbles with the determined optimal acoustic power P. FThe ultrasonic treatment emits an acoustic signal to a microbubble near or at the ultrasonic treatment location within the target area. The reflection from the microbubble can then be measured using, for example, an acoustic signal detector 124. Alternatively, the transducer element 104 may have both emission and detection capabilities. Therefore, at least some of the transducer elements 104 can be configured to measure the acoustic signal reflected from the target area. Methods for configuring the transducer element 104 for detecting the reflected signal are described, for example, in PCT Publication WO2019 / 234497, the contents of which are incorporated herein by reference.

[0082] The measurement signal can be provided to the controller 108 to obtain information associated with the reflection, such as amplitude and / or phase; these can be compared with the amplitude and / or phase associated with the ultrasonic wave emitted from the transducer element 104. Based on the discrepancy, the controller 108 can adjust the transducer parameters (e.g., phase shift and / or amplitude) to compensate for distortion caused by the intervention tissue 206 located between the transducer element 104 and the target 101, thereby improving the focusing properties at the target. In one embodiment, adjusting the ultrasonic parameters to compensate for tissue distortion is determined solely based on focusing events (e.g., reflected signals with sufficient consistency or corresponding to a confined acoustic field at the target) to reduce computational complexity and increase the measurement accuracy of the focusing properties at the target area. Methods for automatically focusing an ultrasonic beam at a target area are illustrated, for example, PCT Publications WO 2018 / 020315 and WO 2020 / 128615, the entire contents of which are incorporated herein by reference.

[0083] Figure 6An exemplary method 600 is shown for automatically focusing an ultrasound beam at a target area using one or more transient reflectors (e.g., one or more microbubbles) through a non-uniform medium. In a first step 602, one or more transient reflectors (e.g., microbubbles) with an initial concentration are generated and / or introduced near the target area or at one or more ultrasound treatment locations in the target area (e.g., less than 5 mm apart). The initial microbubble concentration may be determined based on, for example, preclinical studies, pre-treatment procedures, and / or from known literature. In a second step 604, at least some of the transducer elements 104 are activated to transmit a series of low-power (e.g., 7 watts) ultrasound treatments to the transient reflectors, and reflected signals from the tissue and / or transient reflectors are measured using, for example, an acoustic signal detector 124 and / or the transducer elements 104. In a third step 606, a controller 108 may implement an initial signal processing method to obtain reflected signals from the transient acoustic reflectors (instead of background reflectors). In one embodiment, the reflected signal from the transient acoustic reflector is determined based on the difference between the amplitude and / or phase associated with the reflected signal in two consecutive measurements. Alternatively, a signal selection method can be implemented to select the reflected signal from a single microbubble based on the consistency between the reflected signals (step 608). For example, a consistency function is defined for the travel time and / or phase delay associated with the reflected signal, and the reflected signal is considered sufficiently consistent only if the value of the consistency function is maximized or exceeds a predetermined threshold (e.g., 40%). The controller 108 can then determine, based on the selected reflected signal, whether a sufficient number (e.g., 10, or greater than 30 in some embodiments) or a sufficient occurrence rate (one event per second, or greater than 10 events per second in some embodiments) of focusing events are detected (step 610). In one embodiment, a focusing event is identified based on a comparison of parameter values ​​(e.g., amplitude, phase, etc.) associated with the selected reflected signal between two measurements. A focusing event occurs only when there is a significant (e.g., greater than 50% or 100%) change in the parameter value. Alternatively, focusing events can be identified based on a computationally reconstructed acoustic field at the location of the ultrasound treatment. The acoustic field reconstruction can be based on measured reflected signals from transient reflectors and / or information about tissue distortion at the target / non-target area. In some embodiments, when the controller 108 determines that a sufficient number or rate of focusing events has not yet been reached, the controller determines whether a threshold power corresponding to the nonlinear response of the acoustic reflector has been reached (step 612). For example, the nonlinear response can be determined based on the presence of artifacts in the reflected signals or the ratio of the number of reflected signals with artifacts to the number of focusing events. If the acoustic power of the ultrasound treatment has reached the threshold, the microbubble concentration can be increased (e.g., 5%, or 10% in some embodiments) (step 614). Otherwise, the applied ultrasound treatment power can be increased (step 616).In various embodiments, when a sufficient number (or sufficient occurrence rate) of focused events is measured, controller 108 determines whether too many focused events (e.g., greater than 50, or greater than 80 in some embodiments) have occurred (or an excessively high event occurrence rate is detected) while the acoustic power is still low (e.g., less than 8 watts) (step 618). If so, the concentration of the acoustic reflector can be reduced (e.g., 5%, or 10% in some embodiments) (step 620). Otherwise, the power of the applied ultrasonic treatment can be gradually increased until the optimal power P is reached. F Up to step 622. Steps 602-622 can be performed iteratively until the optimal concentration and optimal acoustic power of the microbubbles are obtained. Subsequently, an autofocusing procedure can be started using the determined optimal acoustic power and optimal concentration of the acoustic reflector (step 624). In addition, based on the focusing events measured during the autofocusing procedure, ultrasound parameters (e.g., amplitude and / or phase) can be adjusted to compensate for tissue distortion, thereby optimizing the focusing properties at each ultrasound treatment location near or in the target area (step 626).

[0084] Therefore, various embodiments provide methods for determining optimal values ​​for one or more parameters (e.g., acoustic power, microbubble concentration, etc.) associated with the ultrasound transducer and / or acoustic reflector 202 to perform an accurate and reliable ultrasound autofocusing procedure. Because optimization can be performed for each patient, the optimal values ​​obtained can be patient-specific. Thus, the autofocusing procedure can be used to compensate for distortions caused by patient-specific interventional tissues and thereby obtain optimal manipulation parameters (e.g., ultrasound amplitude, phase) to focus acoustic energy at the target area.

[0085] In various embodiments, after optimal focusing is achieved at the target area, the peak power or deposited acoustic energy at the target increases, potentially causing undesirable damage to the target and / or non-target tissue. Therefore, it may be necessary to estimate the increase in peak power / energy at the target due to improved focusing properties and adjust ultrasonic parameters (e.g., the acoustic power level applied by the transducer elements) to compensate for this increase. In various embodiments, the estimation of the increase in peak power / energy at target 101 is based on sufficiently consistent reflected signals received from proximity to (e.g., less than 5 mm away from) target 101 or from various ultrasonic processing locations at said target. For example, Figure 7AThe diagram shows four sufficiently coherent reflected signals 702-708 received from transient reflectors 712-718 near (e.g., less than 5 mm apart) the ultrasound treatment positions R1-R4 at the target 101 or the target. Typically, the ultrasound treatment positions are spatially close (e.g., 2 mm apart) such that differences in distortion, such as those caused by movement and / or alteration in the interventional tissue located between the transducer element and the ultrasound treatment positions R1-R4, are negligible. In one embodiment, a physical model and / or imager 122 (or other suitable device) is implemented to predict and / or measure the phase adjustment associated with the transducer element E. The temperature at the ultrasonic treatment position R1 is increased by ΔT1 to generate the optimal focus at the first ultrasonic treatment position R1. The controller 108 can then adjust the phase, for example, to generate the optimal focus at the second ultrasonic treatment position R2. and A comparison is made, and based on the comparison and the predicted / measured temperature increase ΔT1 at the ultrasonic treatment location R1, the temperature increase ΔT2 at the ultrasonic treatment location R2 is estimated. A similar method can be used to estimate the temperature increases ΔT3 and ΔT4 at the ultrasonic treatment locations R3 and R4, respectively.

[0086] In some embodiments, the physical model includes a consistency function.

[0087]

[0088] Where W represents the weighting factor; c represents the average speed of sound in the target region; ω = 2πf, where f represents the frequency of reflected signals 702 and 704; in It is the geometric position of the i-th transient reflector; and for each transducer element, in and These represent the distances between transducer element E and transient reflectors 712 and 714, respectively. Because temperature increases ΔT1 and ΔT2 are highly correlated with phase adjustment... and Furthermore, they are associated with sufficiently consistent reflected signals 702 and 704 respectively, so a consistency function can be used. And ΔT1 estimates the temperature increase ΔT2.

[0089] See Figure 7BIn various embodiments, controller 108 computationally shifts the position of one of the two transient acoustic reflectors (e.g., reflector 712) associated with the two coherent reflected signals to coincide with the position of the other transient acoustic reflector (e.g., reflector 714). Additionally, controller 108 may computationally determine the phase adjustment associated with reflected signal 702 based on the shifted position of reflector 712. Furthermore, as described above, the physical model and / or imager 122 can predict and / or measure the phase adjustment associated with the reflected signal 204. The temperature at the ultrasonic treatment location R2 increases by ΔT2. Again, this is determined by comparing the phase adjustments associated with the shifted reflection signal 702 and the unshifted reflection signal 704, respectively. and And / or based on the predicted / measured temperature increase ΔT2 at the ultrasonic treatment location R2 and the consistency function, the controller 108 can estimate the phase adjustment associated with the shifted reflection signal 702. The temperature at the ultrasonic treatment location R2 increases by ΔT1'. In some embodiments, this is achieved by comparing the phase adjustments associated with the shifted and unshifted reflected signals 702, respectively. and The temperature increase ΔT1' at the ultrasonic treatment position R2 is determined by predicting / measuring the temperature increase ΔT1 and / or a consistency function. A similar method can be used to estimate the temperature increases ΔT3' and ΔT4' at the ultrasonic treatment position R2, respectively, resulting from the positional shift of acoustic reflectors 716 and 718 to coincide with the position of acoustic reflector 714, associated with reflected signals 706 and 708. In various embodiments, the phase adjustment associated with transducer element E for generating the optimal focus at the coincident position (e.g., the position associated with reflector 714) can then be calculated as the average or weighted average of the phases associated with the shifted reflected signals 702, 706, 708, and / or the unshifted reflected signal 704 at said coincident position. Additionally, the temperature increase at the ultrasonic treatment position R2 can be estimated as the average or weighted average of the temperature increases ΔT1', ΔT2, ΔT3', and ΔT4'.

[0090] See Figure 8In some embodiments, the relationship 802 between ultrasound parameters (e.g., the acoustic power level, ultrasound frequency, and / or acoustic energy level applied by transducer element 104) and the resulting temperature / peak power change at the target (and / or ultrasound treatment location) can be established and stored in a database prior to the ultrasound procedure. This relationship can be empirically derived from preclinical studies, pre-treatment procedures, and / or known literature. For example, the relationship can be modeled empirically based on measurements performed using an ex vivo skull. Alternatively, the relationship can be computationally determined using a physical model. For example, using conventional techniques implemented without improper experimentation, a physical model can predict focusing properties (e.g., the shape, size, location, and peak acoustic power of the focal region) based on information about the geometry of transducer element 104 and its position and orientation relative to the target region 101, as well as the power level and phase of the ultrasound waves emitted from element 104. Additionally, the physical model may include parameters, such as material properties of the target and interventional tissues along the beam path (e.g., energy absorption of the tissue or the velocity of sound at the frequency used), to predict distortions caused by the interventional tissue and / or temperature at target 101 immediately after the application of ultrasound. Material properties can be collected using imager 122 as described above and / or other suitable devices. For example, based on the acquired images, a tissue model characterizing the material properties of the interventional and target tissues can be constructed. The tissue model may take the form of a 3D table corresponding to voxels representing the interventional and / or target tissues; the cells have attributes whose values ​​represent energy absorption-related properties of the tissue, such as absorption coefficients. The voxels obtained by imager 122 in a tomographic manner and the type of tissue represented by each voxel can be automatically determined by conventional tissue analysis software. The cells of the tissue model can be populated using a lookup table of determined tissue types and tissue parameters (e.g., absorption coefficients by tissue type). Further details regarding the creation of tissue models for identifying the energy absorption coefficient, thermal sensitivity, and / or thermal tolerance of various tissues can be found in U.S. Patent Publication No. 2012 / 0029396, the entire contents of which are hereby incorporated by reference.

[0091] In various embodiments, the ultrasonic parameters (e.g., frequency, acoustic power level and / or acoustic energy level applied by the transducer elements) are combined with the resulting temperature change at the target (and / or ultrasonic treatment location) and the temperature change at the ultrasonic treatment location R. 2-4 The estimated temperature at that location increases by ΔT 2-4 Based on the relationship between the ultrasonic parameters, controller 108 can determine adjustments to compensate for the estimated temperature increase ΔT. 2-4 Based on this, the transducer elements can then be activated using adjusted ultrasound parameters (e.g., power level, frequency, and / or energy level) and adjusted phase for use at the ultrasound treatment location R, respectively. 2-4It generates high-quality focus while avoiding overheating of the target / non-target organization.

[0092] In various embodiments, a physical model can also be used to computationally estimate the relationship between phase changes associated with transducer elements and peak power / temperature changes at the focal point. For example, by providing certain inputs, such as the expected phase adjustment associated with the transducer elements, the physical model, together with the tissue model, can be used to calculate the peak power / temperature increase at target 101. This method avoids the need to measure the temperature increase ΔT1 at the ultrasound treatment location R1, thereby advantageously avoiding overheating of the tissue at the ultrasound treatment location R1.

[0093] Alternatively, the relationship between phase adjustment associated with the transducer element and peak power / temperature change at the focal point, and the relationship between peak power / temperature change at the focal point and ultrasound parameters (e.g., frequency, acoustic power level and / or acoustic energy level applied by the transducer element), can be computationally determined using physical and tissue models and / or empirically determined based on a patient's treatment profile from previous ultrasound procedures. The treatment profile can be stored in a database accessible by the controller 108 and can specify treatment parameters such as the geometry of the transducer element 104 and its position and orientation relative to the target area 101, tissue characteristics of the target and interventional tissues (e.g., location, thickness, density, material properties, etc.), the required phase adjustment for generating optimal focus at the target area, the increase in peak power / temperature at the focal point resulting from the phase adjustment, acoustic power adjustment, and frequencies and / or energy levels associated with the transducer element to compensate for the increase in peak power / temperature to avoid overheating of the target / non-target tissues, etc. In various embodiments, prior to performing an ultrasound procedure on the current patient, imager 122 is activated to acquire an image associated with target 101 of the current patient, and based on this, tissue characteristics associated with the target tissue and the interventional tissue, as well as the geometry of the position and orientation of target 101 relative to the transducer element, are directly determined. Controller 108 may then use one or more conventional matching algorithms (e.g., block matching algorithms, phase correlation and frequency domain methods, pixel recursion algorithms, Bayesian methods, optical flow methods, etc.) to find the treatment profile that best matches the current treatment parameters. Based on this, controller 108 may determine the required phase adjustment for generating optimal focus at target 101 and the required power level / energy level / frequency adjustment associated with the transducer element to compensate for the temperature increase resulting from the improved focusing properties at the focus (due to the phase adjustment). Again, the transducer element may then be activated based on the determined phase and power adjustments.

[0094] Figure 9A and 9BExemplary methods 900 and 930 are described, which are used to predict / measure changes in temperature or peak power of an ultrasound focal point resulting from optimization (or at least improvement) of focusing properties, and based on this, adjust one or more ultrasound parameters (e.g., acoustic power level, ultrasound frequency, and / or acoustic energy level) to avoid overheating of target and / or non-target tissues during an ultrasound procedure. In a first step 902, a relationship between one or more ultrasound parameters and the resulting temperature change at the target (and / or ultrasound treatment location) is established and stored in a database prior to the ultrasound procedure. The relationship can be determined computationally using a physical model and / or empirically derived from preclinical studies, pre-treatment procedures, and / or known literature. The ultrasound procedure can be initiated by generating / introducing an ultrasound focal point with optimal concentration (e.g., using...) Figure 6 A transient acoustic reflector (e.g., a microbubble) is positioned near or at an ultrasound treatment location in the target area, as determined by the method described in step 904, and a transducer element is activated to treat the target using optimal ultrasound parameters, such as the acoustic power level determined in step 600 (step 904). The reflected signals from the acoustic reflector can then be measured and selected (e.g., based on their consistency) (step 906). Additionally, the selected reflected signals can be analyzed to determine ultrasound parameters (e.g., amplitude and / or phase) of the transducer element to compensate for distortions caused by the interventional tissue, thereby optimizing (or at least improving) the focusing properties at each ultrasound treatment location near or at the target area (step 908).

[0095] In one embodiment, a physical model and / or imager is implemented to predict and / or measure the peak power / temperature change at a first ultrasound treatment location (step 910). Based on the predicted / measured peak power / temperature change at the first ultrasound treatment location and a comparison of the phase adjustment associated with the reflected signal from the first ultrasound treatment location and the phase adjustment associated with the reflected signal from other ultrasound treatment locations, the peak power / temperature change at other ultrasound treatment locations can be estimated (step 912). In one embodiment, the controller 108 determines whether the predicted / measured change in peak power / temperature at each ultrasound treatment location exceeds a maximum permissible change (e.g., 3°C per second) or causes the peak power / temperature at the target location to exceed a target value (e.g., 60°C) (step 914); and if so, the controller can adjust ultrasound parameter values ​​(e.g., power level, frequency, and / or energy level) based on the predicted / measured peak power / temperature change at each ultrasound treatment location and the relationship established in step 902 to reduce the predicted change at the ultrasound treatment location (step 916). Subsequently, the transducer element can be operated based on the adjusted parameter values ​​(step 918).

[0096] See Figure 9BIn some embodiments, the reflections are determined to be sufficiently consistent. All (or at least some) transient acoustic reflectors can be computationally shifted to coincide at a single location (step 932), and the phase associated with the shifted and / or unshifted reflected signals at the coincident location can be computationally determined (step 934). The phase associated with each transducer element of the measured reflected signal can then be calculated as an average or weighted average of the phases associated with the shifted and / or unshifted reflected signals at the coincident location (step 936). Additionally, the acoustic power / temperature increase at the coincident location caused by each of the shifted and / or unshifted reflected signals can be determined (e.g., using a consistency function) (step 938). The peak power / temperature increase at the coincident location can then be estimated as an average or weighted average of the temperature increase caused by phase adjustments of the shifted and / or unshifted reflected signals at the coincident location (step 940). In some embodiments, the controller 108 then determines whether the estimated peak power / temperature change at the overlapping location exceeds the maximum permissible change or causes the peak power / temperature at the target to exceed the target value (step 942). If so, the controller can adjust the ultrasonic parameter values ​​of one or more transducer elements based on the predicted / measured peak power / temperature change at the overlapping location and the relationship established in step 902 to compensate for the peak power / temperature change (step 916), thereby preventing overheating of the target and / or non-target tissues. Subsequently, the transducer elements can be operated based on the adjusted parameter values ​​(step 918).

[0097] Figure 9CAnother method 950 describes a method for predicting / measuring changes in temperature or peak power of the ultrasound focus resulting from optimization (or at least improvement) of focusing properties, and based on this, adjusting one or more ultrasound parameters (e.g., acoustic power level, ultrasound frequency, and / or acoustic energy level) to avoid overheating of target and / or non-target tissues during the ultrasound procedure. In the first step 902, prior to the ultrasound procedure, a treatment profile for a patient who has previously undergone an ultrasound procedure is created and stored in a database accessible to controller 108. The treatment profile may specify various treatment parameters, such as the geometry of the transducer elements and their position and orientation relative to the target area, the tissue characteristics of the target and / or interventional tissue, the required phase adjustment for generating optimal focus at the target area, the increase in peak power / temperature at the focus resulting from the phase adjustment, acoustic power adjustments associated with the transducer elements to compensate for the increase in peak power / temperature to avoid overheating of the target / non-target tissue, etc. Additionally, the treatment profile may include (i) the relationship between ultrasound parameters (e.g., sound power level, ultrasound frequency, and / or sound energy level) and the resulting temperature change at the target (and / or ultrasound treatment location), and (ii) the relationship between the phase adjustment associated with transducer element 104 and the peak power / temperature change at the focal point. In one embodiment, before performing an ultrasound procedure on the current patient, imager 122 is activated to acquire an image associated with the target 101 of the current patient (step 954). Based on the image, one or more treatment parameters associated with the current patient (e.g., tissue characteristics associated with the target tissue and / or interventional tissue, and the geometry of the target's position and orientation relative to the transducer element) may be determined (step 956). Controller 108 may then search the treatment profile to identify the treatment parameters that most closely match the treatment parameters of the current patient (step 958), and based thereon determine the required phase adjustment for generating the optimal focal point at target 101 and the required power level / frequency / energy level adjustment to compensate for the increase in peak power / temperature resulting from the optimization / improvement of the focusing properties at the focal point (due to the phase adjustment) (step 960). The transducer element can then be operated based on adjustments to the determined phase, power level, frequency, and / or energy level (step 962).

[0098] In some embodiments, the ultrasound parameter adjustment methods 900, 930, and 950 described above are implemented when the properties of the tissue being intervened change during the ultrasound procedure. For example, during a prolonged ultrasound procedure for ablating a brain tumor, the properties of the skull through which the ultrasound waves travel before reaching the target tumor may change due to accumulated heat therein. To compensate for the change in skull properties and maintain focused properties at the target, it may be necessary to adjust the configuration associated with the transducer element (e.g., amplitude and / or phase) (again, because after phase adjustment, the energy deposited at the focal region may increase significantly and can have adverse effects on the target / non-target tissue). Therefore, the acoustic power adjustment methods described above can be implemented to reduce the acoustic power level applied by the transducer element 104, thereby compensating for the increase in peak power / energy at the focal region.

[0099] As used herein, the terms “optimal” and “optimized” generally refer to a substantial improvement over the prior art (e.g., greater than 10%, greater than 20%, or greater than 30%), but do not necessarily imply achieving the theoretically possible energy of the optimal solution. Additionally, the functionality for performing automatic focusing of the ultrasonic beam and adjusting ultrasonic parameters (e.g., phase, acoustic power level, frequency, acoustic energy level, etc.) includes, for example, selecting reflected signals from acoustic reflectors based on the difference between amplitude and / or phase associated with reflected signals in two consecutive measurements, computationally reconstructing the acoustic field at the ultrasonic processing location, selecting reflected signals from individual acoustic reflectors based on the consistency between the reflected signals and / or the reconstructed acoustic field, determining whether a sufficient number (or sufficient occurrence rate) of focusing events have been detected, and determining whether a threshold power corresponding to the nonlinear response of the acoustic reflector has been reached, causing an increase in the acoustic power of the applied ultrasonic processing. The concentration of acoustic reflectors may increase or decrease, determining whether too many focusing events have occurred when the acoustic power is still low. An autofocusing procedure is initiated based on the determined optimal acoustic power and optimal acoustic reflector concentration. Ultrasonic parameters are adjusted based on focusing events measured during the autofocusing procedure. A relationship between ultrasonic parameters and the resulting temperature change at the target location is established empirically or using a physical model. The peak power / temperature change at the first ultrasonic treatment location is predicted. The peak power / temperature change at other ultrasonic treatment locations is estimated, at least in part, based on the predicted / measured peak power / temperature change at the first ultrasonic treatment location. The peak power / temperature change at each ultrasonic treatment location is determined. To determine whether the predicted / measured change in peak power / temperature exceeds the maximum permissible change or causes the peak power / temperature at the target location to exceed the target value, adjust the ultrasonic parameter values ​​to reduce the predicted peak power / temperature change at the ultrasonic treatment location. Calculately shift all (or at least some) transient acoustic reflectors to coincide at a single location. Calculately determine the phase associated with the shifted and / or unshifted reflected signals at the coincided location. Based on the phase associated with the shifted and / or unshifted reflected signals, determine the phase associated with each transducer element. Determine the acoustic power generated by each of the shifted and / or unshifted reflected signals. The acoustic power / temperature increase at the overlapping location is determined based on the acoustic power / temperature increase generated by the shifted and / or unshifted reflected signals. A treatment profile of the patient who has previously undergone ultrasound procedures is established. Images associated with the target area of ​​the current patient are acquired. Based on the acquired images, one or more treatment parameters associated with the target of the current patient are determined. The treatment parameters that most closely match the treatment parameters of the current patient in the treatment profile are identified. The required phase adjustment for generating the optimal focus at the target location of the current patient and the required adjustments of the power level / frequency / energy level associated with the transducer are determined to reduce acoustic power / temperature changes, as described above. Figure 6 and 9AAs described in -9C, whether integrated within the imager's controller, application system, and / or ultrasound system, or provided by a separate external controller, the functionality can be structured in one or more modules implemented in hardware, software, or a combination of both. For embodiments providing functionality as one or more software programs, the programs can be written in any of a number of high-level languages, such as PYTHON, FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and / or HTML. Alternatively, the software can be implemented using assembly language for a microprocessor residing on a target computer (e.g., the controller); for example, if the software is configured to run on an IBM PC or a PC clone, then the software can be implemented using Intel 80x86 assembly language. Software can be embodied in an article of art, 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 systems may be implemented using, for example, one or more FPGAs, CPLDs, or ASIC processors.

[0100] In addition, the term “controller” as used herein broadly includes all necessary hardware components and / or software modules for performing any of the functions described above; a controller may contain multiple hardware components and / or software modules, and the functionality may be distributed among different components and / or modules.

[0101] Some embodiments of the present invention have been described above. However, it should be clearly noted that the present invention is not limited to those embodiments; in fact, additions and modifications to the content expressly described herein are also included within the scope of the present invention.

Claims

1. A system for focusing an ultrasonic transducer, the system comprising: An ultrasonic transducer comprising a plurality of transducer elements for providing a series of ultrasonic treatments to at least one target region; as well as The controller is configured to: (a) The transducer generates a first ultrasonic treatment in the ultrasonic treatment series for the at least one target area, and the first set of reflected signals generated by the first ultrasonic treatment is measured. (b) Based on the first set of reflected signals, determine whether the target number or target occurrence rate of the focusing event has been reached; as well as (c) If not achieved, then the transducer generates a second ultrasonic treatment of the adjusted acoustic power for the at least one target area, and a second set of reflected signals generated by the second ultrasonic treatment is measured; as well as (d) Based at least in part on the second set of reflected signals, adjust the parameter values ​​associated with at least one of the transducer elements to improve the ultrasonic focus at the at least one target area.

2. The system of claim 1, wherein the focusing event is a reflected signal reflected by at least one transient acoustic reflector located near or at the at least one target area.

3. The system of claim 1, wherein the controller is further configured to determine the focusing event based at least in part on a change in parameters associated with the first set of reflected signals.

4. The system of claim 3, wherein the parameters associated with the first set of reflected signals include phase or amplitude.

5. The system of claim 1, wherein the controller is further configured to: The sound field at the at least one target region is computationally reconstructed, at least in part, based on the first set of reflected signals; and The focusing event is identified at least in part based on the reconstructed sound field.

6. The system of claim 5, wherein the focusing event is identified only when the reconstructed sound field converges to the at least one target region.

7. The system of claim 1, wherein the controller is further configured to: The second set of reflected signals is selected at least in part based on the consistency among them, and The parameter values ​​associated with at least one of the transducer elements are determined at least in part based on a selected second set of reflected signals.

8. The system of claim 1, wherein the controller is further configured to repeatedly determine whether the target number or target occurrence rate of the focusing events has been reached before adjusting the parameter value associated with at least one of the transducer elements, and if not, to cause the transducer to generate the second ultrasonic treatment of the target region at adjusted acoustic power, and to measure the second set of reflected signals of the second ultrasonic treatment until the target number or target occurrence rate of the focusing events has been reached.

9. The system of claim 8, wherein the controller is further configured to adjust the parameter value associated with at least one of the transducer elements based at least in part on the adjusted acoustic power.

10. The system of claim 1, further comprising application means for approaching or introducing a transient acoustic reflector at the at least one target area, wherein at least one of the first set of reflected signals or the second set of reflected signals originates from the transient acoustic reflector.

11. The system of claim 10, wherein the application device is an automatic application device or a manual application device.

12. The system of claim 10, wherein the controller is further configured to: Determine whether an artifact exists in at least one of the first set of reflected signals or the second set of reflected signals; and After determining that the number of targets or the target occurrence rate that have not yet reached the focusing event and that there is an artifact in at least one of the first set of reflected signals or the second set of reflected signals, the application device is immediately adjusted to adjust the parameters associated with the transient acoustic reflector.

13. The system of claim 12, wherein the controller is further configured to determine whether the artifact exists in the first set of reflected signals before causing the transducer to generate the second ultrasonic processing.

14. The system of claim 12, wherein the parameter associated with the acoustic reflector includes at least one of concentration, size, or reagent type.

15. The system of claim 14, wherein the controller is further configured to immediately increase the concentration of the acoustic reflector after determining that the number of targets or the target occurrence rate that have not yet reached the focusing event and that the artifact exists in at least one of the first set of reflected signals or the second set of reflected signals.

16. The system of claim 10, wherein the controller is further configured to, before adjusting the parameter value associated with at least one of the transducer elements: Based on the second set of reflected signals, determine whether the target number or target occurrence rate of the focusing event has been reached; Determine whether the adjusted acoustic power associated with the second ultrasonic processing is lower than the target power level; as well as Once it is determined that the target number or target occurrence rate of the focused event has been reached and the adjusted acoustic power associated with the second ultrasound treatment is lower than the target power level, the application device immediately reduces the concentration of the transient acoustic reflector.

17. The system of claim 1, wherein the controller is further configured to cause the transducer to generate acoustic energy for approaching or creating a transient acoustic reflector at the at least one target area, wherein at least one of the first set of reflected signals or the second set of reflected signals originates from the transient acoustic reflector.

18. The system of claim 1, wherein the parameter value associated with the at least one transducer element includes at least one of the phase or amplitude of the signal driving the at least one transducer element.

19. The system of claim 1, wherein the controller is further configured to cause at least some of the transducer elements to measure at least one of the first set of reflected signals or the second set of reflected signals.

20. The system of claim 1, further comprising an acoustic signal detector for measuring at least one of the first set of reflected signals or the second set of reflected signals.

21. The system of claim 1, wherein the controller is further configured to: (e) Predicting therapeutic or acoustic changes in the at least one target area resulting from adjustments to the parameter values; (f) If the predicted change exceeds the maximum permissible change or causes the therapeutic or acoustic change in the at least one target area to exceed a target value, then determine at least one of the power level, ultrasonic frequency, or energy level associated with the first and / or the second of the transducer elements to reduce the predicted therapeutic or acoustic change; and (g) The ultrasonic transducer is activated at least in part based on the parameter value determined in step (d) and at least one of the power level, ultrasonic frequency or energy level determined in step (f).

22. A non-transitory computer-readable storage medium storing a computer program, which, when executed by a controller of a system for focusing an ultrasonic transducer comprising a plurality of transducer elements, causes the controller to perform the following steps: (a) Generate a first ultrasonic process on at least one target area and measure a first set of reflected signals generated by the first ultrasonic process; (b) Based on the first set of reflected signals, determine whether the target number or target occurrence rate of the focusing event has been reached; as well as (c) If not achieved, then a second ultrasonic process with adjusted acoustic power is generated for the at least one target area, and a second set of reflected signals generated by the second ultrasonic process is measured; as well as (d) Based at least in part on the second set of reflected signals, adjust the parameter values ​​associated with at least one of the transducer elements to improve the ultrasonic focus at the at least one target area.

23. The non-transient computer-readable storage medium storing a computer program according to claim 22, wherein the focusing event is a reflected signal reflected by at least one transient acoustic reflector located near or at the at least one target area.

24. The non-transient computer-readable storage medium storing a computer program as claimed in claim 22, causing the controller to perform the following steps: determining the focusing event based at least in part on a change in parameters associated with the first set of reflected signals.

25. The non-transient computer-readable storage medium storing a computer program as claimed in claim 24, wherein the parameters associated with the first set of reflected signals include phase or amplitude.

26. The non-transitory computer-readable storage medium storing a computer program as claimed in claim 22, causing the controller to perform the following steps: The sound field at the at least one target region is computationally reconstructed, at least in part, based on the first set of reflected signals; and The focusing event is identified at least in part based on the reconstructed sound field.

27. The non-transient computer-readable storage medium storing a computer program according to claim 26, wherein the focusing event is identified only when the reconstructed sound field converges to the at least one target region.

28. The non-transitory computer-readable storage medium storing a computer program as claimed in claim 22, causing the controller to perform the following steps: The second set of reflected signals is selected at least in part based on the consistency among them, and The parameter values ​​associated with at least one of the transducer elements are determined at least in part based on the selected second set of reflected signals.

29. The non-transient computer-readable storage medium storing a computer program according to claim 22, causing the controller to perform the following steps: before adjusting the parameter value associated with at least one of the transducer elements, repeatedly determining whether the target number or target occurrence rate of the focusing events has been reached, and if not, causing the transducer to generate a second ultrasonic treatment of the target region at the adjusted acoustic power, and measuring a second set of reflected signals of the second ultrasonic treatment until the target number or target occurrence rate of the focusing events has been reached.

30. The non-transient computer-readable storage medium storing a computer program according to claim 29, causing the controller to perform the step of: adjusting the parameter value associated with at least one of the transducer elements based at least in part on the adjusted acoustic power.

31. The non-transient computer-readable storage medium storing a computer program according to claim 22, causing the controller to perform the steps of: approaching or introducing a transient acoustic reflector at the at least one target area, wherein at least one of the first set of reflected signals or the second set of reflected signals originates from the transient acoustic reflector.

32. The non-transitory computer-readable storage medium storing a computer program as claimed in claim 31, causing the controller to perform the following steps: Determine whether an artifact exists in at least one of the first set of reflected signals or the second set of reflected signals; and After determining that the number of targets or the target occurrence rate that have not yet reached the focusing event and that the artifact exists in at least one of the first set of reflected signals or the second set of reflected signals, the application device is immediately adjusted to adjust the parameters associated with the transient acoustic reflector.

33. The non-transitory computer-readable storage medium storing a computer program according to claim 32, causing the controller to perform the following steps: determining whether the artifact exists in the first set of reflected signals before generating the second ultrasonic processing.

34. The non-transitory computer-readable storage medium storing a computer program according to claim 32, wherein the parameter associated with the acoustic reflector includes at least one of concentration, size, or reagent type.

35. The non-transient computer-readable storage medium storing a computer program according to claim 34, causing the controller to perform the following steps: immediately increasing the concentration of the acoustic reflector after determining that the number of targets or the target occurrence rate that have not yet reached the focusing event and that the artifact exists in at least one of the first set of reflected signals or the second set of reflected signals.

36. The non-transitory computer-readable storage medium storing a computer program according to claim 31, causing the controller to perform the following steps: before adjusting the parameter value associated with at least one of the transducer elements: Based on the second set of reflected signals, determine whether the target number or target occurrence rate of the focusing event has been reached; Determine whether the adjusted acoustic power associated with the second ultrasonic processing is lower than the target power level; as well as Once it is determined that the target number or target occurrence rate of the focused event has been reached and the adjusted acoustic power associated with the second ultrasound processing is lower than the target power level, the concentration of the transient acoustic reflector is immediately reduced.

37. The non-transitory computer-readable storage medium storing a computer program as claimed in claim 22, causing the controller to perform the following steps: Generate acoustic energy for approaching or creating a transient acoustic reflector at the at least one target area. At least one of the first set of reflected signals or the second set of reflected signals comes from the transient acoustic reflector.

38. The non-transitory computer-readable storage medium storing a computer program according to claim 22, wherein the parameter value associated with the at least one transducer element includes at least one of the phase or amplitude of the signal driving the at least one transducer element.

39. The non-transitory computer-readable storage medium storing a computer program as claimed in claim 22, causing the controller to perform the following steps: (e) Predicting therapeutic or acoustic changes in the at least one target area resulting from adjustments to the parameter values; (f) If the predicted change exceeds the maximum permissible change or causes the therapeutic or acoustic change in the at least one target area to exceed the target value, then determine at least one of the power level, ultrasonic frequency, or energy level associated with the first and / or the second of the transducer elements to reduce the predicted therapeutic or acoustic change. as well as (g) The ultrasonic transducer is activated at least in part based on the parameter value determined in step (d) and at least one of the power level, ultrasonic frequency or energy level determined in step (f).

40. A system for focusing an ultrasonic transducer, the system comprising: An ultrasonic transducer comprising a plurality of transducer elements for providing a series of ultrasonic treatments to at least one target region; as well as The controller is configured to: (a) The transducer generates a first ultrasonic treatment in the ultrasonic treatment series for the at least one target area, and the first set of reflected signals generated by the first ultrasonic treatment is measured. (b) Based on the first set of reflected signals, determine whether the target number or target occurrence rate of the focusing event has been reached; (c) If not achieved, then the transducer generates a second ultrasonic treatment of the adjusted acoustic power for the at least one target area, and a second set of reflected signals generated by the second ultrasonic treatment is measured; (d) Based at least in part on the second set of reflected signals, adjust the parameter values ​​associated with at least one of the transducer elements to improve the ultrasonic focus at the at least one target region; (e) Predicting therapeutic or acoustic changes in the at least one target area resulting from adjustments to the parameter values; as well as (f) If the predicted change exceeds the maximum permissible change or causes the therapeutic or acoustic change in the at least one target area to exceed a target value, then at least one of the power level, ultrasonic frequency, or energy level associated with the first and / or the second of the transducer elements is determined to reduce the predicted therapeutic or acoustic change, and the ultrasonic transducer is activated at least in part based on the parameter value in step (d) and the at least one determined power level, ultrasonic frequency, or energy level.

41. A non-transitory computer-readable storage medium storing a computer program, which, when executed by a controller of a system for focusing an ultrasonic transducer, causes the controller to perform the following steps: (a) Generate a first ultrasonic process on at least one target area and measure a first set of reflected signals generated by the first ultrasonic process; (b) Based on the first set of reflected signals, determine whether the target number or target occurrence rate of the focusing event has been reached; (c) If not achieved, then a second ultrasonic process with adjusted acoustic power is generated for the at least one target area, and a second set of reflected signals generated by the second ultrasonic process is measured; (d) Based at least in part on the second set of reflected signals, adjust the parameter values ​​associated with at least one of the transducer elements to improve the ultrasonic focus at the at least one target region; (e) Predicting therapeutic or acoustic changes in the at least one target area resulting from adjustments to the parameter values; and (f) If the predicted change exceeds the maximum permissible change or causes the therapeutic or acoustic change in the at least one target area to exceed a target value, then at least one of the power level, ultrasonic frequency, or energy level associated with the first and / or the second of the transducer elements is determined to reduce the predicted therapeutic or acoustic change, and the ultrasonic transducer is activated at least in part based on the parameter value in step (d) and the determined power level, ultrasonic frequency, or energy level.

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