Control of ultrasound treatment by monitoring microbubble response

Abstract

An ultrasonic transducer sonicates the target volume to alter its tissue properties by transmitting a sequence of acoustic pulses to the target volume, while at least one acoustic detector detects the ultrasonic reflected signal from the target volume following each acoustic pulse. A controller (i) estimates the activity of the contrast agent in the target volume based on a comparison of signal parameter values ​​in the reflected signals following consecutive acoustic pulses, and (ii) controls the ultrasonic transducer to alter the tissue properties based on the estimated activity.

Description

Technical Field

[0001] The present disclosure relates to systems and methods for monitoring contrast agent response and controlling focused ultrasound therapy.

Background Art

[0002] The use of focused ultrasound (FUS) in combination with microbubbles has shown great therapeutic promise for non-invasively treating medical conditions affecting the central nervous system. One application involves disruption of the blood-brain barrier (BBB), which can enable delivery of drugs to the brain parenchyma that would otherwise be excluded.

[0003] To reversibly open the BBB, it is necessary to apply FUS at an intensity sufficient for the therapeutic agent to penetrate to the tissue. However, if the intensity of the FUS is excessive, there is a risk of damaging other tissues and / or causing some degree of permanent penetration.

Summary of the Invention

Means for Solving the Problems

[0004] Therefore, careful control of the FUS intensity is essential to enable effective drug delivery without causing damage when using FUS for BBB opening. To ensure effective treatment and minimize collateral damage, such control should provide real-time feedback responsive to both the degree of BBB opening and the risk of tissue damage.

[0005] In one embodiment, a system for controllably altering tissue properties in the presence of a contrast agent suspension is described. The system includes an ultrasonic transducer for sonicating a target volume to alter its tissue properties, wherein the ultrasonic transducer transmits a sequence of acoustic pulses to the target volume; at least one acoustic detector for detecting ultrasonic reflected signals from the target volume following each acoustic pulse; and a controller configured to (i) estimate the activity of the contrast agent in the target volume based on a comparison of signal parameter values ​​in the reflected signals following consecutive acoustic pulses, and (ii) control the ultrasonic transducer to alter the tissue properties based on the estimated activity.

[0006] In another embodiment, a method for controllingly altering tissue properties within a target volume in the presence of a contrast agent is described. The method includes the steps of: applying a sequence of acoustic pulses to a target volume; detecting reflected signals from the target volume following each acoustic pulse; computationally estimating the activity of the contrast agent in the target volume based on a comparison of signal parameter values ​​in the reflected signals following successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties.

[0007] In another embodiment, a system for monitoring cavitation within an internal tissue region in response to applied acoustic energy is described. The system includes an ultrasonic transducer, each comprising a plurality of spatially dispersed elements for transmitting a sequence of acoustic pulses to a target volume and causing cavitation of a suspension of contrast agent within the target volume; a plurality of spatially dispersed acoustic detectors for detecting ultrasonic reflected signals from the target volume following each acoustic pulse; and a controller configured to receive data characterizing the detected reflected signals from the acoustic detectors and to estimate cavitation levels at a plurality of voxel locations extending at least spatially within the target volume, based at least on (i) the received data, (ii) the location of the acoustic detectors, and (iii) the velocity of sound between the acoustic detectors and the target volume.

[0008] In another embodiment, a method for treating a neurological disorder in a subject requiring treatment is described, characterized in that the neurological disorder has a site of abnormal production, aggregation, and / or deposition of a protein or another biomolecule in the brain, and a therapeutic agent and / or contrast agent composition is to be administered, has been administered, or has been administered to the subject. The method includes applying a sequence of acoustic pulses to a target volume encompassing the site and adjacent blood-brain barrier (BBB); detecting reflected signals from the target volume following each acoustic pulse; computationally estimating the activity of the contrast agent in the target volume based on a comparison of signal parameter values ​​in the reflected signals following consecutive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site.

[0009] In the drawings, similar reference letters generally refer to the same parts throughout different drawings. Furthermore, the drawings are not necessarily at a fixed scale; instead, the emphasis is generally on illustrating the principles of this disclosure. Various embodiments of this disclosure are described below with reference to the following drawings. [Brief explanation of the drawing]

[0010] [Figure 1A] Exemplary ultrasonic systems according to various embodiments of this disclosure are schematically illustrated. [Figure 1B] Exemplary MRI systems according to various embodiments of this disclosure are schematically illustrated. [Figure 2] Several embodiments illustrating the implementation of an acoustic reflector that is substantially close to the target area are shown. [Figure 3] This graph illustrates the observed and actual concentrations of contrast agent during focused ultrasound treatment in several embodiments. [Figure 4]This graph illustrates indicators of cavitation during focused ultrasound treatment, including multiple ultrasonic treatments, according to several embodiments. [Figure 5] This graph illustrates indicators of cavitation during focused ultrasound treatment, including multiple ultrasonic treatments, according to several embodiments. [Figure 6] This graph illustrates indicators of cavitation during focused ultrasound treatment, including multiple ultrasonic treatments, according to several embodiments. [Figure 7] This graph illustrates indicators of cavitation during focused ultrasound treatment, including multiple ultrasonic treatments, according to several embodiments. [Figure 8] This graph illustrates indicators of cavitation during focused ultrasound treatment, including multiple ultrasonic treatments, according to several embodiments. [Figure 9] This graph illustrates indicators of cavitation during focused ultrasound treatment, including multiple ultrasonic treatments, according to several embodiments. [Figure 10] Difference images reflecting microbubble cavitation in several embodiments are illustrated. [Figure 11] This flowchart illustrates an exemplary approach to controllably altering tissue properties within a target volume in the presence of a contrast agent. [Modes for carrying out the invention]

[0011] Figure 1A illustrates an exemplary ultrasound system 100 for generating a focused acoustic energy beam and delivering it to a target region 101 within a patient's body. The exemplary system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 that drives the phased array 102, a controller 108 that communicates with the beamformer 106, and a frequency generator 110 that provides input electronic signals to the beamformer 106.

[0012] The array 102 may have a curved (e.g., spherical or parabolic) or other contoured shape suitable for placement on the surface of the patient's body, or may include one or more planar or other shape divisions. Its dimensions may vary from millimeters to tens of centimeters. The transducer elements 104 of the array 102 may be piezoelectric ceramic elements and may be mounted on silicone rubber or any other material suitable for damping the mechanical coupling between the elements 104. Piezoelectric composite materials, or in general any material capable of converting electrical energy into acoustic energy, may also be used. To ensure maximum power transmission to the transducer elements 104, the elements 104 may be configured for electrical resonance at 50 Ω, matching the input connector impedance.

[0013] The transducer array 102 is coupled to a beamformer 106, which drives individual transducer elements 104 that collectively generate a focused ultrasonic beam or field. For N transducer elements, the beamformer 106 may include n drive circuits, each containing an amplifier 118 and a phase delay circuit 120, or composed of them, with each drive circuit driving one of the transducer elements 104. The beamformer 106 receives a radio frequency (RF) input signal, typically in the range of 0.1 MHz to 10 MHz, from a frequency generator 110, which may be, for example, a Model DS345 generator available from Stanford Research Systems. The input signal can be divided into n channels of the n amplifiers 118 and delay circuits 120 of the beamformer 106. In some embodiments, the frequency generator 110 is integrated with the beamformer 106. The radio frequency generator 110 and 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.

[0014] The amplification or attenuation coefficients α1 to αn and the phase shifts a1 to an imposed by the beamformer 106 help transmit ultrasonic energy through the intermediate tissue located between the transducer element 104 and the target region, focus it onto the target region 101, and account for wave distortion induced within the intermediate tissue. The amplification coefficients and phase shifts are calculated using the controller 108, which may provide computational capabilities via software, hardware, firmware, hardware wiring, or any combination thereof. In various embodiments, the controller 108 conventionally, without excessive experimentation, utilizes a software-programmed general-purpose or special-purpose digital data processor to determine the frequency, phase shift, and / or amplification coefficients required to obtain a desired focus or any other desired spatial field pattern in the target region 101. In certain embodiments, the calculations are based on detailed information regarding the characteristics of the intermediate tissue located between the transducer element 104 and the target (e.g., type, size, location, characteristics, structure, thickness, density, etc.) and their effect on the propagation of acoustic energy. Such information may be obtained from the imager 112. The imager 112 may be, for example, a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, a positron emission tomography (PET) device, a single-photon emission computed tomography (SPECT) device, or an ultrasound device. Image acquisition may be three-dimensional (3D), or alternatively, the imager 112 may provide a set of two-dimensional (2D) images suitable for reconstructing a three-dimensional image of the target region 101 and / or other regions (e.g., the region surrounding the target 101 or another target region). Image manipulation functions may be implemented within the imager 112, within the controller 108, or in a separate device. In addition, the ultrasound system 100 and / or the imager 112 may be used to detect signals from an acoustic reflector (e.g., a microbubble 202, see Figure 2) located substantially close to the target region 101, as will be further described below.Additionally or alternatively, system 100 may include an acoustic signal detection device (such as a hydrophone or a preferred alternative) 124 for detecting ultrasound transmitted or reflected from an acoustic reflector, which may provide the signal it receives to a controller 108 for further processing. In addition, the ultrasound system 100 may include a delivery system 126 for parenterally introducing the acoustic reflector into the patient's body. The imager 112, the acoustic signal detection device 124, and / or the delivery system 126 may operate using the same controller 108 to facilitate transducer operation, or alternatively, they may be controlled separately by one or more distinct controllers communicating with each other.

[0015] Figure 1B illustrates an exemplary imager, i.e., an MRI apparatus 112. The apparatus 112 may include a cylindrical electromagnet 134 that generates the necessary static magnetic field within a cavity 136 of the electromagnet 134. During the medical procedure, the patient is positioned inside the cavity 136 on a movable support table 138. A region of interest 140 within the patient (e.g., the patient's head) may be positioned within an imaging area 142 where the electromagnet 134 generates a substantially uniform field. A set of cylindrical magnetic field gradient coils 144 may also be provided within the cavity 136 and surround the patient. The gradient coils 144 generate a magnetic field gradient of a predetermined magnitude at a predetermined time and in three mutually orthogonal directions. The magnetic field gradient allows different spatial locations to be associated with different precession frequencies, thereby giving the magnetic resonance (MR) image its spatial resolution. RF transmitter coils 146 surrounding the imaging area 142 radiate RF pulses into the imaging area 142, causing the patient's tissues to radiate MR response signals. The raw MR response signal is sensed by the RF coil 146 and passed to the MR controller 148, which then calculates an MR image that can be displayed to the user. Alternatively, separate MR transmitter and receiver coils may be used. Images acquired using the MRI apparatus 112 can provide radiologists and physicians with visual contrasts between different tissues and detailed internal diagrams of the patient's anatomical structures that cannot be visualized with conventional X-ray techniques.

[0016] The MRI controller 148 can control the pulse sequence, i.e., the relative timing and intensity of the magnetic field gradient and RF excitation pulses, as well as the response detection period. The MR response signal is amplified, conditioned, digitized into raw data using a conventional image processing system, and further converted into an array of image data by methods known to those skilled in the art. Based on the image data, a target region (e.g., a tumor or target BBB) can be identified.

[0017] To perform targeted drug delivery or tumor ablation, it is necessary to accurately determine the location of the target region 101. Thus, in various embodiments, the imager 112 first acquires images of the target region 101 and / or non-target regions (e.g., healthy tissue surrounding the target region, intervening tissue located between the transducer array 102 and the target region 101, and / or any region located near the target), and is operative to determine the associated anatomical features (e.g., tissue type, location, size, thickness, density, structure, shape, vasculature) based thereon. For example, a tissue volume can be represented as a 3D set of voxels based on a 3D image or a series of 2D image slices, and can include the target region 101 and / or non-target regions.

[0018] To create a high-quality focus at the target region 101, it may be necessary to calibrate the transducer elements 104 and account for, for example, geometric defects of the transducers due to movement, shift, and / or deformation of the transducer elements 104 from their expected locations. Additionally, since ultrasound can scatter, absorb, reflect, and / or refract as it travels through non-uniform intervening tissue located between the transducer elements 104 and the target region 101, it may also be necessary to account for the distortion of these waves to improve the focusing characteristics at the target region 101.

[0019] Referring to FIG. 2, the ultrasonic waves transmitted from all (or at least some) of the transducer elements 104 are reflected by the acoustic reflector 202. The acoustic reflector 202 can be essentially composed of microbubbles generated by ultrasonic waves and / or microbubbles introduced parenterally by the administration system. In some embodiments, the administration system 126 introduces seed microbubbles into the target region 101 and then operates the transducer 102 to transmit ultrasonic waves to the seed microbubbles to generate a cloud of microbubbles. Approaches for generating microbubbles and / or approaches for introducing microbubbles into the target region 101 are provided, for example, in PCT Publication No. WO2018 / 020315, PCT Application No. PCT / US2018 / 064058 (filed on December 5, 2018), PCT / IB2018 / 001103 (filed on August 14, 2018), PCT / US2018 / 064892 (filed on December 11, 2018), PCT / IB2018 / 000841 (filed on June 29, 2018), and PCT / US2018 / 064066 (filed on December 5, 2018), US Patent Application Publication No. 2019 / 0083065, and US Patent Application No. 15 / 837,392 (filed on December 11, 2017), the contents of which are incorporated herein by reference.

[0020] For the evaluation of hemoperfusion, it has been proposed in the past to use the reflection signal from an acoustic contrast agent containing microbubbles 202. Referring to FIG. 3, the first ultrasonic irradiation destroys some of the microbubbles of the contrast agent by cavitation. The intensity of the reflection signal from the second ultrasonic irradiation depends on the degree of this destruction and the delay between the ultrasonic irradiations during which the concentration of microbubbles is replenished by hemoperfusion. By fitting the reflection intensity of successive ultrasonic irradiations to a model, the hemoperfusion coefficient can be extracted.

[0021] In Figure 3, the “Observed Concentration” curve corresponds to the magnitude of the reflected signal for each ultrasound irradiation. The “Actual Concentration” curve shows how the ultrasound irradiation pulse destroys some of the microbubbles and the concentration partially recovers as a result of circulation. Consequently, this destruction and recovery cycle reflects the perfusion rate and can be used to estimate it. If the FUS intensity is not sufficient to generate microbubble cavitation, a flat (stable) reflected signal is obtained from all pulses in the pulse train.

[0022] According to embodiments described herein, reflected measurements of such pulse sequences can be used to detect the onset of microbubble dynamic cavitation and to estimate the degree of this cavitation activity. Since cavitation underlies BBB breakdown, such measurements can be used to monitor and control the degree of BBB breakdown. In particular, detected variations in the reflected signals from pulses within a pulse sequence can be used to identify the onset of microbubble cavitation. Furthermore, it is possible to quantify this difference to estimate a quantitative value of cavitation activity, which is consequently related to the probability and degree of BBB breakdown.

[0023] In various embodiments, the analysis is performed using the first harmonic of the transmitted signal (i.e., using the reflected signal at the same frequency as the transmitted signal). However, it should be understood that it is possible to use any other frequency band of the reflected signal. For the measurement itself, a single hydrophone or an array thereof may be used. Without loss of generality, the following description assumes that the signal is detected using a hydrophone array. System calibration is generally not required to obtain quantitative results, as the difference between the two reflected signals through the skull is monitored and effects due to aberrations and attenuations are eliminated.

[0024] Several mathematical methods exist that can be used to analyze the measured data. One approach is to compare the reflected signal intensities of two consecutive pulses. If there are three or more pulses in a pulse sequence, the intensity variance within the sequence can be used as a measure. For more quantitative results, statistical analysis methods such as analysis of variance (ANOVA) and analysis of means (ANOM) can be used. These approaches can be used for data from a single hydrophone or a hydrophone array.

[0025] When using hydrophone arrays, there are significant advantages to using ANOVA or ANOM to monitor cavitation. In these approaches, an ensemble of amplitude measurements for each pulse is compared. Due to the large number of readings, the analysis tends to be more sensitive to variance and quantify the differences between pulses, leading to a quantitative estimate of cavitation levels.

[0026] The reflected signal has two components: amplitude and phase. Statistical analysis can be applied to the phase portion and amplitude, and the difference between phase ensembles can also be used to identify the onset of cavitation. Combining results from multiple analytical techniques on different components of the measured data can contribute to the statistical confidence level of the obtained results.

[0027] When using ultrasonic frequencies between 100kHz and 1000kHz, a typical pulse in a pulse train is 10msec to 100msec in length. Different pulse lengths may be used, especially when using different FUS frequencies. The typical delay between pulses in a pulse sequence is 0.5 to 5msec. To improve measurement sensitivity, it may be preferable to use a shorter delay time (approximately 1msec).

[0028] Using such short pulses in a hydrophone array enables the generation of a 3D acoustic activity map of a target region, a procedure also known as passive acoustic mapping or PAM. This can be achieved by constructing a 3D image of the spatial acoustic field using reflected signals from spatially dispersed transducer elements 104. The distance between each transducer element and each voxel in the spatial region of interest is known, as is the speed of sound through the relevant tissue. Therefore, the response to an event in each voxel can be calculated based on time-of-flight and by aggregating measurements from all sensing transducer elements to eliminate degeneracy. As a result, the analytical method described above can be implemented per voxel unit in a target region or volume, providing spatial information relevant to the progression, efficacy, and safety of the treatment.

[0029] Specifically, generating a cavitation activity map for each pulse in a sequence facilitates comparison between two pulses (e.g., the first and second pulses in a sequence), and thus facilitates the generation of a 3D map of effective dynamic cavitation and BBB breakdown probability. These probability maps can be overlaid on an MRI map to estimate the effectiveness and coverage of the treatment.

[0030] Another approach to 3D spatial reconstruction is to reconstruct a single 2D plane within the target and use the angular spectral method to create a 3D spatial map of adjacent planes. The angular spectral method can involve unfolding a complex wave field into a sum of plane waves of the same frequency but different directions. This technique can predict the acoustic pressure field distribution across planes based on knowledge of the pressure field distribution in parallel planes.

[0031] The following paragraphs present the results of a typical experiment involving 10 sonication cycles, each cycle being a sequence of 10 ultrasonic irradiations. The drive voltage increases by 0.05V with each consecutive sonication, thereby increasing the FUS output. Figure 4 illustrates the average signal from all hydrophones in the array as a function of individual ultrasonic irradiations; the array contained 1024 hydrophones. The drive voltage and sonication number are also shown. As the FUS output increases, the total reflection signal increases. The plot shows that dynamic cavitation begins at sonication 5 (S5). This is better represented in Figure 5, where the data is normalized to the maximum value per sonication. Returning to Figure 4, the response decreases along the sonication from sonication 5 (S5) onward. It is assumed that some microbubbles are destroyed by sonication after each pulse in the sonicated area, and therefore the response in the next pulse is lower. Fitting the average response level of each pulse showing the decrease in response can serve as a qualitative and quantitative indicator of cavitation. In other words, in addition to the quantitative characteristics that can be derived from the decrease in response, the decrease itself can provide a qualitative impression of the cavitation being exhibited. As can be seen from Figure 4, the variation in response is a continuous decrease, not chaotic. Therefore, the controller or observer can qualitatively determine when cavitation is first exhibited (specifically, in Figure 4, S5) by the decrease itself.

[0032] Applying ANOVA to normalized data allows for earlier detection of the onset of dynamic cavitation. Figure 6 illustrates the Fisher ratio (F) and the probability that a new dataset is equivalent to a previous set. This evaluation is performed sequentially after each sonication cycle. The upper and lower dashed lines represent 95% and 99% confidence levels, respectively. Dynamic cavitation is detected with 99% confidence in sonication 4 (S4).

[0033] Figure 7 shows the results of applying ANOM to the same dataset. In this case, the mean of data per sonication is compared to the 95% lower decision line (LDL). If the result is above the zero line, it can be stated with a 95% confidence level that the dataset is not equivalent to the previous set. In this example, the sensitivity of the method is lower than that of ANOVA.

[0034] To obtain quantitative information on dynamic cavitation activity and estimate the probability of BBB failure, it may be preferable to evaluate the differences between iterations within the sonication sequence (Figure 8). Since ANOVA exhibits low sensitivity to the onset of cavitation on this dataset (Figure 9), it is preferable to quantify the cavitation activity once detected using normalized mean and amplitude differences for cavitation detection.

[0035] The calculated degree of cavitation may be used in a control loop in which the FUS output is gradually increased until cavitation is first detected, and then until the difference in average amplitude between consecutive pulses reaches a level indicating the degree of cavitation corresponding to the desired degree of BBB opening (or the likelihood that the BBB will open to the desired degree). In some cases, there is no upper limit to the desired degree of BBB opening, and the FUS output may be increased until the level of cavitation reaches a level that poses a risk of tissue damage, at which point it may be stopped or the output may be reduced. In other cases, for example, a specific amount of BBB opening is desired that corresponds to an effective porosity substantially matching the molecular size of the therapeutic agent. By avoiding excessive BBB opening, when sonication is stopped and the BBB begins to re-close, target molecules that have passed through the BBB may be trapped behind it to some extent.

[0036] The combination of short pulses and multiple dispersed acoustic sensors also enables a simple 3D reconstruction of the acoustic activity following each pulse. This can be achieved by constructing a 3D image of the spatial acoustic field using reflected signals from spatially dispersed transducer elements. The distance between each transducer element and each voxel in the spatial region of interest is known, as is the speed of sound through the relevant tissue. Therefore, the response to an event at each voxel can be calculated based on time-of-flight and by aggregating measurements from all sensing transducer elements to eliminate degeneracy. As a result, the analytical method described above can be implemented per voxel unit in a target region or volume, providing spatial information relevant to the progression, effectiveness, and safety of treatment.

[0037] Figure 10 illustrates a difference image reflecting microbubble cavitation (axial dimensions are in millimeters). When the ultrasonic irradiation output reaches the cavitation threshold, acoustic activity is observed that deviates slightly from the target (0,0,0) (Figures 10a and 10b). As the output increases (Figures 10c and 10d), the cavitation level increases, as does the volume at which this activity occurs. Once calibrated, the measured values ​​can be used to represent the probability of BBB breakdown in a specific region of the targeted volume.

[0038] Embodiments of the present invention relate to antibodies and therapeutic agents (e.g., busulfan, thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), temozolomide, methotrexate, topotecan, cisplatin, etoposide, irinotecan / SN-38, carbop) for the treatment of tumors such as GMB, neurodegenerative diseases (e.g., anti-amyloid beta antibodies, aducanumab, and anti-tau antibodies), and CNS infections. It may increase blood-brain barrier permeability to allow the passage of biologics such as latin, doxorubicin, vinblastine, vincristine, procarbazine, paclitaxel, fotemustine, ifosfamide / 4-hydroxyifosfamide / aldoiphosfamide, bevacizumab, 5-fluorouracil, bleomycin, hydroxyurea, docetaxel, or cytarabine (cytosine arabinoside, ara-C) / ara-U).

[0039] A typical hardware platform for an implementation of the present invention is described in U.S. Patent Application Publication No. 2020 / 0139158, the full disclosure of which is incorporated herein by reference. The hardware system may include an imaging device (e.g., a magnetic resonance imaging (MRI) device) for characterizing the tissue type and / or characteristics of the tissue in a target BBB region and / or surrounding tissue, where each type and location of tissue may have a corresponding tolerance for cavitation depending on its characteristics, and therefore the imaging device may be used to spatially characterize the tissue tolerance, and this spatial representation may be used for comparison with a spatial map of cavitation effects generated and updated as described above. The '9158 application also describes a preferred ultrasonic transducer arrangement and driver circuit.

[0040] More generally, the functionality for carrying out a controlled and reversible breach of a targeted BBB region may be structured in one or more modules implemented in hardware, software, or a combination of both. In embodiments where the functionality is provided as one or more software programs, the programs may be written in one of several high-level languages, such as PYTHON®, FORTRAN, PASCAL, JAVA®, C, C++, C#, BASIC, various scripting languages, and / or HTML. Additionally, the software may be implemented in assembly language directed to a microprocessor residing on the target computer; for example, if the software is configured to run on an IBM PC or PC clone, it may be implemented in Intel 80x86 assembly language. The software may be embodied on products including, but are not limited to, floppy disks, jump drives, hard disks, optical disks, magnetic tapes, PROMs, EPROMs, EEPROMs, field-programmable gate arrays, or CD-ROMs. Embodiments using hardware circuitry may be implemented, for example, using one or more FPGAs, CPLDs, or ASIC processors.

[0041] As used herein, the term “substantially” means ±10% of tissue volume, and in some embodiments, ±5% of tissue volume. “Clinically significant” means that a clinician considers the undesirable (or less desirable) effect on the tissue to be substantial, e.g., causing damage unjustified in a particular treatment.

[0042] In one embodiment, the present invention relates to a method for treating a neurological disorder or impairment in a subject requiring treatment, characterized in that the neurological disorder or impairment has a site of abnormal production, aggregation, and / or deposition of a protein or another biomolecule in the brain, and a therapeutic agent and / or microbubble composition is to be administered to, has been administered to, or has been administered to, the subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing the site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following consecutive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or microbubble composition. In other embodiments, the control is the level of drug delivery in the target to be treated prior to the administration of a sequence of acoustic pulses and / or a microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including but not limited to, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents.

[0043] In various embodiments, the neurological disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Lewy body dementia, spinocerebellar ataxia, amyotrophic lateral sclerosis, frontotemporal disease, multiple system atrophy, 4-repeat tauopathy, and prion disease. In some embodiments, the site is selected from senile plaques, neurofibrillary tangles, intraneuronal inclusions, Lewy bodies, glial intracellular inclusions, cytoplasmic inclusions, and polyglutamine aggregates. In some embodiments, the protein exhibiting abnormal production, aggregation, and / or deposition is selected from amyloid-beta (Aβ), tau protein, TDP-43, α-synuclein, FUS / TLS, SOD1, and huntingtin.

[0044] In various embodiments, the therapeutic agent comprises a small molecule or a biological drug. In some embodiments, the therapeutic agent is a biological drug or comprises a biological drug. In some embodiments, the therapeutic agent is selected from gene therapies, vaccines, antisense oligonucleotides (ASOs), protein therapies, modified mRNA agents, and RNAi agents.

[0045] In some embodiments, the therapeutic agent is an antibody, an antibody-like molecule, or an antigen-binding fragment thereof, or comprises them. In some embodiments, the therapeutic agent specifically binds to a protein or another biomolecule that exhibits abnormal production, aggregation, and / or deposition. In some embodiments, the therapeutic agent is selected from nonspecific clearing antibodies (e.g., intravenous immunoglobulin, also known as IVIg), anti-amyloid-beta antibodies (e.g., aducanumab, gantenerumab, lecanemab, and donanemab), anti-tau antibodies (e.g., semolinemab, goslanemab, tiravonemab, and zagotenemab), anti-TREM2 antibodies (e.g., AL002), anti-alpha-synuclein antibodies (e.g., simpanemab, pracinezumab, Lu AF82422, ABBV-0805, and MEDI1341), and / or combinations thereof.

[0046] In some embodiments, the therapeutic agent is a small molecule drug or comprises a small molecule drug. In some embodiments, the therapeutic agent provides one or more of the following: synaptic plasticity, neuroprotection, inflammation reduction, neurotransmitter receptor modulation, and oxidative stress reduction. In some embodiments, the therapeutic agent is selected from donepezil, galantamine, rivastigmine, memantine, suvorexant, carbidopa / levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, neuprazide, istradefylline, and amantadine, as well as combinations thereof.

[0047] In some embodiments, the therapeutic agent is formulated in liposomes. In some embodiments, the therapeutic agent is delivered via a viral vector.

[0048] Figure 1 is a flowchart illustrating an exemplary process 400 for controllingly inducing tissue destruction in a targeted internal anatomical region, in several implementation configurations. The process may be managed by instructions stored in computer memory or a non-temporary computer-readable storage medium. The instructions may be contained in one or more programs stored in the non-temporary computer-readable storage medium. When executed by one or more processors (e.g., 108 and / or 148), the instructions cause the system to carry out the process. The non-temporary computer-readable storage medium may include one or more solid-state storage devices (e.g., flash memory), magnetic or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that can be interpreted by one or more processors. Several operations within the process may be combined, and the order of several operations may be changed.

[0049] Figure 11 is a flowchart illustrating an exemplary process 1100 for controllably altering tissue properties in the presence of a contrast agent suspension, according to several implementations. The process may be managed by instructions stored in computer memory or a non-temporary computer-readable storage medium. The instructions may be contained in one or more programs stored in the non-temporary computer-readable storage medium. When executed by one or more processors (e.g., 108 and / or 148), the instructions cause the system to carry out the process. The non-temporary computer-readable storage medium may include one or more solid-state storage devices (e.g., flash memory), magnetic or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that can be interpreted by one or more processors. Several operations within the process may be combined, and the order of several operations may be changed.

[0050] In operation 1102, an ultrasonic transducer (e.g., 102) transmits a sequence of acoustic pulses to the target volume.

[0051] In operation 1104, at least one acoustic detector (e.g., element 104 or hydrophone) detects an ultrasonic reflected signal from the target volume following each acoustic pulse.

[0052] In operation 1106, the controller (e.g., 108 and / or 148) computationally estimates the activity of the contrast agent in the target volume based on a comparison of signal parameter values ​​in the reflected signals following a series of acoustic pulses.

[0053] In operation 1108, the controller controls the ultrasound transducer based on estimated activity to alter tissue properties. In some implementations, the controller controls the ultrasound transducer based on estimated activity to alter tissue properties without clinically significant impact on non-target tissue.

[0054] In some implementations, changes to tissue properties include disruption of the tissue barrier to increase barrier permeability, neuromodulation of tissue neurons, activation of ultrasound-mechanical therapeutics, activation of contrast agent carriers for drug and / or gene delivery, thrombolysis, and / or induction of ischemic effects.

[0055] In some implementations, the change in tissue properties is a disruption of the tissue barrier to increase the permeability of the barrier, where the tissue barrier is the blood-brain barrier, blood-retinal barrier, skin, mucous membrane, cell membrane, or nuclear membrane, and the permeability is increased sufficiently to allow the passage of a therapeutic agent, which is selected for the treatment of tumors, neurodegenerative diseases, enzyme deficiencies, or CNS infections.

[0056] In some implementations, the comparison is based on the variance of the signal amplitude measured by multiple acoustic detectors, the ratio of the mean to the variance or the mean to the standard deviation, the full frequency spectrum of the reflected signal, the first harmonic of the reflected signal, or an indicator of the decrease in the signal amplitude measured by multiple acoustic detectors.

[0057] In some implementations, the contrast agent comprises gas-filled bubbles or phase-shifted droplets having a size in the range of 150 nm to 20 μm, and the activity of the contrast agent is the initiation and / or degree of cavitation, the degree of cavitation is estimated based on the difference between the average measured amplitudes of consecutive pulses.

[0058] In some implementations, the interval between consecutive acoustic pulses is 3 ms or less, the signal parameter is phase or amplitude, and the comparison between the values ​​of the signal parameter in the reflected signal follows the first harmonic of the emission spectrum of the consecutive acoustic pulses.

[0059] Treatment examples In some embodiments, the Disclosure provides methods for treating neurological disorders in subjects requiring treatment of a neurological disorder or impairment, wherein the neurological disorder or impairment is characterized by the abnormal production, aggregation, and / or deposition of proteins or other biomolecules in the brain. In some embodiments, the neurological disorder or impairment is selected from Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Lewy body dementia, spinocerebellar ataxia, amyotrophic lateral sclerosis, frontotemporal disorders, multiple system atrophy, 4-repeat tauopathy, and prion diseases.

[0060] Patients with Alzheimer's disease present with senile plaques primarily composed of amyloid-beta (Aβ), neurofibrillary tangles containing tau protein, intraneuronal inclusions of TDP-43, and Lewy bodies containing α-synuclein. Patients with Parkinson's disease present with Lewy bodies containing α-synuclein. Patients with amyotrophic lateral sclerosis (ALS) have intraneuronal inclusions containing TAR DNA-binding protein 43 (TDP-43), fusion in sarcoma / translocation in liposarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). Huntington's disease is a progressive brain disorder caused by mutations in the gene encoding the Huntin protein, resulting in an abnormal mutant protein that gradually damages brain cells. Lewy body dementia is characterized by Lewy bodies, including senile plaques primarily composed of α-synuclein and amyloid-beta (Aβ), and neurofibrillary tangles containing tau protein. Patients with frontotemporal disease exhibit intraneuronal and glial inclusions composed of tau, TDP-43, and FUS / TLS. Multiple system atrophy is characterized by glial cytoplasmic inclusions of α-synuclein. Therefore, there appears to be overlap among the proteins exhibiting abnormal production, aggregation, and / or deposition associated with these diseases. A single neurodegenerative disease can be associated with multiple proteins (or other biomolecules) exhibiting abnormal production, aggregation, and / or deposition. Conversely, a single protein exhibiting abnormal production, aggregation, and / or deposition can also be associated with multiple diseases. For example, Aβ plaques and tau tangles are paradigms of Alzheimer's disease, while the typical Lewy bodies of Parkinson's disease are found in over 50% of Alzheimer's disease cases, and intraneuronal inclusions composed of the protein TDP-43 are found in over 40%. Similarly, in dementia with Lewy bodies, a type of dementia closely related to Parkinson's disease with some features of Alzheimer's disease, typical α-synuclein-rich Lewy bodies are accompanied by Aβ plaques in 60% of cases and tau tangles in 50%.Similarly, four-repeat tauopathy, a group of neurodegenerative diseases defined by cytoplasmic inclusions primarily composed of tau protein isoforms with four microtubule-binding domains, is associated with at least three clinical findings: (1) progressive supranuclear palsy, presenting with trunk rigidity and eye movement problems in addition to atypical parkinsonism; (2) corticobasal degeneration, such as frontal lobe dementia, presenting with focal cortical syndromes including progressive apraxia or progressive aphasia; and (3) argyrophilic granulosis, a disease affecting the medial temporal lobe that is becoming increasingly recognized in older adults and is associated with memory-loss-related cognitive impairment.

[0061] Accordingly, in some embodiments, the present disclosure provides a method for treating a neurological disorder or impairment in a subject requiring treatment, wherein the neurological disorder or impairment is characterized by abnormal production, aggregation, and / or deposition of proteins or other biomolecules in the brain, and a therapeutic agent and / or microbubble composition is to be administered, has been administered, or has been administered to the subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing the site and adjacent blood-brain barrier (BBB); detecting reflected signals from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in reflected signals following consecutive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or microbubble composition. In other embodiments, the control is the level of drug delivery in the target to be treated prior to the administration of a sequence of acoustic pulses and / or a microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including but not limited to, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of a tracer, imaging agent, and / or contrast agent. In some embodiments, the neurological disease or disorder is Alzheimer's disease, and the site is selected from senile plaques containing amyloid-beta (Aβ), neurofibrillary tangles containing tau protein, intraneuronal inclusions containing TDP-43, and Lewy bodies containing α-synuclein. In some embodiments, the neurological disease or disorder is Parkinson's disease, and the site is Lewy bodies containing α-synuclein.In some embodiments, the neurological disease or disorder is amyotrophic lateral sclerosis (ALS), and the site is an intracellular inclusion of TAR DNA-binding protein 43 (TDP-43), fusion in sarcoma / translocation in liposarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). In some embodiments, the neurological disease or disorder is Huntington's disease, and the locus is an intranuclear inclusion of huntingtin. In some embodiments, the neurological disease or disorder is dementia with Lewy bodies, and the site is a Lewy body containing α-synuclein, amyloid-beta (Aβ) containing senile plaques, and neurofibrillary tangles containing tau protein. In some embodiments, the neurological disease or disorder is frontotemporal disease, and the site is an intracellular and glial cytoplasmic inclusion of tau, TDP-43, and FUS / TLS. In some embodiments, the neurological disease or disorder is multiple system atrophy, and the site is an intracellular glial cytoplasmic inclusion of α-synuclein. In some embodiments, the neurological disorder or disorder is a 4-repeat tauopathy, and the site is primarily an intracytoplasmic inclusion body composed of tau protein isoforms having four microtubule-binding domains.

[0062] Diseases associated with the aggregation and / or accumulation of proteins (or other biomolecules) exhibiting abnormal production, aggregation, and / or deposition also include prion diseases, namely transmissible spongiform encephalopathy such as bovine spongiform encephalopathy (BSE or mad cow disease) and Creutzfeldt-Jakob disease. These diseases are characterized by senile plaques composed of PrP proteins. Accordingly, in some embodiments, the Disclosure provides a method for treating a prion disease, wherein a therapeutic agent and / or a microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing a site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including, but not limited to, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents.

[0063] Alzheimer's disease Alzheimer's disease (AD) is a complex, progressively debilitating, and often fatal neurodegenerative disease. As the world's population ages, the prevalence of AD is rapidly increasing. Currently, there are an estimated 6.5 million people with AD in the United States, a number projected to grow to over 13 million by 2050. Approximately 15% of the US population aged 60 and over have prodromal AD, and about 40% have preclinical AD. A similar trend is observed globally, and unless a means of delaying, preventing, or treating AD is found, the global population of people with AD dementia is projected to exceed 100 million by 2050. There is a great need for treatments that can halt or reverse the underlying pathology of AD.

[0064] The cellular and molecular mechanisms of Alzheimer's disease (AD) are still not well understood. Researchers have reported that AD is associated with genetic and environmental factors as well as lifestyle. AD patients are heterogeneous in that they may be on a continuum of preclinical AD for more than 20 years without presenting with any clinical symptoms, namely mild cognitive impairment (MCI), AD dementia, or functional decline. Furthermore, misdiagnosis of AD patients is common, with 10–30% of individuals clinically diagnosed with AD dementia showing no AD neurodegeneration at autopsy.

[0065] Across all types of AD therapies, the failure rate is over 99%, and in disease-modifying therapies (DMTs), the failure rate is 100%. Therefore, in addition to new approaches for developing therapeutic agents, approaches such as those disclosed herein for targeted delivery of therapeutic agents are needed.

[0066] Alzheimer's disease is associated with senile plaques composed of amyloid-beta (Aβ), neurofibrillary tangles containing tau protein, intracellular inclusions of TDP-43, and Lewy bodies containing α-synuclein. Aβ is a relatively small peptide of 4–4.4 kDa that is a major component of amyloid deposits. Intracellular Aβ protein is widely found in neurons and is associated with inflammatory and antioxidant activity, regulation of cholesterol transport, and activation of kinase enzymes. However, Aβ is one of the most well-known components in the formation of neurodegenerative diseases, including AD. Aβ is composed of approximately 36–43 amino acids and derives from amyloid precursor protein (APP), a glycoprotein of 695–770 amino acids. APP can be cleaved into fragments by α, β, and γ selectases, and the Aβ protein is formed by the action of β and γ selectases. The Aβ protein contains two key regions that play a major role in the formation of insoluble amyloid fibrils.

[0067] Microtubule-associated tau protein, derived from the "tubulin-associated unit," is highly expressed in the brain. Microtubules are major proteins in the cytoskeleton. The primary function of tau protein is to bind to microtubules and other proteins to stabilize them. To perform these functions, tau protein is phosphorylated at normal levels. Hyperphosphorylation of tau protein is thought to cause conformational changes and aggregation. Other post-translational modifications, such as glycosylation, glycylation, polyamination, and nitration, may also play a role in aggregation. Accordingly, in some embodiments, the Disclosure provides a method for treating Alzheimer's disease (AD) in which a therapeutic agent and / or a microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing a site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including, but not limited to, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents.In some embodiments, the proteins exhibiting abnormal production, aggregation, and / or deposition are selected from amyloid-beta peptide (Aβ), neurofibrillary tangles, and tau proteins. In some embodiments, the therapeutic agent is selected from nonspecific clearing antibodies (e.g., intravenous immunoglobulin, also known as IVIg), anti-amyloid-beta antibodies (e.g., aducanumab, gantenerumab, lecanemab, and donanemab), anti-tau antibodies (e.g., semolinemab, goslanemab, tiravonemab, and zagotenemab), anti-TREM2 antibodies (e.g., AL002), donepezil, rivastigmine, memantine, and galantamine, as well as combinations thereof. In some embodiments, the therapeutic agent is aducanumab. Some therapeutic agents are disclosed in WO2014 / 089500 and WO2021 / 108861, the contents of which are incorporated herein by reference.

[0068] Parkinson's disease Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that causes involuntary or uncontrollable movements, such as tremors, rigidity, and difficulty with balance and coordination. Symptoms usually begin gradually and worsen over time. As the disease progresses, walking and speaking may become difficult. They may also have mental and behavioral changes, sleep disturbances, depression, memory impairment, and fatigue. The onset of the disease is characterized by the accumulation of misfolded alpha-synuclein protein in the brain. Generally, anxiety, tremors, rigidity, depression, bradykinesia, and postural abnormalities are the most common symptoms in Parkinson's disease.

[0069] Lewy bodies (LBs), primarily composed of α-syn, are a neuropathological feature of Parkinson's disease (PD). However, PD is often associated with cognitive impairment, and it is increasingly recognized that dementia eventually develops in a significant number of patients.

[0070] Alpha-synuclein is associated with several neurodegenerative diseases known as "synucleinopathy." Naturally occurring alpha-synuclein (α-Syn) is a highly conserved 14kDa protein that localizes to different regions of the brain. The protein's name was preferred as "alpha-synuclein" due to its synaptic and nuclear localization. α-Syn modulates dopaminergic neurotransmission by regulating vesicular dopamine storage. It interacts with tubulin and can function like a tau protein. α-Syn also exhibits molecular chaperone activity in the folding of SNARE (soluble N-ethylmaleimide-sensitive factor-adhering protein receptor) proteins. Because α-Syn is a major fibrillary component of ruby ​​bodies, it plays a crucial role in PD. Two mutations in the α-Syn gene, A53T and A30P, as well as overexpression of wild-type α-Syn, increase the misfolding process and aggregation. Furthermore, the accumulation of abnormal morphologies of α-Syn can inhibit proteasome function. In the brains of Parkinson's disease (PD), α-Syn is found to be phosphorylated at Ser87 and Ser129 in aggregates. These serine residues are phosphorylated by casein kinase 1 (CK1) and casein kinase 2 (CK2). This post-translational modification is thought to play a pathological role in α-Syn fibrillation.

[0071] Accordingly, in some embodiments, the Disclosure provides a method for treating Parkinson's disease (PD), wherein a therapeutic agent and / or a microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing a site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including but not limited to diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents. In some embodiments, the protein exhibiting abnormal production, aggregation, and / or deposition is alpha-synuclein. In some embodiments, the therapeutic agent is selected from anti-alpha-synuclein antibodies (e.g., simpanemab, pracinezumab, Lu AF82422, ABBV-0805, and MEDI1341), carbidopa / levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, neuprazide, istradefylline, and amantadine, as well as combinations thereof.

[0072] Multiple system atrophy is characterized by glial cytoplasmic inclusions of alpha-synuclein. Accordingly, in some embodiments, the present disclosure provides a method for treating multiple system atrophy, wherein a therapeutic agent and / or a microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing a site and adjacent blood-brain barrier (BBB); detecting reflected signals from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in reflected signals following consecutive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including but not limited to diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents. In some embodiments, the protein exhibiting abnormal production, aggregation, and / or deposition is alpha-synuclein. In some embodiments, the therapeutic agent is selected from anti-alpha-synuclein antibodies (e.g., simpanemab, pracinezumab, Lu AF82422, ABBV-0805, and MEDI1341), carbidopa / levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, neuprazide, istradefylline, and amantadine, as well as combinations thereof.

[0073] Dementia with Lewy bodies Lewy body dementia is characterized by Lewy bodies, which are senile plaques primarily composed of alpha-synuclein, amyloid-beta (Aβ), and neurofibrillary tangles of tau protein. Lewy body dementia (DLB) is a type of progressive dementia that leads to a decline in thinking, reasoning, and independent living abilities. Its features may include spontaneous changes in attention and arousal, recurrent visual hallucinations, REM sleep behavior disorder, and bradykinesia, tremors, or rigidity. Mutations in genes known as SNCA and SNCB can cause Lewy body dementia. Mutations in another gene called GBA or certain genotypes of a gene called APOE increase the risk of developing the disease, but are not the direct cause. Accordingly, in some embodiments, the Disclosure provides a method for treating dementia with Lewy bodies, wherein a therapeutic agent and / or a microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing a site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including, but not limited to, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents.In some embodiments, the protein exhibiting abnormal production, aggregation, and / or deposition is alpha-synuclein. In some embodiments, the therapeutic agent is selected from anti-alpha-synuclein antibodies (e.g., simpanemab, pracinezumab, Lu AF82422, ABBV-0805, and MEDI1341), rivastigmine, donepezil, galantamine, memantine, carbidopa / levodopa, and combinations thereof. In some embodiments, the methods disclosed herein further include detecting brain-derived biomarkers in a plasma sample of interest. In some embodiments, the methods detect mutations in genes selected from SNCA, SNCB, and APOE.

[0074] Huntington's disease Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by autosomal dominant inheritance. Individuals with HD exhibit involuntary muscle contractions, motor impairments, and mental disorders. The disease is inherited as an autosomal dominant disorder and affects the brain and nervous system. The Huntington's protein undergoes conformational changes due to mutations, leading to a tendency towards aggregation.

[0075] In HD, neuropathology is characterized by the accumulation of Htt protein aggregates. HD is caused by several CAG repeats in the gene. The CAG repeat (poly-Q) is considered the most important promoter of Htt protein aggregate toxicity. The poly-Q region begins at residue 18, and the number of glutamine residues is the most important marker in HD. Surprisingly, more than 40 CAG repeats always cause neurological damage, while fewer than 35 CAG repeats never do. However, in childhood, 27-35 CAG repeats can potentially cause neurological damage. Accordingly, in some embodiments, the Disclosure provides a method for treating Huntington's disease (HD) in which a therapeutic agent and / or a microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing the site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including, but not limited to, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents.In some embodiments, the protein exhibiting abnormal production, aggregation, and / or deposition is huntingtin. In some embodiments, the therapeutic agent is selected from anti-huntingtin antibodies and anti-SEMA4D antibodies (e.g., pepinemab).

[0076] Amyotrophic lateral sclerosis (ALS) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by degeneration of both upper and lower motor neurons, leading to progressive paralysis of the muscles of the limbs, speech, swallowing, and respiration. Patients with ALS have intracellular inclusions of TAR DNA-binding protein 43 (TDP-43), fusion in sarcoma / translocation in liposarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). ALS pathology is thought to begin at a single focal or multifocal site and spread along the neural axis in a spatiotemporal manner. Insoluble TDP-43 from the brain of diseased patients has been reported to induce TDP-43 pathology in neuroblastoma cells overexpressing wtTDP-43, as detected by TDP-43 hyperphosphorylation, ubiquitination, and aggregation. Accordingly, in some embodiments, the present disclosure provides a method for treating amyotrophic lateral sclerosis (ALS), wherein a therapeutic agent and / or a microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing a site and adjacent blood-brain barrier (BBB); detecting reflected signals from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in reflected signals following consecutive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition.In any embodiment, the level of drug delivery may be measured using imaging techniques, including but not limited to diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or combinations thereof, with the optional use of tracers, imaging agents, and / or contrast agents. In some embodiments, the proteins exhibiting abnormal production, aggregation, and / or deposition are TAR DNA-binding protein 43 (TDP-43), fusion in sarcoma / translocation in liposarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). In some embodiments, the therapeutic agent is selected from anti-TDP-43 antibody, anti-SOD1 antibody, riluzole, edaravone, and sodium phenylbutyrate and taursodiol, or combinations thereof.

[0077] Spinocerebellar ataxia Spinocerebellar ataxia (SCA) is a complex group of neurodegenerative diseases characterized by progressive cerebellar ataxia of the gait and limbs, and is associated with various other conditions including ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, retinopathy pigmentosa, and peripheral neuropathy. Onset is typically between 30 and 50 years of age, but early childhood onset and late onset after 60 years of age have also been reported. The prognosis varies depending on the underlying cause of the spinocerebellar ataxia subtype. Mutations in ATXN1, ATXN2, ATXN3, SCA4, SPTBN2, CACNAIA, ATXN7, KLHL1AS, ATXN10, SCA11, PPP2R2B, KCNC3, and PRKCG are found in SCA. In addition, seven subtypes of spinocerebellar ataxia, including SCA1, 2, 3 / Machado-Joseph disease, 6, 7, 17, and dentatorubral-pallidoluysian atrophy (DRPLA), are caused by elongation of CAG repeat sequences in specific genes, leading to abnormally long polyQ chains in the encoded proteins. Proteins with elongated polyglutamine stretches appear to take on abnormal configurations, resulting in the formation and deposition of polyglutamine aggregates within diseased neurons, forming characteristic intranuclear or intracytoplasmic inclusions, which are neuropathological features in these diseases. Accordingly, in some embodiments, the present disclosure provides a method for treating the spinocerebellar, wherein a therapeutic agent and / or a microbubble composition is to be administered, administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing the site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition.In other embodiments, the control is the level of therapeutic agent delivery in the target to be treated prior to the administration of a sequence of acoustic pulses and / or a microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including but not limited to, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of a tracer, imaging agent, and / or contrast agent. In some embodiments, the protein exhibiting abnormal production, aggregation, and / or deposition is a mutant protein having an elongated polyglutamine chain. In some embodiments, the therapeutic agent is selected from anti-polyglutamine antibodies.

[0078] frontotemporal disease The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, although processes such as neuroinflammation may be common across the disease spectrum. In recent years, attention has been focused on understanding the role of protein misfolding and aggregation in pathogenicity, a key feature of the postmortem diagnostic criteria for frontotemporal lobar degeneration (FTLD). These diseases are associated with intraneuronal and glial inclusions composed of tau, TDP-43, and FUS / TLS. Frontotemporal dementia with parkinsonism 17 (FTDP-17) is a progressive neurodegenerative disease caused by mutations in the tau gene. The tau gene mutates in familial FTDP-17, and this mutation accelerates the formation of neurofibrillary tangles (NFTs) in the brain. Furthermore, hyperphosphorylation is promoted by this mutation. In some embodiments, the Disclosure provides a method for treating frontotemporal dementia, wherein a therapeutic agent and / or a microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing a site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition.In any embodiment, the level of drug delivery may be measured using imaging techniques, including but not limited to diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents. In some embodiments, the site is intracellular and glial intracellular inclusions composed of tau, TDP-43, and FUS / TLS. In some embodiments, the therapeutic agent is an anti-tau antibody.

[0079] 4 Repeat Tauopathy 4-repeat (4R) tauopathy is a group of neurodegenerative diseases defined by intracytoplasmic inclusions of tau protein isoforms. Progressive supranuclear palsy, corticobasal degeneration, argyrophilic tauopathy, or glial globulin tauopathy belong to the 4R tauopathy group. Tau is a microtubule-associated protein with versatile functions in the dynamic assembly of the neuronal cytoskeleton, and in these diseases, intracytoplasmic inclusions are found that are mainly composed of tau protein isoforms with four microtubule-binding domains. Furthermore, while tau proteins are generally located in axons, in tauopathy they are located in dendrites. Therefore, the neuronal transport system can be disrupted, and microtubules may not function properly. Accordingly, in some embodiments, the present disclosure provides a method for treating 4-repeat (4R) tauopathy, wherein a therapeutic agent and / or microbubble composition is to be administered, has been administered, or has been administered to a subject, and the method comprises: applying a sequence of acoustic pulses to a target volume encompassing the site and adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume following each acoustic pulse; computationally estimating the activity of microbubbles in the target volume based on a comparison of signal parameter values ​​in the reflected signals following consecutive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without clinically significant impact on non-target tissue, thereby increasing the delivery of a certain level of therapeutic agent to the site compared to a control. In some embodiments, the control is the level of therapeutic agent delivery in a subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of therapeutic agent delivery in the subject being treated before administration of the sequence of acoustic pulses and / or the microbubble composition. In any embodiment, the level of drug delivery may be measured using imaging techniques, including, but not limited to, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoelectroencephalography (MEG), and functional near-infrared spectroscopy (fNIRS), or a combination thereof, with the optional use of tracers, imaging agents, and / or contrast agents.In some embodiments, the protein exhibiting abnormal production, aggregation, and / or deposition is a tau protein. In some embodiments, the therapeutic agent is an anti-tau antibody.

[0080] Disclosure Notes Various implementation configurations have been referenced in detail, and examples of these are illustrated in the accompanying drawings. The above detailed description includes many specific details to provide a complete understanding of the present invention and the described implementation configurations. However, the present invention can be practiced without these specific details. In other cases, well-known methods, procedures, components, and circuits are not described in detail so as not to unnecessarily obscure the configuration of the implementation configuration.

[0081] Terms such as "first" and "second" may be used herein to describe various elements, but it should be understood that these elements should not be limited by these terms. These terms are used solely to distinguish one element from another. For example, a first device may be referred to as a second device, and similarly, a second device may be referred to as a first device, provided that all occurrences of the first device are consistently renamed without altering the meaning of the description. Both the first and second devices are devices, but they are not the same device.

[0082] The terminology used herein is intended solely to describe specific implementations and is not intended to limit the scope of the claims. Where used in descriptions of implementations and the accompanying claims, the singular forms “a,” “an,” and “the” are also intended to include plural forms unless the context clearly indicates otherwise. Where used herein, the term “and / or” is also understood to refer to and include any and all possible combinations of one or more of the enumerated items relating to the description. For example, “A, B, and / or C” means A only, B only, C only, A and B, A and C, B and C, or A, B, and C. Where used herein, the terms “comprises” and / or “comprising” specify the presence of the described features, components, steps, operations, elements, and / or components, but are not intended to exclude the presence or addition of one or more other features, components, steps, operations, elements, components, and / or groups thereof.

[0083] As used herein, the term "if" may, depending on the context, be interpreted as meaning "when" or "upon" or "in accordance with" or "in accordance with" the determination that the preceding stated condition is true. Similarly, depending on the context, the phrases "[if] it is determined that the preceding stated condition is true" or "[if] the preceding stated condition is true" or "[when] the preceding stated condition is true" may be interpreted as meaning "after" or "in accordance with" or "in accordance with" or "after" or "in accordance with" the preceding stated condition being true.

[0084] The above description is provided with reference to specific implementations for illustrative purposes. However, the above illustrative considerations are not intended to be exhaustive or to limit the invention to the exact form disclosed. Many modifications and variations are possible in light of the above teachings. The implementations are selected and described to best illustrate the principles of the invention and its practical applications, thereby enabling those skilled in the art to best utilize various implementations with various modifications suitable for the invention and the specific use it is intended for.

Claims

1. A system for controllingly altering tissue properties in the presence of a contrast agent suspension, wherein the system is An ultrasonic transducer for ultrasonically treating a target volume to alter its tissue properties, wherein the ultrasonic transducer transmits a sequence of acoustic pulses to the target volume. At least one acoustic detector for detecting ultrasonic reflection signals from the target volume following each acoustic pulse, A system comprising: (i) estimating the activity of the contrast agent in the target volume based on a comparison of signal parameter values ​​in the reflected signal following a series of acoustic pulses; and (ii) a controller configured to control the ultrasonic transducer based on the estimated activity, thereby changing the tissue properties.

2. The above change in the tissue characteristics is Breakdown of the tissue barrier, to increase the permeability of the said barrier, Neural regulation of tissue neurons, Activation of ultrasonic mechanical therapeutic agents, Activation of contrast agent carriers for drug and / or gene delivery, Thrombolysis, and / or The system according to claim 1, which induces an ischemic effect.

3. The change in the tissue properties is a breakdown of the tissue barrier that increases the permeability of the barrier, and the tissue barrier is the blood-brain barrier, the blood-retinal barrier, the skin, mucous membrane, cell membrane, or nuclear membrane. The system according to claim 1, wherein the permeability is increased sufficiently to allow the therapeutic agent to pass through the tissue barrier, and the therapeutic agent is selected for the treatment of tumors, neurodegenerative diseases, enzyme deficiencies, or CNS infections.

4. The aforementioned comparison, The variance of the signal amplitude measured by multiple acoustic detectors, The ratio of mean to variance or mean to standard deviation. The entire frequency spectrum of the reflected signal, The first harmonic of the reflected signal, or An indicator that the signal amplitude measured by the aforementioned multiple acoustic detectors is decreasing. The system according to claim 1, based on the above.

5. The contrast agent comprises gas-filled bubbles or phase-shifted droplets having a size in the range of 150 nm to 20 μm. The activity of the contrast agent is Initiation of cavitation, and / or The system according to claim 1, wherein the degree of cavitation is estimated based on the difference between the average measured amplitudes of consecutive pulses.

6. The interval between consecutive acoustic pulses is 3 ms or less. The aforementioned signal parameter is either phase or amplitude. The system according to claim 1, wherein the comparison between the values ​​of the signal parameters in the reflected signal follows the first harmonic of the radiation spectrum of the continuous acoustic pulses.

7. A method for controllingly altering tissue properties within a target volume in the presence of a contrast agent, wherein the method is: A step of applying a sequence of acoustic pulses to the target volume, A step of detecting the reflected signal from the target volume following each acoustic pulse, A step of computationally estimating the activity of the contrast agent in the target volume based on a comparison of the values ​​of signal parameters in the reflected signal following a series of acoustic pulses. A method comprising the step of controlling the application of the acoustic pulse based on the estimated activity, thereby altering the tissue properties.

8. The above change in the tissue characteristics is Breakdown of the tissue barrier, to increase the permeability of the said barrier, Neural regulation of tissue neurons, Activation of ultrasonic mechanical therapeutic agents, Activation of contrast agent carriers for drug and / or gene delivery, Thrombolysis, and / or The method according to claim 7, which induces an ischemic effect.

9. The change in the tissue properties is a breakdown of the tissue barrier that increases the permeability of the barrier, and the tissue barrier is the blood-brain barrier, the blood-retinal barrier, the skin, mucous membrane, cell membrane, or nuclear membrane. The method according to claim 7, wherein the permeability is increased sufficiently to allow the therapeutic agent to pass through the tissue barrier, and the therapeutic agent is selected for the treatment of tumors, neurodegenerative diseases, enzyme deficiencies, or CNS infections.

10. The aforementioned comparison, The variance of the signal amplitude measured by multiple acoustic detectors, The ratio of mean to variance or mean to standard deviation. The entire frequency spectrum of the reflected signal, The first harmonic of the reflected signal, or An indicator that the signal amplitude measured by the aforementioned multiple acoustic detectors is decreasing. The method according to claim 7, based on the present invention.

11. The contrast agent comprises gas-filled bubbles or phase-shifted droplets having a size in the range of 150 nm to 20 μm. The activity of the contrast agent is Initiation of cavitation, and / or The method according to claim 7, wherein the degree of cavitation is estimated based on the difference between the average measured amplitudes of consecutive pulses.

12. The interval between consecutive acoustic pulses is 3 ms or less. The aforementioned signal parameter is either phase or amplitude. The method according to claim 7, wherein the comparison between the values ​​of the signal parameters in the reflected signal follows the first harmonic of the radiation spectrum of the continuous acoustic pulses.

13. A system for monitoring cavitation within an internal tissue region in response to applied acoustic energy, wherein the system is An ultrasonic transducer comprising a plurality of spatially dispersed elements, each transmitting a sequence of acoustic pulses to the target volume and causing cavitation of the contrast agent suspension within the target volume, Multiple spatially dispersed acoustic detectors for detecting ultrasonic reflection signals from the target volume following each acoustic pulse, A system comprising: a controller configured to receive data characterizing the detected reflected signal from the acoustic detector, and to estimate cavitation levels at a plurality of voxel locations extending at least spatially into the target volume, based at least on the received data, (ii) the location of the acoustic detector, and (iii) the speed of sound between the acoustic detector and the target volume.

14. A method for treating a neurological disorder or impairment in a subject requiring treatment, wherein the neurological disorder or impairment is characterized by having a site of abnormal production, aggregation, and / or deposition of a protein or another biomolecule in the brain, and the therapeutic agent and / or contrast agent composition is to be administered, has been administered, or has been administered to the subject, and the method is Applying a sequence of acoustic pulses to the target volume, wherein the target volume includes the site and the adjacent blood-brain barrier (BBB), To detect the reflected signal from the target volume following each acoustic pulse, Computationally estimating the activity of the contrast agent in the target volume based on a comparison of signal parameter values ​​in the reflected signal following a series of acoustic pulses, A method comprising controlling the application of the acoustic pulse based on the estimated activity, thereby altering the tissue properties without clinically significant impact on non-target tissue, and thereby increasing the delivery level of the therapeutic agent to the site.

15. The delivery level of the therapeutic agent is compared with that of a control. The aforementioned comparison is, The sequence of acoustic pulses and / or the delivery level of the therapeutic agent in a subject not receiving the contrast agent composition, or The method according to claim 14, wherein the sequence of acoustic pulses and / or the delivery level of the therapeutic agent in the target to be treated prior to administration of the contrast agent composition.

16. The method according to claim 14, wherein the site is selected from senile plaques, neurofibrillary tangles, intraneuronal inclusions, Lewy bodies, glial intracellular inclusions, cytoplasmic inclusions, and polyglutamine aggregates.

17. The method according to claim 14, wherein the protein exhibiting abnormal production, aggregation, and / or deposition is selected from amyloid-beta (Aβ), tau protein, TDP-43, α-synuclein, FUS / TLS, SOD1, and huntingtin.

18. The method according to claim 14, wherein the therapeutic agent is a biological drug or comprises a biological drug.

19. The method according to claim 18, wherein the therapeutic agent is a gene therapy agent, a vaccine, an antisense oligonucleotide (ASO), a protein therapy agent, a modified mRNA agent, or an RNAi agent.

20. The method according to claim 14, wherein the therapeutic agent is an antibody, an antibody-like molecule, or an antigen-binding fragment thereof, or comprises an antibody, an antibody-like molecule, or an antigen-binding fragment thereof.

21. The therapeutic agent specifically binds to the protein or other biomolecule that exhibits abnormal production, aggregation, and / or deposition. The method according to claim 20, wherein the therapeutic agent is a nonspecific clearing antibody, an anti-amyloid-beta antibody, an anti-tau antibody, an anti-TREM2 antibody, and / or an anti-alpha-synuclein antibody.

22. The method according to claim 14, wherein the therapeutic agent is a low-molecular-weight drug or comprises a low-molecular-weight drug.

23. The therapeutic agent provides synaptic plasticity, neuroprotection, inflammation reduction, neurotransmitter receptor modulation, and / or reduction of oxidative stress. The method according to claim 22, wherein the therapeutic agent is donepezil, galantamine, rivastigmine, memantine, suvorexant, carbidopa / levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, neuprazide, istradefylline, and / or amantadine.

24. The method according to any one of claims 14 to 23, wherein the therapeutic agent is formulated in liposomes or delivered via a viral vector.

25. The method according to any one of claims 14 to 23, wherein the neurological disease or disorder is Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Lewy body dementia, spinocerebellar ataxia, amyotrophic lateral sclerosis, frontotemporal disease, multiple system atrophy, 4-repeat tauopathy, or prion disease.

26. The neurological disorder or disability is a tumor, and the therapeutic agent is selected for the treatment of the tumor. The neurological disease or disorder is a central nervous system infection, and the therapeutic agent includes an antibiotic, an antiviral agent, an antiretroviral agent, and / or an antifungal agent, or The method according to any one of claims 14 to 23, wherein the neurological disease or disorder is a congenital enzyme deficiency, and the therapeutic agent includes enzyme replacement therapy.

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