Control of ultrasound procedures by monitoring microbubble response

Abstract

An ultrasound transducer sonicates a target volume to change tissue properties by transmitting a sequence of acoustic pulses to the target volume, while at least one acoustic detector detects an ultrasound reflection signal from the target volume following each acoustic pulse, and a controller (i) estimates an activity of the contrast agent at the target volume based on a comparison between values of a signal parameter in the reflection signals following successive acoustic pulses, and (ii) controls the ultrasound transducer based on the estimated activity so as to change the tissue properties.

Description

CONTROL OF ULTRASOUND PROCEDURES BY MONITORING MICROBUBBLE RESPONSETECHNICAL FIELD

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

[0002] The use of focused ultrasound (FUS) in combination with microbubbles to noninvasively treat pathologies affecting the central nervous system shows great therapeutic promise. One application involves disruption of the blood-brain barrier (BBB), which may permit delivery into the brain parenchyma of drugs the BBB would otherwise exclude.

[0003] In order to reversibly open the BBB, it is necessary to apply FUS at a sufficient intensity to permeabilize the tissue to a therapeutic agent. If FUS intensity is excessive, however, it risks damaging other tissues and / or making the permeabilization permanent to some degree.SUMMARY

[0004] Accordingly, in order to use FUS for BBB opening and enable effective drug delivery without causing damage, careful control of FUS intensity is essential. To ensure efficacious treatment and minimize collateral damage, such control should provide real-time feedback responsive both to the degree of BBB opening and the risks of tissue injury.

[0005] In one aspect, a system is described for controllably changing tissue properties in the presence of a suspension of a contrast agent. The system includes: an ultrasound transducer for sonicating a target volume to change tissue properties, the ultrasound transducer transmitting a sequence of acoustic pulses to the target volume; at least one acoustic detector for detecting an ultrasound reflection signal from the target volume following each acoustic pulse; and a controller configured to (i) estimate an activity of the contrast agent at the target volume based on a comparison between values of a signal parameter in the reflection signals following successive acoustic pulses and (ii) control the ultrasound transducer based on the estimated activity so as to change the tissue properties.

[0006] In another aspect, a method is described for controllably changing tissue properties in a target volume in the presence of a contrast agent. The method includes the steps of: applying a sequence of acoustic pulses to the target volume; detecting a reflectionsignal from the target volume following each acoustic pulse; computationally estimating an activity of the contrast agent at the target volume based on a comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on the estimated activity so as to change the tissue properties.

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

[0008] In another aspect, a method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by having a locus of abnormal production, aggregation, and / or deposition of a protein or another biomolecule in the brain and wherein a therapeutic agent and / or a contrast agent composition will be, is being, or has been administrated to the subject, is described. The method includes: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the contrast agent at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on the estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, thereby increasing delivery of a level of delivery of the therapeutic agent to the locus.BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

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

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

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

[0016] Figure 11 is a flow chart illustrating an exemplary approach for controllably changing tissue properties in a target volume in the presence of a contrast agent.DETAILED DESCRIPTION

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

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

[0019] The transducer array 102 is coupled to the beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasonic beam or field. For n transducer elements, the beamformer 106 may contain n driver circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120; each drive circuit drives one of the transducer elements 104. The beamformer 106 receives a radio frequency (RF) input signal, typically in the range from 0.1 MHz to 10 MHz, from the frequency generator 110, which may, for example, be a Model DS345 generator available from Stanford Research Systems. The input signal may be split into n channels for the n amplifiers 118 and delay circuits 120 of the beamformer 106. In some embodiments, the frequency generator 110 is integrated with the beamformer 106. The radio frequency generator 110 and the beamformer 106 are configured to drive the individual transducer elements 104 of the transducer array 102 at the same frequency, but at different phases and / or different amplitudes.

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

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

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

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

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

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

[0026] It has been proposed in the past to use the reflected signal from acoustic contrast agents, which contain microbubbles 202, for the evaluation of blood perfusion. With reference to FIG. 3, the first insonation destroys some of the microbubbles of the contrast agent by cavitation. The intensity of the reflected signal from the second insonation depends on the extent of this destruction and the delay between insonations, during which the microbubbles’ concentration is replenished through blood perfusion. By fitting reflection intensities of successive insonations to a model, one can extract the blood perfusion coefficient.

[0027] In FIG. 3, the “observed concentration” curve corresponds to the magnitude of the reflection signal at each insonation. The “actual concentration” curve shows how the insonation pulse destroys a fraction of the microbubbles, and the concentration partially recovers as a result of the circulation; as a result, this cycle of destruction and recovery reflects and can be used to estimate the perfusion rate. When the FUS intensity is not sufficient to generate microbubble cavitation, a flat (steady) reflected signal from all the pulses in the pulse train is obtained.

[0028] In accordance with embodiments described herein, the reflection measurements of such a pulse sequence may be used to detect the onset of microbubble dynamic cavitation and to estimate the extent of this cavitation activity. As cavitation underlies disruption of the BBB, such measurements can be used to monitor and control the extent of BBB disruption. In particular, detected variations in the reflected signals from pulses in the pulse sequence may be used to identify the onset of microbubble cavitation. Moreover, it is possible to quantify this difference to deduce a quantitative value for cavitation activity, which in turn relates to the probability and degree of BBB disruption.

[0029] In various embodiments, the analysis is performed using the first harmonic of the transmission signal (i.e., using the reflected signal at the same frequency as the transmitted signal). It should be understood, however, that it is possible to use any other frequency band of the reflected signal. For the measurement itself, a single hydrophone or an array of them may be employed. Without loss of generality, the following description assumes that the signal is detected using a hydrophone array. As the difference between two reflected signals through the skull is monitored, effects due to aberration and attenuation are eliminated, and system calibration is generally unnecessary to obtain quantitative results.

[0030] There are several mathematical methods that can be used to analyze the measured data. One approach is to compare the reflected signal intensities of two successive pulses. If there are more than two pulses in a pulse sequence, the intensity variance in the sequence may be used as a measure. Statistical analysis methods such as analysis of variance (ANOVA) and analysis of means (ANOM) may be employed to obtain more quantitative results. These approaches can be used for data from a single hydrophone or a hydrophone array.

[0031] When using a hydrophone array, there is a significant advantage in using ANOVA or ANOM to monitor cavitation. In these approaches, the ensembles of amplitude measurements for each pulse are compared. Due to the large number of readings, the analysis tends to be more sensitive to variations and quantifies the difference between pulses, resulting in a quantitative estimate of cavitation level.

[0032] The reflected signal has two components: amplitude and phase. Statistical analysis can be applied to the phase part as well as the amplitude, and differences between phase ensembles can be used to identify the onset of cavitation as well. A combination of results using a plurality of analysis techniques on different components of the measured data can contribute to the statistical confidence level of the obtained result.

[0033] When using an ultrasound frequency of 100 kHz to 1000 kHz, typical pulses in a pulse train are 10 msec to 100 msec long. Different pulse lengths may be used, especially when using different FUS frequencies. A typical delay between pulses in the pulse sequence is 0.5 to 5 msec. To increase measurement sensitivity, it may be preferred to use a shorter delay time (~1 msec).

[0034] Using such short pulses with a hydrophone array enables generation of 3D acoustic activity maps of the target area, a procedure also known as passive acoustic mappingor PAM. This may be accomplished by constructing a 3D image of the spatial acoustic field using reflected signals from the spatially distributed 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; accordingly, based on the time of flight and by aggregating measurements from all sensing transducer elements to resolve degeneracies, the response to an event at each voxel can be computed. As a result, the analysis methods described above can be implemented on a per-voxel basis in the target region or volume, providing spatial information relating to treatment progress, efficacy, and safety.

[0035] Specifically, generating a cavitation activity map for each pulse in the sequence facilitates comparison between two pulses (e.g., the first and second pulses in the sequence) and thus generation of a 3D map of the effective dynamic cavitation and BBB disruption probability. These probability maps can be overlayed on MRI maps to estimate treatment efficacy and coverage.

[0036] Another approach to 3D spatial reconstruction is to reconstruct a single 2D plane within the target and use an angular spectrum method to create adjacent planes and, hence, a 3D spatial map. The angular spectrum method may involve expanding a complex wave field into a summation of plane waves of the same frequency and different directions. The technique can predict an acoustic pressure field distribution over a plane, based upon knowledge of the pressure field distribution at a parallel plane.

[0037] The following paragraphs present the results of a typical experiment involving 10 sonication cycles, where each cycle is a sequence of 10 insonations. The driving voltage is increased by 0.05 V in each successive sonication, which in turn increases FUS power. FIG. 4 illustrates the averaged signal from all hydrophones in the array as a function of individual insonation; there were 1024 hydrophones in the array. The driving voltage and sonication number are indicated as well. As FUS power is increased, the total reflected signal increases. The plot shows that dynamic cavitation starts at sonication 5 (S5). This is better represented in FIG. 5, in which the data is normalized to the maximum value per sonication. Referring back to FIG. 4, from sonication 5 (S5) and on, response decreases along the sonication. It is assumed that a fraction of the microbubbles are destroyed by sonication after each pulse at the sonicated area, and therefore the response at the next pulse is lower. A fit to the average response level of each pulse that shows decrease of the response can be a qualitative and a quantitative indication for the cavitation. Stated another way, in addition to the quantitative characteristics that may be derived from the decrease of the response, the decrease itself mayprovide a qualitative impression of the indicated cavitation. As can be seen in FIG. 4, the variation of the response is not chaotic, but a consecutive decline. Therefore, a controller or an observer can qualitatively determine, by virtue of the decline itself, when cavitation is first indicated (specifically, in FIG. 4, during S5).

[0038] Applying ANOVA to the normalized data allows the onset of dynamic cavitation to be detected earlier. FIG. 6 illustrates the Fisher ratio (F) and the probability that the new set of data is equivalent to the previous sets. This evaluation is performed successively after each sonication cycle. The dashed upper and lower lines represent, respectively, 95% and 99% confidence levels. Dynamic cavitation is detected in sonication 4 (S4) with 99% confidence.

[0039] FIG. 7 shows the result of applying ANOM to the same data set. In this case the data mean per sonication is compared with the 95% lower decision line (LDL). Once the result crosses the zero line, it can be stated with 95% confidence level that the set of data is not equivalent to the previous sets. In the illustrated case, the sensitivity of the method is inferior to that of ANOVA.

[0040] To obtain quantitative information regarding dynamic cavitation activity and estimate the probability of BBB disruption, it may be preferred to evaluate differences between repetitions within a sonication sequence (FIG. 8). ANOVA exhibits less sensitivity to the onset of cavitation on this data set (FIG. 9), so it is preferable to use the normalized average for cavitation detection and amplitude differences to quantify cavitation activity once detected.

[0041] The computed degree of cavitation may be used in a control loop whereby FUS power is progressively increased until, first, cavitation is detected, and then until the difference in mean amplitude between successive pulses reaches a level indicating a degree of cavitation corresponding to a desired degree of BBB opening (or a high probability that the BBB will open to a desired extent). In some cases, there is no ceiling on the desirable degree of BBB opening, and FUS power may be increased until the level of cavitation reaches a level that risks tissue damage, at which point it may be stopped or the power decreased. In other cases, a specific amount of BBB opening is desired, e.g., corresponding to an effective porosity substantially matching the molecular size of a therapeutic agent. By avoiding excessive BBB opening, target molecules that have passed through the BBB may to some extent be trapped behind it when sonication is stopped and the BBB begins to re-close.

[0042] The combination of short pulses and multiple distributed acoustic sensors also enables a simple 3D reconstruction of the acoustic activity following each pulse. This may be accomplished by constructing a 3D image of the spatial acoustic field using reflected signals from the spatially distributed transducer elements. The distance between each transducer element and each voxel in the spatial region of interest is known, as is the speed of sound through the relevant tissue; accordingly, based on the time of flight and by aggregating measurements from all sensing transducer elements to resolve degeneracies, the response to an event at each voxel can be computed. As a result, the analysis methods described above can be implemented on a per-voxel basis in the target region or volume, providing spatial information relating to treatment progress, efficacy, and safety.

[0043] FIG. 10 illustrates subtraction images that reflect microbubble cavitation (axis dimensions are millimeters). As insonation power reaches the cavitation threshold, acoustic activity that deviates slightly from the target (0,0,0) is observed (FIGS. 10a and 10b). As power increases (FIGS. 10c and lOd), the cavitation level increases as does the volume in which this activity occurs. Once calibrated, the measured values can be used to express the probability of BBB disruption in specific regions of the targeted volume.

[0044] Embodiments of the present invention may increase the permeability of the BBB to allow passage of biologies such as antibodies and therapeutics (e.g., Busulfan, Thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU (nimustine), Temozolomide, Methotrexate, Topotecan, Cisplatin, Etoposide, Irinotecan / SN-38, Carboplatin, Doxorubicin, Vinblastine, Vincristine, Procarbazine, Paclitaxel, Fotemustine, Ifosfamide / 4-Hydroxyifosfamide / aldoifosfamide, Bevacizumab, 5-Fluorouracil, Bleomycin, Hydroxyurea, Docetaxel, or Cytarabine (cytosine arabinoside, ara-C) / ara-U), for the treatment of tumors such as GMB, for the treatment of neurodegenerative diseases (e.g., anti-amyloid beta antibodies Aducanumab and anti-tau antibodies), and for the treatment of CNS infections.

[0045] A representative hardware platform for implementation of the present invention is described in U.S. Patent Publ. No. 2020 / 0139158, the entire disclosure of which is hereby incorporated by reference. The hardware system may include an imaging device (e.g., a magnetic resonance imaging (MRI) device) to characterize tissue types and / or properties of the target BBB region and / or its surrounding tissue; each type and location of tissue, depending on its properties, may have corresponding tolerances for cavitation; accordingly, the imaging device may be used to spatially characterize tissue tolerance, and this spatial representation may be used for comparison to a spatial map of cavitation effects generatedand updated as described above. The ’9158 application also describes suitable ultrasound transducer arrangements and driver circuitry.

[0046] More generally, functionality for performing disruption of a target BBB region in a controlled and reversible manner may be structured in one or more modules implemented in hardware, software, or a combination of both. For embodiments in which the functions are provided as one or more software programs, the programs may be written in any of a number of high level languages such as PYTHON, FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and / or HTML. Additionally, the software can be implemented in an assembly language directed to the microprocessor resident on a target computer; for example, the software may be implemented in Intel 80x86 assembly language if it is configured to run on an IBM PC or PC clone. The software may be embodied on an article of manufacture including, but not limited to, a floppy disk, a jump drive, a hard disk, an optical disk, a magnetic tape, a PROM, an EPROM, EEPROM, field-programmable gate array, or CD-ROM. Embodiments using hardware circuitry may be implemented using, for example, one or more FPGA, CPLD or ASIC processors.

[0047] As used herein, the term “substantially” refers to ± 10% of the tissue volume, in some embodiments, ± 5% of the tissue volume. By “clinically significant” is meant that the clinician believes that an undesirable (sometimes less desirable) effect on the tissue is significant, e.g., causing injury that is not justified in the specific treatment.

[0048] In one aspect, the invention relates to a method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by having a locus of abnormal production, aggregation, and / or deposition of a protein or another biomolecule in the brain and wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of thetherapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional near-infrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent.

[0049] In various embodiments, the neurological disease or disorder is selected from the Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies, spinocerebellar ataxia, and amyotrophic lateral sclerosis, frontotemporal diseases, multiple system atrophy, four-repeat tauopathy and prion diseases. In some embodiments, the locus is selected from senile plaques, neurofibrillary tangles, neuronal inclusions, Lewy bodies, glial inclusions, cytoplasmic inclusions, and polyglutamine aggregates. In some embodiments, the protein showing abnormal production, aggregation, and / or deposition is selected from amyloid-P (AP), Tau protein, of TDP-43, a-Synuclein, FUS / TLS, SOD1, and Huntingtin.

[0050] In various embodiments, the therapeutic agent comprises a small molecule or a biologic drug. In some embodiments, the therapeutic agent is or comprises a biologic drug. In some embodiments, the therapeutic agent is selected from a gene therapy agent, a vaccine, an antisense oligonucleotide (ASO), a protein therapeutic, a modified mRNA agent, and a RNAi agent.

[0051] In some embodiments, the therapeutic agent is or comprises an antibody, antibody -like molecule or an antigen-binding fragment thereof. In some embodiments, the therapeutic agent specifically binds the protein or another biomolecule that that exhibits abnormal production, aggregation, and / or deposition. In some embodiments, the therapeutic agent is selected from a nonspecific clearing antibody (e.g., intravenous immunoglobulin aka IVIg), an anti-amyloid-P antibody (e.g., aducanumab, gantenerumab, lecanemab, and donanemab), an anti -tau antibody (e.g., semorinemab, gosuranemab, tilavonemab, and zagotenemab), an anti-TREM2 antibody (e.g., AL002), an anti-alpha-synuclein antibody (e.g., Cinpanemab, Prasinezumab, Lu AF82422, ABBV-0805, and MEDI1341), and or a combination thereof.

[0052] In some embodiments, the therapeutic agent is or comprises a small molecule drug. In some embodiments, the therapeutic agent provides one or more of synaptic plasticity, neuroprotection, reduction of inflammation, neurotransmitter receptor modulation, reduction of oxidative stress. In some embodiments, the therapeutic agent is selected from donepezil, galantamine, rivastigmine, memantine, suvorexant, carbidopa-levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, nuplazid, istradefylline and amantadine, and a combination thereof.

[0053] In some embodiments, the therapeutic agent is formulated in a liposome. In some embodiments, the therapeutic agent is delivered via a viral vector.

[0054] Figure l is a flow diagram illustrating an example process 400 for controllably causing tissue destruction in a target internal anatomic region in accordance with some implementations. The process may be governed by instructions that are stored in a computer memory or non-transitory computer readable storage medium. The instructions may be included in one or more programs stored in the non-transitory computer readable storage medium. When executed by one or more processors (e.g., 108 and / or 148), the instructions cause the system to perform the process. The non-transitory computer readable storage medium may include one or more solid state storage devices (e.g., Flash memory), magnetic or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that can be interpreted by one or more processors. Some operations in the process may be combined, and the order of some operations may be changed.

[0055] Figure 11 is a flow diagram illustrating an example process 1100 for controllably changing tissue properties in the presence of a suspension of a contrast agent in accordance with some implementations. The process may be governed by instructions that are stored in a computer memory or non-transitory computer readable storage medium. The instructions may be included in one or more programs stored in the non-transitory computer readable storage medium. When executed by one or more processors (e.g., 108 and / or 148), the instructions cause the system to perform the process. The non-transitory computer readable storage medium may include one or more solid state storage devices (e.g., Flash memory), magnetic or optical disk storage devices, or other non-volatile memory devices. The instructions may include source code, assembly language code, object code, or any other instruction format that can be interpreted by one or more processors. Some operations in the process may be combined, and the order of some operations may be changed.

[0056] In operation 1102, an ultrasound transducer (e.g., 102) transmits a sequence of acoustic pulses to a target volume.

[0057] In operation 1104, at least one acoustic detector (e.g., element 104 or a hydrophone) detects an ultrasound reflection signal from the target volume following each acoustic pulse.

[0058] In operation 1106, a controller (e.g., 108 and / or 148) computationally estimates an activity of the contrast agent at the target volume based on a comparison between values of a signal parameter in the reflection signals following successive acoustic pulses.

[0059] In operation 1108, the controller controls the ultrasound transducer based on the estimated activity so as to change the tissue properties. In some implementations, the controller controls the ultrasound transducer based on the estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue.

[0060] In some implementations, the change to the tissue properties is: a disruption of a tissue barrier to increase permeability of the barrier; a neuromodulation of tissue neurons; an activation of a sonodynamic therapy drug; an activation of contrast agent carriers for drug and / or gene delivery; a thrombolysis; and / or an induction of an ischemic effect.

[0061] In some implementations, the change to the tissue properties is a disruption of a tissue barrier to increase permeability of the barrier, wherein the tissue barrier is a bloodbrain barrier, a blood-retina barrier, skin, a mucosal membrane, a cell membrane, or a nuclear membrane; and permeability is increased sufficiently to permit passage of a therapeutic agent therethrough, wherein the therapeutic agent is selected for treatment of a tumor, a neurogenerative disease, an enzymatic deficiency, or a CNS infection.

[0062] In some implementations, the comparison is based on: a variance of signal amplitudes measured by a plurality of acoustic detectors; a ratio of mean to variance or mean to standard deviation; a full -frequency spectrum of the reflection signals; a first harmonic of the reflection signals; or an indication that signal amplitudes measured by the plurality of acoustic detectors are decreasing.

[0063] In some implementations, the contrast agent comprises gas-filled bubbles or phase-shifting droplets having a size in a range of 150 nm to 20 pm; and the activity of the contrast agent is: an onset of cavitation; and / or an extent of cavitation, wherein the extent of cavitation is estimated based on a difference between mean measured amplitudes of successive pulses.

[0064] In some implementations, an interval between successive acoustic pulses is no greater than 3 ms; the signal parameter is a phase or an amplitude; and the comparison between values of the signal parameter in the reflection signals is in accordance with a first harmonic of an emission spectrum of the successive acoustic pulses.Treatment Examples

[0065] In some aspects, the present disclosure provides a method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by abnormal production, aggregation, and / or deposition of a protein or another biomolecule in the brain. In some embodiments, neurological disease or disorder is selected from the Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies, spinocerebellar ataxia, and amyotrophic lateral sclerosis, frontotemporal diseases, multiple system atrophy, four-repeat tauopathy and prion diseases.

[0066] Alzheimer’s Disease patients exhibit senile plaques that are mainly composed of amyloid-P (A|3), neurofibrillary tangles, which include Tau protein, neuronal inclusions of TDP-43 as well as Lewy bodies, which include a-Synuclein. Parkinson's Disease patients exhibit Lewy bodies, which include a-Synuclein. Patients suffering from amyotrophic lateral sclerosis have neuronal inclusions that include TAR DNA-binding protein 43 (TDP-43), fused in sarcoma / translocated in liposarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). Huntington’s Disease is a progressive brain disorder caused by a mutation in the gene coding for the huntingtin protein, resulting in an abnormal mutant protein that gradually damages brain cells. Dementia with Lewy bodies features Lewy bodies, which include a- Synuclein, senile plaques that are mainly composed of amyloid-P (AP) and neurofibrillary tangles of Tau protein. The patients having frontotemporal diseases show neuronal and glial inclusions composed of Tau, TDP-43, and FUS / TLS. Multiple system atrophy features glial cytoplasmic inclusions of a-synuclein. Thus, there appears to be an overlap between the proteins that exhibits abnormal production, aggregation, and / or deposition associated with these diseases. A single neurodegenerative disease can be associated with multiple proteins (or another biomolecules) that exhibits abnormal production, aggregation, and / or deposition. On the other hand, a single the protein that exhibits abnormal production, aggregation, and / or deposition can also be associated with multiple diseases. For example, although Ap plaques and tau tangles are paradigmatic of Alzheimer's Disease, Lewy bodies typical of Parkinson's Disease are found in more than 50 percent of Alzheimer's cases, and neuronal inclusionsconsisting of the protein TDP-43 are found in more than 40 percent. Similarly in dementia with Lewy bodies, a dementing disorder closely allied to Parkinson's disease having some features of Alzheimer's, the paradigmatic a-Synuclein-rich Lewy bodies are accompanied by Ap plaques in 60 percent of cases and tau tangles in 50 percent. Likewise, four-repeat tauopathies, a group of neurodegenerative diseases defined by cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains, is associated with at least three clinical presentations: (1) progressive supranuclear palsy presents with an axial rigidity and eye movement problems, in addition to atypical Parkinsonism; (2) corticobasal degeneration presents like a frontal lobe dementia, with focal cortical syndromes, including progressive apraxia or progressive aphasia; and (3) argyrophilic grain disease is an increasingly recognized disorder of the elderly that affects the medial temporal lobe and is associated with an amnesic cognitive impairment.

[0067] Accordingly, in some aspects, the present disclosure provides a method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by abnormal production, aggregation, and / or deposition of a protein or another biomolecule in the brain, wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional near-infrared spectroscopy (fNIRS),or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the neurological disease or disorder is Alzheimer’s Disease and the locus is selected from a senile plaque comprising amyloid-P (AP), neurofibrillary tangles comprising Tau protein, neuronal inclusions comprising TDP-43, and Lewy bodies comprising a-Synuclein. In some embodiments, the neurological disease or disorder is Parkinson's Disease and the locus is Lewy bodies comprising a-Synuclein. In some embodiments, the neurological disease or disorder is amyotrophic lateral sclerosis and the locus is a neuronal inclusion comprising TAR DNA-binding protein 43 (TDP-43), fused in sarcoma / translocated 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 neuronal intranuclear inclusions of Huntingtin. In some embodiments, the neurological disease or disorder is dementia with Lewy bodies and the locus is Lewy bodies comprising a-Synuclein, senile plaques comprising amyloid-P (AP), and neurofibrillary tangles comprising Tau protein. In some embodiments, the neurological disease or disorder is frontotemporal diseases and the locus is neuronal and glial inclusions composed of Tau, TDP-43, and FUS / TLS. In some embodiments, the neurological disease or disorder is multiple system atrophy, and the locus is glial cytoplasmic inclusions of a-synuclein. In some embodiments, the neurological disease or disorder is four-repeat tauopathy, and the locus is cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains.

[0068] The diseases that are associated with aggregation and / or accumulation of the protein (or another biomolecule) that exhibits abnormal production, aggregation, and / or deposition also include prion diseases, i.e., the transmissible spongiform encephalopathies such as bovine spongiform encephalopathy (BSE or mad cow disease) and Creutzfeldt-Jakob disease. These diseases feature senile plaques made of PrP protein. Accordingly, in some aspects, the present disclosure provides a method of treating a prion disease, wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent bloodbrain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses basedon an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional nearinfrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent.Alzheimer’s Disease

[0069] Alzheimer’s disease (AD) is a complex, progressively debilitating, and fatal neurodegenerative disease. AD is rapidly increasing in frequency as the world’s population ages. There are currently an estimated 6.5 million individuals with AD in the US, and this number is expected to increase to more than 13 million by 2050. Approximately 15% of the US population over age 60 has prodromal AD and approximately 40% has preclinical AD. Similar trends are seen globally with an anticipated worldwide population of AD dementia patients exceeding 100 million by 2050 unless means of delaying, preventing, or treating AD are found. There is a significant need for therapeutics that halt or reverse the underlying pathology of AD.

[0070] Cellular and molecular mechanisms of AD are not well understood yet. Researchers have been reported that AD is associated with genetic and environmental factors and life-style. AD patients are heterogeneous in that they could be in preclinical AD continuum spanning up to two decades or more without exhibiting any clinical symptoms, i.e., mild cognitive impairment (MCI), AD dementia, or functional decline. Furthermore, misdiagnosis of AD patients is common in that 10-30% of individuals clinically diagnosed as AD dementia do not display AD neurodegeneration at autopsy.

[0071] Across all types of AD therapies, the failure rate is more than 99%, and for 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 the therapeutic agents is required.

[0072] Alzheimer’s Disease is associated senile plaques composed of amyloid-P (Ap), neurofibrillary tangles, which include Tau protein, neuronal inclusions of TDP-43 as well as Lewy bodies, which include a-Synuclein. Ap is a relatively small peptide of 4 to 4.4 kDa that is the major component of amyloid deposits. Intracellular Ap protein is widely found in neurons and it is associated with inflammatory and antioxidant activity, regulation of cholesterol transport, and activation of kinase enzyme. However, Ap is one of the best known components in formation of neurodegenerative diseases including AD. Ap is approximately composed of 36-43 amino acids and it originates from amyloid precursor protein (APP), which is a glycoprotein of 695-770 amino acids. APP can be cleaved into fragments by a, P, and y secretases and Ap protein is formed by the action of the P and y secretases. Ap protein contains two important regions which play a major role in the formation insoluble amyloid fibrils.

[0073] The microtubule associated Tau protein, the name of which is derived from “tubulin associated unit,” is highly expressed in brain. Microtubules are major proteins of the cytoskeleton. The main function of the Tau protein is to stabilize microtubules with binding to microtubules and to other proteins. To perform these functions, Tau protein is phosphorylated at normal level. Hyperphosphorylation of Tau protein is believed to cause conformational changes and aggregation of tau proteins. Other post-translational modifications such as glycosylation, glycation, polyamination, and nitration may play roles in aggregation. Accordingly, in some aspects, the present disclosure provides a method of treating Alzheimer’s Disease (AD, wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent inthe subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional near-infrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is selected from amyloid-P peptide (AP), neurofibrillary tangles and tau protein. In some embodiments, the therapeutic agent is selected from a nonspecific clearing antibody (e.g., intravenous immunoglobulin aka IVIg), an anti-amyloid-P antibody (e.g., aducanumab, gantenerumab, lecanemab, and donanemab), an anti-tau antibody (e.g., semorinemab, gosuranemab, tilavonemab, and zagotenemab), an anti-TREM2 antibody (e.g., AL002), donepezil, rivastigmine, memantine and galantamine and a combination thereof. In some embodiments, the therapeutic agent is aducanumab. Some therapeutic agents are disclosed in WO 2014 / 089500 and WO 2021 / 108861, and the content of which is incorporated herein by reference.Parkinson’s Disease

[0074] Parkinson’s disease (PD) is a long-term degenerative disorder of the central nervous system that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination. Symptoms usually begin gradually and worsen over time. As the disease progresses, people may have difficulty walking and talking. They may also have mental and behavioral changes, sleep problems, depression, memory difficulties, and fatigue. The occurrence of the illness is characterized by accumulation of misfolded a-synuclein protein in brain. Generally; anxiety, tremor, rigidity, depression, bradykinesia, and postural abnormalities are the most common symptoms in Parkinson’s disease.

[0075] Lewy bodies (LBs), which mainly consist of a-syn, are neuropathological hallmarks of patients with Parkinson’s disease (PD). It has been increasingly recognized, however, that PD is frequently associated with cognitive deficits, and that dementia eventually develops in a substantial number of patients.

[0076] a-synuclein is associated with a number of neurodegenerative diseases that are known as “Synucleinopathies.” Natively unfolded a- synuclein (a-Syn) is a 14 kDa and highly conserved protein that localize different regions of the brain. The name of protein waspreferred as “a-synuclein” because of it shows synaptic and nuclear localization. a-Syn regulates dopamine neurotransmission by modulation of vesicular dopamine storage. It interacts with tubulin and can function like tau protein. Also, a-Syn shows a molecular chaperon activity in folding of SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor) proteins. a-Syn plays crucial role in PD because a-Syn is a major fibrillary component for Lewy bodies. Two mutations, A53T and A30P, in the a-Syn gene and overexpression of wild type a-Syn are increases misfolding processes and aggregation. Also, accumulation of abnormal form of a-Syn can inhibit proteasomal functions. In PD brains, a-Syn is found to be phosphorylated at Ser87 and Serl29 in aggregates. These serine residues are phosphorylated with casein kinase 1 (CK1) and casein kinase 2 (CK2). It is believed that this post translational modification has a pathological role in fibrillation of a-Syn.

[0077] Accordingly, in some aspects, the present disclosure provides a method of treating Parkinson’s Disease (PD), wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional near-infrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is alpha-synuclein.In some embodiments, the therapeutic agent is selected from an anti-alpha-synuclein antibody (e.g., Cinpanemab, Prasinezumab, Lu AF82422, ABBV-0805, and MEDI1341), carbidopa- levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, nuplazid, istradefylline and amantadine, and a combination thereof.

[0078] Multiple system atrophy features glial cytoplasmic inclusions of a-synuclein. Accordingly, in some aspects, the present disclosure provides a method of treating multiple system atrophy, wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional nearinfrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is alpha-synuclein. In some embodiments, the therapeutic agent is selected from an anti-alpha-synuclein antibody (e.g., Cinpanemab, Prasinezumab, Lu AF82422, ABBV-0805, and MEDI1341), carbidopa- levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, nuplazid, istradefylline and amantadine, and a combination thereof.Dementia with Lewy bodies

[0079] Dementia with Lewy bodies features Lewy bodies, which include a-Synuclein, senile plaques that are mainly composed of amyloid-P (A|3) and neurofibrillary tangles of Tauprotein. Dementia with Lewy bodies (DLB) is a type of progressive dementia that leads to a decline in thinking, reasoning and independent function. Its features may include spontaneous changes in attention and alertness, recurrent visual hallucinations, REM sleep behavior disorder, and slow movement, tremors or rigidity. Mutations in genes known as SNCA and SNCB can cause dementia with Lewy bodies. Mutations in another gene called GBA or a certain version of a gene called APOE increase the risk of developing the condition, but are not a direct cause. Accordingly, in some aspects, the present disclosure provides a method of treating dementia with Lewy bodies, wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional near-infrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is alpha-synuclein. In some embodiments, the therapeutic agent is selected from an anti-alpha-synuclein antibody (e.g., Cinpanemab, Prasinezumab, Lu AF82422, ABBV-0805, and MEDI1341), rivastigmine, donepezil, galantamine, memantine, carbidopa- levodopa, and a combination thereof. In some embodiments, the methods disclosed herein further comprises detecting a brain-derived biomarker in a plasma sample of the subject. In some embodiments, the method detects a mutation in a gene selected from SNCA, SNCB, and APOE.Huntington’s Disease

[0080] Huntington’s disease (HD) is a genetic neurodegenerative disorder and the disease is caused by autosomal dominant inheritance. HD patients show involuntary muscle contractions, movement, and mental disorders. The disease is inherited as an autosomal dominant and effects brain and nervous systems. Huntington protein undergoes conformational changes with mutation and it shows aggregation tendency.

[0081] In HD, the neuropathology is characterized with accumulation of Htt protein aggregates. HD is caused by a number of CAG repeats in the gene. It is believed that the CAG repeats (polyQ) are the most important promoter for toxicity of Htt protein aggregates. The polyQ region starts at residue 18 and the number of glutamine residues are the most important marker in HD. Surprisingly, 40 or more CAG repeats are always generated neuropathy, while 35 or fewer CAG repeats are never generated neuropathy. However, in childhood, CAG repeats from 27 to 35 can develop neuropathy. Accordingly, in some aspects, the present disclosure provides a method of treating Huntington’s Disease (HD), wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent bloodbrain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional nearinfrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the protein that exhibitsabnormal production, aggregation, and / or deposition is huntingtin. In some embodiments, the therapeutic agent is selected from anti-huntingtin antibody and an anti- SEMA4D antibody (e.g., Pepinemab).Amyotrophic Lateral Sclerosis (ALS)

[0082] Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by degeneration of both upper and lower motor neurons, leading to progressive paralysis in muscles of the limbs, speech, swallowing and respiration. Patients suffering from amyotrophic lateral sclerosis have neuronal inclusions that include TAR DNA-binding protein 43 (TDP-43), fused in sarcoma / translocated in liposarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). ALS pathology is believed to begin at a single focal or multifocal sites and spread through the neuroaxis in a spatiotemporal manner. Insoluble TDP- 43 from diseased brains has been reported to induce TDP-43 pathology in neuroblastoma cells that overexpress wtTDP-43 as detected by TDP-43 hyperphosphorylation, ubiquitination and aggregation. Accordingly, in some aspects, the present disclosure provides a method of treating amyotrophic lateral sclerosis (ALS), wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional near-infrared spectroscopy (fNTRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or acontrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is TAR DNA-binding protein 43 (TDP-43), fused in sarcoma / translocated in liposarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). In some embodiments, the therapeutic agent is selected from an anti-TDP-43 antibody, an anti- SOD1 antibody, riluzole, edaravone, and sodium phenylbutyrate and taurursodiol, or a combination thereof.Spinocerebellar Ataxia

[0083] Spinocerebellar ataxia (SCAs) is a complex group of neurodegenerative disorders characterized by progressive cerebellar ataxia of gait and limbs variably associated with ophthalmoplegia, pyramidal and extrapy rami dal signs, dementia, pigmentary retinopathy and peripheral neuropathy. Disease onset is usually between 30 and 50 years of age, although early onset in childhood and onset in later decades after 60 years have been reported. The prognosis is variable depending on the underlying cause of the spinocerebellar ataxia subtype. Mutations in ATXN1, ATXN2, ATXN3, SCA4, SPTBN2, CACNAIA, ATXN7, KLHL1AS, ATXN10, SCA11, PPP2R2B, KCNC3, PRKCG, etc. are found in SCAs. In addition, seven spinocerebellar ataxia subtypes including SCAs 1, 2, 3 / Machado- Joseph disease, 6, 7, 17 and dentatorubral pallidoluysian atrophy (DRPLA) are caused by the expansion of a CAG-repeat sequence in specific genes, leading to abnormally long polyQ tracts in the encoded proteins. Proteins with expanded stretches of polyglutamine appear to take on an abnormal configuration resulting in the formation and deposition of polyglutamine aggregates in disease neurons forming characteristic nuclear or cytoplasmic inclusions, which are neuropathological hallmarks in these diseases. Accordingly, in some aspects, the present disclosure provides a method of treating spinocerebellar, wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of thetherapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional near-infrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is a mutant protein having expanded polyglutamine tracts. In some embodiments, the therapeutic agent is selected from an anti-polyglutamine antibodyFrontotemporal Diseases

[0084] The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. In recent years, attention has focused on understanding the pathogenic role of protein misfolding and aggregation, which is a cardinal feature of the post-mortem diagnostic criteria for frontotemporal lobar degeneration (FTLD). These diseases are associated neuronal and glial inclusions composed of Tau, TDP-43, and FUS / TLS. Frontotemporal dementia with parkinsonism- 17 (FTDP-17) is a progressive neurodegenerative disease which is caused by mutations in the tau gene. The tau gene is mutated in familial FTDP-17 and this mutation accelerates formation of neurofibrillary tangles (NFTs) in the brain. Furthermore, hyperphosphorylation is promoted by this mutation. In some aspects, the present disclosure provides a method of treating frontotemporal dementia, wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the controlis level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional nearinfrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the locus is neuronal and glial inclusions composed of Tau, TDP-43, and FUS / TLS. In some embodiments, the therapeutic agent is an anti-tau antibody.Four-Repeat Tauopathy

[0085] Four-repeat (4R-) tauopathies are a group of neurodegenerative diseases defined by cytoplasmic inclusions of tau protein isoforms. Progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease or glial globular tauopathy belong to the group of 4R-tauopathies. Tau is a microtubule-associated protein with versatile functions in the dynamic assembly of the neuronal cytoskeleton, and in these diseases, cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains are found. Moreover, Tau protein is generally located in axons, but in tauopathy, it is located in dendrites. Thus, neuron’s transport system may be disintegrated and microtubule cannot function correctly. Accordingly, in some aspects, the present disclosure provides a method of treating a four-repeat (4R-) tauopathy, wherein a therapeutic agent and / or a microbubble composition will be, is being or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the microbubbles at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on an estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, and thereby increasing delivery of a level of delivery of the therapeutic agent to the locus compared to a control. In some embodiments, the control is level of delivery of the therapeutic agent in the subject that has not received the sequence of acoustic pulses and / orthe microbubble composition. In other embodiments, the control is level of delivery of the therapeutic agent in the subject prior to the administration of the sequence of acoustic pulses and / or the microbubble composition. In any of the embodiments, the level of drug delivery may be measured using an imaging technique, including but not limited to diffusion-tensor imaging (DTI), functional magnetic resonance imaging (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) and functional near-infrared spectroscopy (fNIRS), or a combination thereof, optionally with the use of a tracer, an imaging agent and / or a contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is Tau protein. In some embodiments, the therapeutic agent is an anti-tau antibody.Notes Regarding the Disclosure

[0086] Reference have been made in detail to various implementations, examples of which are illustrated in the accompanying drawings. In the above detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention and the described implementations. However, the invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and circuits have not been described in detail so as not to unnecessarily obscure aspects of the implementations.

[0087] It will be understood that, although the terms “first,” “second,” etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first device could be termed a second device, and, similarly, a second device could be termed a first device, without changing the meaning of the description, so long as all occurrences of the first device are renamed consistently and all occurrences of the second device are renamed consistently. The first device and the second device are both devices, but they are not the same device.

[0088] The terminology used herein is for the purpose of describing particular implementations only and is not intended to be limiting of the claims. As used in the description of the implementations and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will also be understood that the term "and / or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. For example, “A, B, and / or C” means: A only; B only; C only; A and B; A and C; B and C;or A, B, and C. It will be further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0089] As used herein, the term “if’ may be construed to mean “when” or “upon” or “in response to determining” or “in accordance with a determination” or “in response to detecting,” that a stated condition precedent is true, depending on the context. Similarly, the phrase “if it is determined [that a stated condition precedent is true]” or “if [a stated condition precedent is true]” or “when [a stated condition precedent is true]” may be construed to mean “upon determining” or “in response to determining” or “in accordance with a determination” or “upon detecting” or “in response to detecting” that the stated condition precedent is true, depending on the context.

[0090] The foregoing description, for purpose of explanation, has been described with reference to specific implementations. However, the illustrative discussions above are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in view of the above teachings. The implementations were chosen and described in order to best explain the principles of the invention and its practical applications, to thereby enable others skilled in the art to best utilize the invention and various implementations with various modifications as are suited to the particular use contemplated.

Claims

CLAIMS1. A system for controllably changing tissue properties in the presence of a suspension of a contrast agent, the system comprising: an ultrasound transducer for sonicating a target volume to change tissue properties, the ultrasound transducer transmitting a sequence of acoustic pulses to the target volume; at least one acoustic detector for detecting an ultrasound reflection signal from the target volume following each acoustic pulse; and a controller configured to (i) estimate an activity of the contrast agent at the target volume based on a comparison between values of a signal parameter in the reflection signals following successive acoustic pulses and (ii) control the ultrasound transducer based on the estimated activity so as to change the tissue properties.

2. The system of claim 1, wherein the change to the tissue properties is: a disruption of a tissue barrier to increase permeability of the barrier; a neuromodulation of tissue neurons; an activation of a sonodynamic therapy drug; an activation of contrast agent carriers for drug and / or gene delivery; a thrombolysis; and / or an induction of an ischemic effect.

3. The system of claim 1, wherein: the change to the tissue properties is a disruption of a tissue barrier to increase permeability of the barrier, wherein the tissue barrier is a blood-brain barrier, a blood-retina barrier, skin, a mucosal membrane, a cell membrane, or a nuclear membrane; and permeability is increased sufficiently to permit passage of a therapeutic agent therethrough, wherein the therapeutic agent is selected for treatment of a tumor, a neurogenerative disease, an enzymatic deficiency, or a CNS infection.

4. The system of claim 1, wherein the comparison is based on: a variance of signal amplitudes measured by a plurality of acoustic detectors; a ratio of mean to variance or mean to standard deviation; a full-frequency spectrum of the reflection signals; a first harmonic of the reflection signals; oran indication that signal amplitudes measured by the plurality of acoustic detectors are decreasing.

5. The system of claim 1, wherein: the contrast agent comprises gas-filled bubbles or phase-shifting droplets having a size in a range of 150 nm to 20 pm; and the activity of the contrast agent is: an onset of cavitation; and / or an extent of cavitation, wherein the extent of cavitation is estimated based on a difference between mean measured amplitudes of successive pulses.

6. The system of claim 1, wherein: an interval between successive acoustic pulses is no greater than 3 ms; the signal parameter is a phase or an amplitude; and the comparison between values of the signal parameter in the reflection signals is in accordance with a first harmonic of an emission spectrum of the successive acoustic pulses.

7. A method of controllably changing tissue properties in a target volume in the presence of a contrast agent, the method comprising the steps of: applying a sequence of acoustic pulses to the target volume; detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the contrast agent at the target volume based on a comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; controlling application of the acoustic pulses based on the estimated activity so as to change the tissue properties.

8. The method of claim 7, wherein the change to the tissue properties is: a disruption of a tissue barrier to increase permeability of the barrier; a neuromodulation of tissue neurons; an activation of a sonodynamic therapy drug; an activation of contrast agent carriers for drug and / or gene delivery; a thrombolysis; and / or an induction of an ischemic effect.

9. The method of claim 7, wherein: the change to the tissue properties is a disruption of a tissue barrier to increase permeability of the barrier, wherein the tissue barrier is a blood-brain barrier, a blood-retina barrier, skin, a mucosal membrane, a cell membrane, or a nuclear membrane; and permeability is increased sufficiently to permit passage of a therapeutic agent therethrough, wherein the therapeutic agent is selected for treatment of a tumor, a neurogenerative disease, an enzymatic deficiency, or a CNS infection.

10. The method of claim 7, wherein the comparison is based on: a variance of signal amplitudes measured by a plurality of acoustic detectors; a ratio of mean to variance or mean to standard deviation; a full-frequency spectrum of the reflection signals; a first harmonic of the reflection signals; or an indication that signal amplitudes measured by the plurality of acoustic detectors are decreasing.

11. The method of claim 7, wherein: the contrast agent comprises gas-filled bubbles or phase-shifting droplets having a size in a range of 150 nm to 20 pm; and the activity of the contrast agent is: an onset of cavitation; and / or an extent of cavitation, wherein the extent of cavitation is estimated based on a difference between mean measured amplitudes of successive pulses.

12. The method of claim 7, wherein: an interval between successive acoustic pulses is no greater than 3 ms; the signal parameter is a phase or an amplitude; and the comparison between values of the signal parameter in the reflection signals is in accordance with a first harmonic of an emission spectrum of the successive acoustic pulses.

13. A system for monitoring cavitation in an internal tissue region in response to applied acoustic energy, the system comprising: an ultrasound transducer comprising a plurality of spatially distributed elements each for transmitting a sequence of acoustic pulses to the target volume and causing cavitation of a suspension of contrast agent therein;a plurality of spatially distributed acoustic detectors for detecting ultrasound reflection signals from the target volume following each acoustic pulse; and a controller configured to receive from the acoustic detectors data characterizing the detected reflection signals and, based on at least (i) the received data, (ii) locations of the acoustic detectors and (iii) a speed of sound between the acoustic detectors and the target volume, estimate a cavitation level at a plurality of voxel locations at least spatially spanning the target volume.

14. A method of treating a neurological disease or disorder in a subject in need thereof, wherein the neurological disease or disorder is characterized by having a locus of abnormal production, aggregation, and / or deposition of a protein or another biomolecule in the brain and wherein a therapeutic agent and / or a contrast agent composition will be, is being, or has been administrated to the subject, the method comprising: applying a sequence of acoustic pulses to the target volume, wherein the target volume encompasses the locus and adjacent blood-brain barrier (BBB); detecting a reflection signal from the target volume following each acoustic pulse; computationally estimating an activity of the contrast agent at the target volume based on comparison between values of a signal parameter in the reflection signals following successive acoustic pulses; and controlling application of the acoustic pulses based on the estimated activity so as to change the tissue properties without a clinically significant effect on non-target tissue, thereby increasing delivery of a level of delivery of the therapeutic agent to the locus.

15. The method of claim 14, wherein: the level of delivery of the therapeutic agent is compared to a control; and the control is: the level of delivery of the therapeutic agent in a subject that has not received the sequence of acoustic pulses and / or the contrast agent composition; or the level of delivery of the therapeutic agent in the treated subject prior to the administration of the sequence of acoustic pulses and / or the contrast agent composition.

16. The method of claim 14, wherein the locus is selected from senile plaques, neurofibrillary tangles, neuronal inclusions, Lewy bodies, glial inclusions, cytoplasmic inclusions, and polyglutamine aggregates.

17. The method of claim 14, wherein the protein showing abnormal production, aggregation, and / or deposition is selected from amyloid-P (AP), Tau protein, of TDP-43, a- Synuclein, FUS / TLS, SOD1, and Huntingtin.

18. The method of claim 14, wherein the therapeutic agent is or comprises a biologic drug.

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

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

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

22. The method of claim 14, wherein the therapeutic agent is or comprises a small molecule drug.

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

24. The method of any of claims 14-23, wherein the therapeutic agent is formulated in a liposome or delivered via a viral vector.

25. The method of any of claims 14-23, wherein the neurological disease or disorder is Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies, spinocerebellar ataxia,amyotrophic lateral sclerosis, frontotemporal diseases, multiple system atrophy, four-repeat tauopathy, or prion diseases.

26. The method of any of claims 14-23, wherein: the neurological disease or disorder is a tumor, and the therapeutic agent is selected for treatment of the tumor; the neurological disease or disorder is a central nervous system infection, and the therapeutic agent comprises an antibiotic, an anti-viral, an anti-retroviral, and / or an antifungal; or the neurological disease or disorder is a congenital enzyme defect, and the therapeutic agent comprises an enzyme replacement therapy.

Images