Controlling ultrasound procedures by monitoring microbubble response

Abstract

An ultrasound transducer ultrasonically processes a target volume by emitting a sequence of acoustic pulses to the target volume to alter tissue properties while at least one acoustic detector detects an ultrasound reflected signal from the target volume after 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 signal parameters in the reflected signal following successive acoustic pulses, and (ii) controls the ultrasound transducer to alter the tissue property based on the estimated activity.

Description

TECHNICAL FIELD

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

[0002] Non-invasive treatment of lesions affecting the central nervous system using focused ultrasound (FUS) in combination with microbubbles shows great therapeutic promise. One application involves disruption of the blood-brain barrier (BBB), which can allow drug delivery into the brain parenchyma that would otherwise be blocked by the BBB.

[0003] To reversibly open the BBB, FUS needs to be applied with sufficient intensity to make the tissue permeable to the therapeutic agent. However, if the FUS intensity is too high, there is a risk of damaging other tissues and / or making the permeability permanent to some extent. SUMMARY

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

[0005] In one aspect, a system for controllably altering a tissue property in the presence of a suspension of contrast agent is described. The system comprises: an ultrasound transducer for ultrasound treating a target volume to alter the tissue property, the ultrasound transducer emitting a sequence of acoustic pulses towards the target volume; at least one acoustic detector for detecting an ultrasound reflection signal from the target volume after 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 after successive acoustic pulses; and (ii) control the ultrasound transducer to alter the tissue property based on the estimated activity.

[0006] In another aspect, a method for controllably altering a tissue property in a target volume in the presence of a contrast agent is described. The method comprises the steps of: applying a sequence of acoustic pulses to the target volume; detecting a reflection signal from the target volume after 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 after successive acoustic pulses; and controlling the application of acoustic pulses to alter the tissue property based on the estimated activity.

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

[0008] In another aspect, the present invention describes a method of treating a nervous system disease or disorder in a subject in need thereof, wherein the nervous system disease or disorder is characterized by a site in the brain having abnormal production, aggregation, and / or deposition of a protein or other biological molecule, and wherein a therapeutic agent and / or a contrast agent composition is to be, is being, or has been administered to the subject. The method comprises: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood brain barrier (BBB); detecting reflection signals from the target volume following each acoustic pulse; computationally estimating 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 the application of acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing delivery of a level of delivery of the therapeutic agent to the site. BRIEF DESCRIPTION OF DRAWINGS

[0009] In the drawings, like reference numerals refer to like parts throughout the various views. Moreover, the drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the present disclosure. In the following description, various embodiments of the present disclosure are described with reference to the following drawings, in which: FIG. 1A schematically depicts an exemplary ultrasound system, in accordance with various embodiments of the present disclosure.

[0010] FIG. IB schematically depicts an exemplary MRI system, in accordance with various embodiments of the present disclosure.

[0011] FIG. 2 depicts an implementation of an acoustic reflector proximate to a target region, in accordance with some embodiments.

[0012] FIG. 3 is a chart depicting observed and actual concentrations of contrast agent during a focused ultrasound procedure, in accordance with some embodiments.

[0013] FIGS. 4-9 are graphs depicting indications of cavitation during a focused ultrasound procedure including multiple ultrasound treatments, according to some embodiments.

[0014] FIG. 10 depicts subtraction images reflecting microbubble cavitation, according to some embodiments.

[0015] FIG. 11 is a flowchart showing an exemplary method of controllably altering tissue properties in a target volume in the presence of a contrast agent. DETAILED DESCRIPTION

[0016] FIG. 1A shows an exemplary ultrasound system 100 for generating and delivering a focused beam of acoustic energy to a target region 101 in a patient. The illustrated system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 that drives the phased array 102, a controller 108 in communication with the beamformer 106, and a frequency generator 110 that provides input electronic signals to the beamformer 106.

[0017] The array 102 can have a curved shape (e.g., spherical or parabolic) or other contoured shape suitable for placement on the surface of a patient's body, or can include one or more planar or otherwise shaped segments. Its dimensions can vary between a few millimeters and a few tens of centimeters. The transducer elements 104 of the array 102 can be piezoelectric ceramic elements and can be mounted in silicone rubber or any other material suitable for attenuating mechanical coupling between the elements 104. Piezoelectric composites, or generally any material capable of converting electrical energy into acoustic energy, can also be used. To ensure maximum power transfer to the transducer elements 104, the elements 104 can be configured for electrical resonance at 50 Ω to match the input connector impedance.

[0018] The transducer array 102 is coupled to a beamformer 106 that drives the individual transducer elements 104 so that they collectively produce a focused ultrasound beam or field. For n transducer elements, the beamformer 106 can contain n driver circuits, each including or consisting of an amplifier 118 and a phase delay circuit 120; each driver circuit drives one of the transducer elements 104. The beamformer 106 receives a radio frequency (RF) input signal from a frequency generator 110, which can be, for example, a model DS345 generator available from Stanford Research Systems, Inc., typically in the range of 0.1 MHz to 10 MHz. The input signal can 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.

[0019] Amplification or attenuation factors a1-an and phase shifts a1-an applied by the beamformer 106 are used to transmit and focus the ultrasonic energy through intervening tissue located between the transducer elements 104 and the target region and onto the target region 101, taking into account wave distortions induced in the intervening tissue. The amplification factors and phase shifts are calculated using a controller 108, which can provide the calculation functionality by software, hardware, firmware, hardwiring, or any combination thereof. In various embodiments, the controller 108 utilizes a general or special purpose digital data processor programmed with software in a conventional manner, and without undue experimentation, determines the frequency, phase shift, and / or amplification factors needed to achieve a desired focal point or any other desired spatial field pattern at the target region 101. In certain embodiments, the calculations are based on detailed information about the characteristics (e.g., type, size, location, properties, structure, thickness, density, structure, etc.) of the intervening tissue located between the transducer elements 104 and the target and its effect on the propagation of acoustic energy. Such information can be obtained from an imager 112. The imager 112 can be, for example, a magnetic resonance imaging (MRI) device, a computed tomography (CT) device, a positron emission tomography (PET) device, a single photon emission computed tomography (SPECT) device, or an ultrasonography device. The image acquisition can be three-dimensional (3D), or alternatively, the imager 112 can 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., a region surrounding the target 101 or another target region). Image processing functionality can be implemented in the imager 112, the controller 108, or a separate device. Furthermore, as described further below, the ultrasound system 100 and / or the imager 112 can be used to detect signals from an acoustic reflector (e.g., microbubbles 202, see FIG. 2) located generally in the vicinity of the target region 101. Additionally or alternatively, the system 100 can 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 can provide its received signals to the controller 108 for further processing. Furthermore, the ultrasound system 100 can 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 can be operated using the same controller 108 that facilitates operation of the transducers; alternatively, they can be controlled separately by one or more separate controllers in communication with each other.

[0020] FIG. IB shows an example imager, MRI device 112. Device 112 can include a cylindrical electromagnet 134 that generates the requisite static magnetic field within a bore 136 of electromagnet 134. During a medical procedure, a patient is placed inside bore 136 on a movable support table 138. A region of interest 140 within the patient (e.g., the patient's head) can be positioned within an imaging region 142 where electromagnet 134 generates a substantially uniform field. A set of cylindrical magnetic field gradient coils 144 can also be disposed within bore 136 and encircle the patient. Gradient coils 144 generate magnetic field gradients of predetermined amplitudes at predetermined times and in three orthogonal directions to one another. With the field gradients, different spatial locations can be associated with different precession frequencies, thereby endowing a magnetic resonance (MR) image with its spatial resolution. An RF transmitter coil 146 encircling imaging region 142 transmits RF pulses into imaging region 142 to cause the patient's tissues to emit MR response signals. The raw MR response signals are sensed by RF coil 146 and passed to MR controller 148, which then computes MR images that can be displayed to a user. Alternatively, separate MR transmitter and receiver coils can be used. Images acquired using MRI device 112 can provide radiologists and physicians with visual contrasts between different tissues and internal detail views of patient anatomy that cannot be visualized using conventional X-ray techniques.

[0021] MRI controller 148 can control the pulse sequence, i.e., the relative timing and strength of the magnetic field gradients and RF excitation pulses and response detection periods. The MR response signals are amplified, conditioned, and digitized into raw data using conventional image processing systems and further converted into an image data array by methods known to those of ordinary skill in the art. Based on the image data, a target region (e.g., a tumor or a target BBB) can be identified.

[0022] To perform targeted drug delivery or tumor ablation, it is desirable to determine the location of target region 101 with high precision. Accordingly, in various embodiments, imager 112 is first activated to acquire images of target region 101 and / or non-target regions (e.g., healthy tissue encircling the target region, intervening tissue between transducer array 102 and target region 101, and / or any region located in the vicinity of the target) and determine anatomical properties (e.g., tissue type, location, size, thickness, density, structure, shape, vascularization) associated therewith based thereon. For example, a tissue volume can be represented as a set of 3D voxels based on a 3D image or a series of 2D image slices, and can include target region 101 and / or non-target regions.

[0023] To produce high quality focusing at the target region 101, it can be desirable to calibrate the transducer elements 104 and account for transducer geometric imperfections resulting from, for example, movement, displacement, and / or deformation of the transducer elements 104 from their intended positions. Furthermore, because scattering, absorption, reflection, and / or refraction of ultrasound waves can occur as the waves travel through non-uniform intervening tissue located between the transducer elements 104 and the target region 101, it can also be desirable to account for these wave distortions in order to improve the focusing properties at the target region 101.

[0024] Referring to FIG. 2, ultrasound waves emitted from all (or at least some) of the transducer elements 104 are reflected by an acoustic reflector 202. The acoustic reflector 202 can consist essentially of microbubbles introduced through ultrasound generation and / or through parenteral administration by the administration system. In some embodiments, the administration system 126 introduces seed microbubbles into the target region 101; the transducer 102 is then activated to emit ultrasound waves to the seed microbubbles for generating a microbubble cloud. Methods of generating microbubbles and / or introducing microbubbles into a target region 101 are provided, for example, in PCT Publication No. WO 2018 / 020315, PCT Application No. PCT / US2018 / 064058 (filed December 5, 2018), PCT / IB2018 / 001103 (filed August 14, 2018), PCT / US2018 / 064892 (filed December 11, 2018), PCT / IB2018 / 000841 (filed June 29, 2018), and PCT / US2018 / 064066 (filed December 5, 2018), U.S. Patent Publication No. 2019 / 0083065, and U.S. Patent Application No. 15 / 837,392 (filed December 11, 2017), the contents of which are incorporated herein by reference.

[0025] It has been proposed in the past to use the reflected signal from an acoustic contrast agent containing microbubbles 202 to assess blood perfusion. Referring to FIG. 3, a first acoustic irradiation destroys some of the microbubbles of the contrast agent by cavitation. The intensity of the reflected signal from a second acoustic irradiation depends on the extent of this destruction and the delay between the acoustic irradiations, during which the concentration of microbubbles is replenished by blood perfusion. By fitting the reflected intensity of successive acoustic irradiations to a model, the blood perfusion coefficient can be extracted.

[0026] In FIG. 3, the “observed concentration” curve corresponds to the amplitude of the reflected signal at each acoustic irradiation. The “actual concentration” curve shows how a fraction of the microbubbles is destroyed by the acoustic irradiation pulses and how the concentration is partially recovered due to circulation; thus, this cycle of destruction and recovery can reflect and be used to estimate the perfusion rate. When the FUS intensity is not sufficient to produce microbubble cavitation, a flat (steady) reflected signal from all pulses in the pulse sequence is obtained.

[0027] According to embodiments described herein, the reflection measurements of such a pulse sequence can be used to detect the onset of microbubble dynamic cavitation and estimate the degree of this cavitation activity. Since cavitation is the basis for BBB disruption, such measurements can be used to monitor and control the degree of BBB disruption. In particular, detected changes in the reflection signal from the pulses in the pulse sequence can be used to identify the onset of microbubble cavitation. Furthermore, this difference can be quantified to infer a quantitative value of the cavitation activity, which in turn correlates to the probability and degree of BBB disruption.

[0028] In various embodiments, the analysis is performed using the first harmonic of the transmitted signal (i.e., using the reflection signal at the same frequency as the transmitted signal). However, it should be understood that any other frequency band of the reflection signal can be used. For the measurement itself, either a single hydrophone or an array of hydrophones can be employed. Without loss of generality, the following description assumes the use of an array of hydrophones to detect the signal. Since what is being monitored is the difference between the two reflection signals that cross the skull, the effects of aberrations and attenuation are eliminated, and quantitative results are typically obtained without the need for system calibration.

[0029] There are several mathematical approaches that can be used to analyze the measurement data. One approach is to compare the reflection signal intensities of two consecutive pulses. If there are more than two pulses in the pulse sequence, then the variance of the intensities in the sequence can be used as a metric. Statistical analysis methods such as analysis of variance (ANOVA) and analysis of means (ANOM) can be employed to obtain more quantitative results. These methods can be used on data from either a single hydrophone or an array of hydrophones.

[0030] There is a significant advantage to using ANOVA or ANOM to monitor cavitation when using an array of hydrophones. In these methods, the set of amplitude measurements for each pulse is compared. Because of the large number of readings, the analysis tends to be more sensitive to changes and quantifies the difference between the pulses, thereby providing a quantitative estimate of the cavitation level.

[0031] The reflection signal has two components: amplitude and phase. Statistical analysis can be applied to the phase portion as well as the amplitude, and the differences between the sets of phases can also be used to identify the onset of cavitation. Combining the results of using multiple analysis techniques on different components of the measurement data can be beneficial to the level of statistical confidence of the resulting conclusions.

[0032] When using ultrasound frequencies of 100 kHz to 1000 kHz, a typical pulse in the pulse sequence is 10 milliseconds to 100 milliseconds long. Different pulse lengths can be used, especially when different FUS frequencies are used. A typical delay between pulses in the pulse sequence is 0.5 milliseconds to 5 milliseconds. To increase the sensitivity of the measurement, it is preferable to use a short delay time (about 1 millisecond).

[0033] The use of such short pulses with a hydrophone array enables the generation of a 3D acoustic activity map of the target region, a procedure also known as passive acoustic mapping or PAM. This can be achieved by constructing a 3D image of the spatial acoustic field using the reflected signals from the spatially distributed transducer elements 104. The distance between each transducer element and each voxel in the spatial region of interest, as well as the speed of sound through the relevant tissue, are known; therefore, based on the time of flight, and by pooling the measurements from all the sensing transducer elements to resolve the degeneracy, the response of each voxel to the event can be calculated. The above analysis method can thus be implemented voxel by voxel in the target region or volume, providing spatial information relevant to treatment progress, efficacy, and safety.

[0034] In particular, generating a cavitation activity map for each pulse in the sequence facilitates the comparison between two pulses (e.g., the first and second pulses in the sequence), and thus the generation of 3D maps of effective dynamic cavitation and BBB disruption probabilities. These probability maps can be overlaid on MRI maps to estimate treatment efficacy and coverage.

[0035] Another 3D spatial reconstruction method is to reconstruct a single 2D plane within the target, and use the angular spectrum method to create adjacent planes, and thus a 3D spatial map. The angular spectrum method can involve expanding a complex wave field into a sum of plane waves with the same frequency and different directions. This technique can predict the acoustic pressure field distribution above a plane based on knowledge of the pressure field distribution at parallel planes.

[0036] The following paragraphs present the results of a typical experiment involving 10 ultrasound treatment cycles, where each cycle is a sequence of 10 ultrasound treatments. In each successive ultrasound treatment, the driving voltage is increased by 0.05 V, which in turn increases the FUS power. Figure 4 shows the average signal from all hydrophones in the array as a function of the individual acoustic exposures; there are 1024 hydrophones in the array. The driving voltage and the ultrasound treatment number are also indicated in the figure. As the FUS power increases, the total reflected signal also increases. The figure shows that dynamic cavitation starts at ultrasound treatment 5 (S5). This is better represented in Figure 5, where the data has been normalized to the maximum value of each ultrasound treatment. Referring back to Figure 4, starting from ultrasound treatment 5 (S5), the response decreases with ultrasound treatment. It is assumed that in the ultrasound treated region, a fraction of the microbubbles is destroyed by the ultrasound treatment after each pulse, and thus the response is lower at the next pulse. A fit to the average response level of each pulse showing a decrease in response can be a qualitative and quantitative indication of cavitation. In other words, in addition to the quantitative characteristics that can be derived from the decrease in response, the decrease itself can provide a qualitative impression of the indicated cavitation. From Figure 4 it can be seen that the change in response is not random, but a continuous decay. Thus, a controller or an observer can qualitatively determine when the first indication of cavitation is made (specifically, during S5 in Figure 4) by means of the decay itself.

[0037] Applying ANOVA to the normalized data allows to detect the start of dynamic cavitation earlier. Figure 6 shows the Fisher ratio (F) and the probability that the new data set is equivalent to the previous data set. This evaluation is performed sequentially after each ultrasound treatment cycle. The upper and lower dashed lines represent the 95% and 99% confidence levels, respectively. Dynamic cavitation is detected in ultrasound treatment 4 (S4) with a 99% confidence level.

[0038] Figure 7 shows the results of applying ANOM to the same data set. In this case, the data mean of each ultrasound treatment is compared to the 95% lower decision line (LDL). As soon as the result crosses the zero line, it can be asserted with a 95% confidence level that the data set is not equivalent to the previous data set. In the presented case, the sensitivity of this method is less than that of ANOVA.

[0039] To obtain quantitative information about the dynamic cavitation activity and to estimate the probability of BBB disruption, it can be preferable to evaluate the difference between the number of repetitions within the ultrasound treatment sequence (Figure 8). ANOVA shows a lower sensitivity to the start of cavitation for this data set (Figure 9), so it is preferable to use the normalized mean and the amplitude difference of the cavitation detection to quantify the detected cavitation activity.

[0040] The calculated cavitation level can be used in a control loop by which the FUS power is gradually increased until cavitation is first detected, and then until the difference in average amplitude between successive pulses reaches a level corresponding to a cavitation level indicative of a desired degree of BBB opening (or a high probability that the BBB will open to a desired degree). In some cases, there is no upper limit to the desired degree of BBB opening, and the FUS power can be increased until the cavitation level reaches a level at which there is a risk of organized damage, at which point the opening can be stopped or the power reduced. In other cases, a particular amount of BBB opening is desired, e.g., an amount corresponding to an effective porosity roughly matching the molecular size of the therapeutic agent. By avoiding excessive opening of the BBB, when the ultrasound treatment is stopped and the BBB begins to close again, target molecules that have passed through the BBB can be trapped to some extent behind it.

[0041] The combination of short pulses and multiple distributed acoustic sensors also enables simple 3D reconstruction of acoustic activity after each pulse. This can be achieved by using the reflected signals from the spatially distributed transducer elements to construct a 3D image of the spatial acoustic field. The distance between each transducer element and each voxel in the region of interest, as well as the speed of sound through the relevant tissue, are known; therefore, based on time of flight, and by pooling the measurements from all the sensing transducer elements to resolve degeneracy, the response of each voxel to the event can be calculated. The analysis method described above can thus be implemented voxel by voxel in the target region or volume, providing spatial information relevant to treatment progress, efficacy, and safety.

[0042] Figure 10 illustrates subtraction images reflecting microbubble cavitation (axes are in millimeters). When the acoustic irradiation power reaches the cavitation threshold, acoustic activity is observed slightly off target (0,0,0) (Figures 10a and 10b). As the power is increased (Figures 10c and 10d), the cavitation level increases, and the volume in which this activity occurs also increases. Once calibrated, the measurements can be used to express the probability of BBB disruption in specific regions of the target volume.

[0043] Embodiments of the present invention can increase the permeability of the BBB to allow passage of biological agents such as antibodies and therapeutic agents (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-beta amyloid antibody Aducanumab and anti-tau antibodies), and for the treatment of central nervous system (CNS) infections.

[0044] A representative hardware platform for implementing the present invention is described in U.S. Patent Publication No. 2020 / 0139158, the entire disclosure of which is hereby incorporated by reference. This hardware system can include an imaging device (e.g., a magnetic resonance imaging (MRI) device) for characterizing the tissue type and / or properties of the target BBB region and / or its surrounding tissue; each tissue type and location, according to its properties, can have a corresponding cavitation tolerance; thus, this imaging device can be used to spatially characterize tissue tolerance, and this spatial representation can be used for comparison with the cavitation effect spatial map generated and updated as described above. The '9158 application also describes suitable ultrasonic transducer devices and driver circuitry.

[0045] More generally, the functionality for carrying out target BBB region disruption in a controlled and reversible manner can be built in one or more modules implemented in hardware, software, or a combination of both. For embodiments in which the functionality is provided as one or more software programs, these programs can be written in any of several high-level languages, such as PYTHON, FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and / or HTML. In addition, the software can be implemented in assembly language for a microprocessor built into the target computer; for example, if the software is configured to run on an IBM PC or PC clone, it can be implemented in Intel 80x86 assembly language. The software can be embodied on an article of manufacture including, but not limited to, a floppy disk, a flash drive, a hard disk, an optical disk, a magnetic tape, a PROM, an EPROM, an EEPROM, a field-programmable gate array, or a CD-ROM. Embodiments using hardware circuitry can be implemented using, for example, one or more FPGA, CPLD, or ASIC processors.

[0046] As used herein, the term "substantially" refers to ±10% of a volume of tissue, and in some embodiments, ±5% of a volume of tissue. "Clinically significant" refers to an adverse (sometimes less than ideal) effect on tissue that a clinician considers to be significant, e.g., causing an unreasonable impairment in a particular treatment.

[0047] In one aspect, the present application relates to a method of treating a nervous system disease or disorder in a subject in need thereof, wherein the nervous system disease or disorder is characterized by a site in the brain having abnormal production, aggregation, and / or deposition of a protein or other biomolecule, and wherein a therapeutic agent and / or a microbubble composition is to be, is being, or has been administered to the subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter a tissue property without producing a clinically significant effect on non-target tissue, thereby increasing a delivery level of the therapeutic agent to the site compared to a control. In some embodiments, the control is a delivery level 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 a delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or contrast agent.

[0048] In various embodiments, the nervous system disease or disorder is selected from Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Lewy body dementia, spinocerebellar ataxia and amyotrophic lateral sclerosis, frontotemporal lobar dementia, multiple system atrophy, tauopathies with quadruple repeat tau, and prion diseases. In some embodiments, the site is selected from senile plaques, neurofibrillary tangles, neuronal inclusion bodies, Lewy bodies, glial inclusions, cytoplasmic inclusions, and polyglutamine aggregates. In some embodiments, the protein that is shown to have abnormal production, aggregation, and / or deposition is selected from beta amyloid (Ab), Tau protein, TDP-43, alpha-synuclein, FUS / TLS, SOD1, and huntingtin.

[0049] 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 gene therapy agents, vaccines, antisense oligonucleotides (ASOs), protein therapeutics, modified mRNA agents, and RNAi agents.

[0050] In some embodiments, the therapeutic agent is or comprises an antibody, antibody-like molecule, or antigen-binding fragment thereof. In some embodiments, the therapeutic agent specifically binds to a protein or other biological molecule that exhibits abnormal production, aggregation, and / or deposition. In some embodiments, the therapeutic agent is selected from non-specific clearing antibodies (e.g., intravenous immunoglobulin, aka IVIg), anti-beta amyloid antibodies (e.g., aducanumab, gantenerumab, lecanemab, and donanemab), anti-tau antibodies (e.g., semorinemab, gosuranemab, tilavonemab, and zagotenemab), anti-TREM2 antibodies (e.g., AL002), anti-alpha-synuclein antibodies (e.g., Cinpanemab, Prasinezumab, Lu AF82422, ABBV-0805, and MEDI1341), and / or combinations thereof.

[0051] 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, inflammation reduction, neurotransmitter receptor modulation, oxidative stress reduction. In some embodiments, the therapeutic agent is selected from donepezil, galantamine, rivastigmine, memantine, sulindac, carbidopa-levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, pimavanserin (nuplazid), istradefylline, and amantadine, and combinations thereof.

[0052] In some embodiments, the therapeutic agent is formulated in a liposome. In some embodiments, the therapeutic agent is delivered via a viral vector.

[0053] FIG. 1 is a flowchart showing an example process 400 for controllably causing tissue disruption in an internal anatomical region of a target, in accordance with some embodiments. The process can be controlled by instructions stored in computer memory or a non-transitory computer-readable storage medium. The instructions can 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 can include one or more solid state storage devices (e.g., flash memory), disk or optical storage devices, or other non-volatile memory devices. The instructions can include source code, assembly language code, object code, or any other format that can be understood by one or more processors. Some operations in the process can be combined and the order of some operations can be changed.

[0054] FIG. 11 is a flowchart showing an example process 1100 for controllably changing tissue properties in the presence of a suspension of contrast agent, in accordance with some embodiments. The process can be controlled by instructions stored in computer memory or a non-transitory computer-readable storage medium. The instructions can 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 can include one or more solid state storage devices (e.g., flash memory), disk or optical storage devices, or other non-volatile memory devices. The instructions can include source code, assembly language code, object code, or any other format that can be understood by one or more processors. Some operations in the process can be combined and the order of some operations can be changed.

[0055] In operation 1102, an ultrasound transducer (e.g., 102) transmits a sequence of acoustic pulses to a target volume.

[0056] In operation 1104, at least one acoustic detector (e.g., elements 104 or a hydrophone) detects ultrasound reflection signals from the target volume after each acoustic pulse.

[0057] In operation 1106, a controller (e.g., 108 and / or 148) computationally estimates an activity of contrast agent at the target volume based on a comparison between values of a signal parameter in the reflection signals following successive acoustic pulses.

[0058] In operation 1108, the controller controls the ultrasound transducer to change tissue properties based on the estimated activity. In some embodiments, the controller controls the ultrasound transducer to change tissue properties based on the estimated activity without producing a clinically significant effect on non-target tissue.

[0059] In some embodiments, the change to the property of the tissue comprises: disruption of a tissue barrier to increase permeability of the barrier; neuromodulation of a tissue neuron; activation of a sonodynamic therapy drug; activation of a contrast agent carrier to perform drug and / or gene delivery; thrombolytic dissolution; and / or induction of an ischemic effect.

[0060] In some embodiments, the change to the property of the tissue is disruption of a tissue barrier to increase permeability of the barrier, wherein the tissue barrier is the blood-brain barrier, the blood-retinal barrier, skin, mucosa, a cell membrane, or a nuclear membrane; and the permeability is increased enough to allow a therapeutic agent to pass therethrough, wherein the therapeutic agent is selected to treat a tumor, a neurodegenerative disease, an enzyme deficiency, or a CNS infection.

[0061] In some embodiments, the comparison is based on: variance of signal amplitudes measured by the plurality of acoustic detectors; a ratio of mean to variance or mean to standard deviation; a full spectrum of the reflected signal; a first harmonic of the reflected signal; or an indication that the signal amplitudes measured by the plurality of acoustic detectors are decreasing.

[0062] In some embodiments, the contrast agent comprises a gas-filled bubble or a phase- shifting droplet having a size in a range of 150 nm to 20 pm; and the activity of the contrast agent is: onset of cavitation; and / or a degree of cavitation, wherein the degree of cavitation is estimated based on a difference between average measured amplitudes of consecutive pulses.

[0063] In some embodiments, the interval between consecutive acoustic pulses is no more than 3 ms; the signal parameter is phase or amplitude; and the comparison between values of the signal parameter in the reflected signal is consistent with a first harmonic of an emission spectrum of the consecutive acoustic pulses.

[0064] Treatment Examples In some aspects, the present disclosure provides a method of treating a nervous system disease or disorder in a subject in need thereof, wherein the nervous system disease or disorder is characterized by abnormal production, aggregation, and / or deposition of a protein or other biological molecule in the brain. In some embodiments, the nervous system disease or disorder is selected from Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Lewy body dementia, spinocerebellar ataxia and amyotrophic lateral sclerosis, frontotemporal lobar dementia, multiple system atrophy, tauopathies with quadruple repeat tau, and prion diseases.

[0065] Alzheimer's disease patients exhibit senile plaques composed primarily of beta amyloid (Ab), neurofibrillary tangles comprising Tau protein, neuronal inclusions of TDP-43, and Lewy bodies comprising alpha-synuclein. Parkinson's disease patients exhibit Lewy bodies comprising alpha-synuclein. Patients with amyotrophic lateral sclerosis have neuronal inclusions of TAR DNA binding protein 43 (TDP-43), myosin fusion / fused in sarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). Huntington's disease is a progressive brain disorder caused by a mutation in the gene encoding the huntingtin protein, leading to abnormal mutant protein that gradually damages brain cells. Lewy body dementia is characterized by Lewy bodies comprising alpha-synuclein, senile plaques composed primarily of beta amyloid (Ab), and neurofibrillary tangles of Tau protein. Patients with frontotemporal lobar disease show neuronal and glial inclusions of Tau, TDP-43, and FUS / TLS. Multiple system atrophy is characterized by glial cytoplasmic inclusions of alpha-synuclein. Thus, there appears to be an overlap between the proteins associated with these diseases that exhibit abnormal production, aggregation, and / or deposition. A single neurodegenerative disease can be associated with multiple proteins (or other biological molecules) that exhibit abnormal production, aggregation, and / or deposition. On the other hand, a single protein that exhibits abnormal production, aggregation, and / or deposition can also be associated with multiple diseases. For example, while Ab plaques and tau tangles are the classic features of Alzheimer's disease, Lewy bodies typical of Parkinson's disease are found in more than 50 percent of Alzheimer's cases, and neuronal inclusions of the protein TDP-43 are found in more than 40 percent of cases. Similarly, in Lewy body dementia, a dementia with some features of Alzheimer's that is closely related to Parkinson's, the classic alpha-synuclein-rich Lewy bodies are accompanied by Ab plaques in 60 percent of cases and tau tangles in 50 percent of cases. Likewise, the tauopathies, a group of neurodegenerative diseases defined by cytoplasmic inclusions composed primarily of a tau protein isoform with four microtubule binding domains, are associated with at least three clinical presentations: (1) progressive supranuclear palsy, which, in addition to classic Parkinson's disease, is manifested as axial rigidity and eye movement problems; (2) corticobasal degeneration, which presents as frontotemporal dementia, with focal cortical syndrome, including progressive apraxia or progressive aphasia; and (3) argyrophilic grain disease, an increasingly recognized disorder of aging that affects the medial temporal lobe and is associated with amnestic cognitive impairment.

[0066] Accordingly, in some aspects, the present disclosure provides a method of treating a nervous system disease or disorder in a subject in need thereof, wherein the nervous system disease or disorder is characterized by abnormal production, aggregation, and / or deposition of a protein or other biological molecule in the brain, wherein a therapeutic agent and / or a microbubble composition is to be, is being, or has been administered to the subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without a clinically significant effect on non-target tissue, thereby increasing a delivery level of the therapeutic agent to the site as compared to a control. In some embodiments, the control is a delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is a delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can 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, and optionally using a tracer, imaging agent, and / or contrast agent. In some embodiments, the nervous system disease or disorder is Alzheimer’s disease, and the site is selected from the group consisting of senile plaques comprising beta-amyloid (Αβ), neurofibrillary tangles comprising Tau protein, neuronal inclusions comprising TDP-43, and Lewy bodies comprising alpha-synuclein. In some embodiments, the nervous system disease or disorder is Parkinson’s disease, and the site is a Lewy body comprising alpha-synuclein. In some embodiments, the nervous system disease or disorder is amyotrophic lateral sclerosis, and the site is a neuronal inclusion comprising TAR DNA-binding protein 43 (TDP-43), sarcoma fusion / fused in sarcoma translocation (FUS / TLS), and superoxide dismutase-1 (SOD1). In some embodiments, the nervous system disease or disorder is Huntington’s disease, and the site is a neuronal intranuclear inclusion of huntingtin protein. In some embodiments, the nervous system disease or disorder is Lewy body dementia, and the site is a Lewy body comprising alpha-synuclein, a senile plaque comprising beta-amyloid (Αβ), and a neurofibrillary tangle comprising Tau protein. In some embodiments, the nervous system disease or disorder is frontotemporal lobar disease, and the site is a neuronal and glial inclusion of Tau, TDP-43, and FUS / TLS. In some embodiments, the nervous system disease or disorder is multiple system atrophy, and the site is a glial cytoplasmic inclusion of alpha-synuclein.In some embodiments, the nervous system disease or disorder is a quadruple repeat tauopathy, and the site is cytoplasmic inclusions consisting primarily of tau protein subtypes having four microtubule binding domains.

[0067] Diseases associated with aggregation and / or accumulation of proteins (or other biological molecules) that exhibit abnormal production, aggregation, and / or deposition also include prion diseases, i.e., transmissible spongiform encephalopathies, such as bovine spongiform encephalopathy (BSE or mad cow disease) and Creutzfeldt-Jakob disease. These diseases are characterized by senile plaques formed from 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 is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site compared to a control. In some embodiments, the control is the delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or contrast agent.

[0068] Alzheimer's disease Alzheimer's disease (AD) is a complex, progressive debilitating and fatal neurodegenerative disease. The frequency of AD is rapidly increasing as the world's population ages. Currently, there are an estimated 6.5 million individuals in the United States with AD, and this number is projected to increase to over 13 million by 2050. Approximately 15% of the U.S. population over 60 years of age has preclinical AD, and approximately 40% has preclinical AD. Similar trends are seen globally, with the projected global population of AD dementia patients expected to exceed 100 million by 2050, unless a means to slow, prevent, or treat AD is discovered. There is an urgent need for therapeutic approaches that halt or reverse the underlying pathology of AD.

[0069] The cellular and molecular mechanisms of AD are not fully understood. Researchers have reported that AD is associated with genetics, environmental factors, and lifestyle. AD patients are heterogeneous in that they can be in a preclinical AD stage for up to twenty years or more without ever exhibiting any clinical symptoms, i.e., mild cognitive impairment (MCI), AD dementia, or functional decline. In addition, misdiagnosis of AD patients is common, as 10% to 30% of individuals clinically diagnosed with AD dementia do not show AD neurodegenerative pathology at autopsy.

[0070] The failure rate for all types of AD therapies exceeds 99%, and for disease modifying therapies (DMTs), the failure rate is 100%. Therefore, in addition to new methods for developing therapeutic agents, there is a need for methods for targeted delivery of therapeutic agents, such as the methods disclosed herein.

[0071] Alzheimer’s disease patients are associated with senile plaques composed of beta amyloid (Aβ), neurofibrillary tangles comprising Tau protein, intraneuronal inclusions of TDP-43, and Lewy bodies comprising alpha-synuclein. As a relatively small peptide of 4 to 4.4 kDa, Aβ is the major component of amyloid deposition. Intracellular Aβ protein is found widely in neurons and is associated with inflammation and anti-oxidative activity, modulation of cholesterol transport, and activation of kinases. However, Aβ is one of the most well-known components in the formation of neurodegenerative diseases, including AD. Aβ is composed of approximately 36 to 43 amino acids and is derived from amyloid precursor protein (APP), which is a glycoprotein having 695 to 770 amino acids. APP can be cleaved into fragments by alpha, beta, and gamma secretases, and Aβ protein is formed by the action of beta and gamma secretases. Aβ protein contains two important regions that play a major role in the formation of insoluble amyloid fibrils.

[0072] Microtubule-associated tau protein (whose name derives from "tubulin-associated unit") is highly expressed in the brain. Microtubules are the main proteins of the cytoskeleton. The main function of tau protein is to stabilize microtubules by binding to them and other proteins. To perform these functions, tau protein is phosphorylated at normal levels. Hyperphosphorylation of tau protein is believed to cause conformational changes and aggregation of tau protein. Other post-translational modifications, such as glycosylation, glycation, polyamination, and nitration, can also play a role 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 is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site compared to a control. In some embodiments, the control is the delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is selected from the group consisting of amyloid-beta peptide (Ab), neurofibrillary tangles, and tau protein. In some embodiments, the therapeutic agent is selected from the group consisting of non-specific clearing antibodies (e.g., intravenous immunoglobulin, aka IVIg), anti-amyloid-beta antibodies (e.g., aducanumab, gantenerumab, lecanemab, and donanemab), anti-tau antibodies (e.g., semorinemab, gosuranemab, tilavonemab, and zagotenemab), anti-TREM2 antibodies (e.g., AL002), donepezil, rivastigmine, memantine, and galantamine, and combinations thereof. In some embodiments, the therapeutic agent is aducanumab. Some therapeutic agents are disclosed in WO 2014 / 089500 and WO 2021 / 108861, and the contents of which are incorporated herein by reference.

[0073] Parkinson’s disease Parkinson's disease (PD) is a long-term central nervous system degenerative disorder that causes unintended or uncontrollable movements such as tremor, rigidity, and difficulty with balance and coordination. Symptoms usually start gradually and worsen over time. As the disease progresses, patients can have difficulty walking and talking. They can also have mental and behavioral changes, sleep problems, depression, difficulty with memory, and fatigue. The disease is characterized by accumulation of misfolded alpha-synuclein in the brain. Typically, anxiety, tremor, rigidity, depression, bradykinesia, and postural abnormalities are the most common symptoms of Parkinson's disease.

[0074] Lewy bodies (LBs) are composed primarily of alpha-synuclein and are a neuropathological feature of patients with Parkinson's disease (PD). However, it is increasingly recognized that PD is often associated with cognitive deficits and a significant number of patients eventually develop dementia.

[0075] Alpha-synuclein is associated with a variety of neurodegenerative diseases known as "synucleinopathies." Alpha-synuclein (a-Syn) is a 14 kDa and highly conserved protein that is located in different regions of the brain. Due to the synapse and nuclear localization shown by this protein, its name is preferably "alpha-synuclein." a-Syn modulates dopamine neurotransmission by regulating vesicular dopamine storage. It interacts with tubulin and functions similarly to tau protein. In addition, a-Syn shows chaperone activity in the folding of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. a-Syn plays a crucial role in PD because a-Syn is the main fibrillar component of Lewy bodies. Two mutations in the a-Syn gene (A53T and A30P) and overexpression of wild-type a-Syn increase the misfolding process and aggregation. In addition, accumulation of abnormal forms of a-Syn inhibits proteasome function. In PD brains, Ser87 and Ser129 of a-Syn are found to be phosphorylated in aggregates. These serine residues are phosphorylated by casein kinase 1 (CK1) and casein kinase 2 (CK2). It is believed that this post-translational modification has a pathological role in the fibrillation of a-Syn.

[0076] 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 is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site of delivery compared to a control. In some embodiments, the control is the delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques 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, and optionally using a tracer, imaging agent, and / or 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 the group consisting of anti-alpha-synuclein antibodies (e.g., Cinpanemab, Prasinezumab, Lu AF82422, ABBV-0805, and MEDI1341), carbidopa-levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, pimavanserin (nuplazid), istradefylline, and amantadine, and combinations thereof.

[0077] Multiple system atrophy is characterized by glial cytoplasmic inclusions of alpha-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 is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery of a level of a therapeutic agent to the site of delivery compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the level of drug delivery can be measured using imaging techniques 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, and optionally using a tracer, imaging agent, and / or 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 the group consisting of anti-alpha-synuclein antibodies (e.g., Cinpanemab, Prasinezumab, Lu AF82422, ABBV-0805, and MEDI1341), carbidopa-levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, pimavanserin (nuplazid), istradefylline, and amantadine, and combinations thereof.

[0078] Lewy body dementia Lou Gehrig's disease is characterized by the presence of Lewy bodies containing alpha-synuclein, senile plaques composed primarily of beta-amyloid (Abeta), and neurofibrillary tangles of tau protein. Lou Gehrig's disease (DLB) is a progressive dementia that leads to a decline in thinking, reasoning, and independent functioning. Its features can include spontaneous changes in attention and alertness, recurrent visual hallucinations, rapid eye movement (REM) sleep behavior disorder, and slowness of movement, tremor, or rigidity. Mutations in genes called SNCA and SNCB can cause Lou Gehrig's disease. Mutations in another gene called GBA or a particular version of the gene called APOE increase the risk of developing this condition, but are not the direct cause. Thus, in some aspects, the present disclosure provides a method of treating Lou Gehrig's disease, wherein a therapeutic agent and / or a microbubble composition is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without a clinically significant effect on non-target tissue, thereby increasing the delivery of a level of a therapeutic agent to the site compared to a control. In some embodiments, the control is the level of delivery of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the level of delivery of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the level of drug delivery can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or 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 the group consisting of anti-alpha-synuclein antibodies (e.g., Cinpanemab, Prasinezumab, Lu AF82422, ABBV-0805, and MEDI1341), rivastigmine, donepezil, galantamine, memantine, carbidopa-levodopa, and combinations thereof. In some embodiments, the methods disclosed herein further comprise detecting a mutation in a gene selected from the group consisting of SNCA, SNCB, and APOE in a sample of plasma from the subject.

[0079] Huntington's disease 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 psychiatric disorders. The disease is inherited in an autosomal dominant manner and affects the brain and nervous system. The huntingtin protein undergoes a conformational change with mutation and shows a tendency to aggregate.

[0080] In HD, the neuropathology is characterized by accumulation of Htt protein aggregates. HD is caused by a large number of CAG repeats in the gene. The CAG repeat (polyQ) is thought to be the most important initiator of toxicity of Htt protein aggregates. The polyQ region starts at residue 18 and the number of glutamine residues is the most important marker in HD. Surprisingly, 40 or more CAG repeats always causes neuropathy, while 35 or fewer CAG repeats never causes neuropathy. However, CAG repeats of 27 to 35 can cause neuropathy in childhood. Accordingly, in some aspects, the present disclosure provides a method of Huntington's disease (HD), wherein a therapeutic agent and / or a microbubble composition is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without a clinically significant effect on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site of delivery compared to a control. In some embodiments, the control is the delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is huntingtin protein. In some embodiments, the therapeutic agent is selected from the group consisting of an anti-huntingtin antibody and an anti-SEMA4D antibody (e.g., pegaptinab).

[0081] Amyotrophic lateral sclerosis (ALS) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the degeneration of both upper and lower motor neurons, leading to progressive paralysis of limb muscles, speech, swallowing, and respiratory function. Patients with amyotrophic lateral sclerosis have neuronal inclusions containing TAR DNA-binding protein 43 (TDP-43), Fused in Sarcoma / Translocated in Liposarcoma (FUS / TLS), and superoxide dismutase-1 (SOD1). ALS pathology is thought to originate in a single or multiple focal sites and spread through the neural axis in a spatiotemporal manner. Insoluble TDP-43 from diseased brains has been reported to induce TDP-43 pathology in neuroblastoma cells overexpressing wtTDP-43, which can be detected by TDP-43 hyperphosphorylation, ubiquitination, and aggregation. Accordingly, in some aspects, the present disclosure provides a method of amyotrophic lateral sclerosis (ALS), wherein a therapeutic agent and / or a microbubble composition is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood-brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site as compared to a control. In some embodiments, the control is the delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or contrast 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, sodium phenylbutyrate, and taurine dioxyld, or a combination thereof.

[0082] Spinocerebellar ataxia Spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders characterized by progressive cerebellar gait and limb ataxia, associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, and peripheral neuropathy. Disease onset is usually between 30 and 50 years of age, but early childhood onset and decades after 60 years of age have also been reported. Prognosis varies depending on the underlying cause of the spinocerebellar ataxia subtype. Mutations in ATXN1, ATXN2, ATXN3, SCA4, SPTBN2, CACNA1A, ATXN7, KLHL1AS, ATXN10, SCA11, PPP2R2B, KCNC3, PRKCG, and others have been found in SCAs. Additionally, seven spinocerebellar ataxia subtypes, including SCAs 1, 2, 3 / Machado-Joseph disease, 6, 7, 17, and dentatorubral-pallidoluysian atrophy (DRPLA), are caused by expansions of CAG repeat sequences in specific genes, leading to abnormally long polyQ tracts in the encoded proteins. Proteins containing expanded polyglutamine segments appear to adopt abnormal conformations, leading to the formation and deposition of polyglutamine aggregates in the affected neurons, forming characteristic nuclear or cytoplasmic inclusions, which are a neuropathological hallmark of these diseases. Accordingly, in some aspects, the present disclosure provides a method of treating spinocerebellar ataxia, wherein a therapeutic agent and / or a microbubble composition is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and the adjacent blood brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site compared to a control. In some embodiments, the control is the delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is a mutant protein having an expanded polyglutamine tract. In some embodiments, the therapeutic agent is selected from an anti-polyglutamine antibody.

[0083] Frontotemporal lobar disease The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation can be common across the disease spectrum. In recent years, attention has focused on understanding the pathogenic role of protein misfolding and aggregation, a major feature of post-mortem diagnostic criteria for frontotemporal lobar degeneration (FTLD). These diseases are associated with neuronal and glial inclusions composed of Tau, TDP-43, and FUS / TLS. Frontotemporal dementia with Parkinsonism-17 (FTDP-17) is a progressive neurodegenerative disease caused by mutations in the tau gene. In familial FTDP-17, the tau gene is mutated, and the mutation accelerates the formation of neurofibrillary tangles (NFTs) in the brain. In addition, the mutation also promotes hyperphosphorylation. In some aspects, the present disclosure provides a method of treating frontotemporal dementia, wherein a therapeutic agent and / or a microbubble composition is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without a clinically significant effect on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site compared to a control. In some embodiments, the control is the delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or contrast agent. In some embodiments, the site is a neuronal and glial inclusion composed of Tau, TDP-43, and FUS / TLS. In some embodiments, the therapeutic agent is an anti-tau antibody.

[0084] Tetranucleotide tauopathies 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 globular glial tauopathies are all 4R-tauopathies. Tau is a microtubule-associated protein with multiple functions in the dynamic assembly of the neuronal cytoskeleton, and in these diseases cytoplasmic inclusions are found that are composed mainly of tau protein isoforms with four microtubule binding domains. In addition, tau protein is normally located in axons, but in tauopathies it is located in dendrites. Thus, the transport system of neurons can be disorganized and microtubules cannot function properly. 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 is to be, is being, or has been administered to a subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood brain barrier (BBB); detecting a reflected signal from the target volume after each acoustic pulse; computationally estimating the activity of microbubbles at the target volume based on a comparison between values of a signal parameter in the reflected signal after successive acoustic pulses; and controlling the application of acoustic pulses based on the estimated activity to alter tissue properties without a clinically significant effect on non-target tissue, thereby increasing the delivery level of the therapeutic agent to the site as compared to a control. In some embodiments, the control is the delivery level of the therapeutic agent in a subject who has not received the sequence of acoustic pulses and / or the microbubble composition. In other embodiments, the control is the delivery level of the therapeutic agent in the subject prior to administration of the sequence of acoustic pulses and / or the microbubble composition. In either embodiment, the drug delivery level can be measured using imaging techniques, 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, and optionally using a tracer, imaging agent, and / or contrast agent. In some embodiments, the protein that exhibits abnormal production, aggregation, and / or deposition is a Tau protein. In some embodiments, the therapeutic agent is an anti-tau antibody.

[0085] Notes on the disclosure Reference has been made to various embodiments herein. While the application has been described in terms of particular embodiments, and illustrative examples, it will be apparent to those skilled in the art that various modifications, including use of alternative materials and changes in form and details, can be made within the scope of the application. The description and drawings are to be regarded as illustrative in nature and not as restrictive.

[0086] It should be understood that, although terms “first,” “second,” etc. can 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.

[0087] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present application. As used herein, the singular forms “a,” “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. 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.

[0088] As used herein, the term “if’ can be construed to mean “when” or “once” or “in response to determining” or “in accordance with a determination” or “in response to detecting” that a stated condition or event is true, depending on the context. Similarly, the phrase “if it is determined (that a stated condition or event is true)” or “if (a stated condition or event is true)” or “when (a stated condition or event is true)” can 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 or event is true.

[0089] The foregoing description has been set forth for the purpose of explaining the embodiments. The above detailed description is not intended to be exhaustive or to limit the application to the precise form disclosed. While specific embodiments of, and examples for, the application are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the application, as those skilled in the relevant art will recognize. The embodiments were chosen and described in order to best explain the principles of the application and its practical application, to thereby enable others skilled in the art to best utilize the application, and various embodiments with appropriate modifications as are suited to the particular use contemplated.

Claims

1. A system for controllably altering tissue properties in the presence of a suspension of contrast agents, the system comprising: an ultrasound transducer for sonicating a target volume to alter tissue properties, the ultrasound transducer emitting a sequence of acoustic pulses to the target volume; at least one acoustic detector for detecting an ultrasonic reflection signal from the target volume after each acoustic pulse; and a controller configured to: (i) estimate activity of the contrast agents at the target volume based on a comparison between values of a signal parameter in the reflection signal after successive acoustic pulses; and (ii) control the ultrasound transducer based on the estimated activity to alter the tissue properties.

2. The system of claim 1, wherein the alteration of the tissue properties comprises: disrupting a tissue barrier to increase permeability of the barrier; neuromodulating a tissue neuron; activating a sonodynamic therapy drug; activating a contrast agent carrier to perform drug and / or gene delivery; thrombus dissolution; and / or inducing an ischemic effect.

3. The system of claim 1, wherein: the alteration of the tissue properties is disrupting a tissue barrier to increase permeability of the barrier, wherein the tissue barrier is a blood-brain barrier, a blood-retinal barrier, skin, a mucous membrane, a cell membrane, or a nuclear membrane; and the permeability is increased enough to allow a therapeutic agent to pass therethrough, wherein the therapeutic agent is selected to treat a tumor, a neurodegenerative disease, an enzyme 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 spectrum of the reflection signal; a first harmonic of the reflection signal; or an indication that signal amplitudes measured by the plurality of acoustic detectors are decreasing.

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

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

7. A method of controllably altering tissue properties in a target volume in the presence of contrast agents, the method comprising the steps of: applying a sequence of acoustic pulses to the target volume; detecting a reflection signal from the target volume after each acoustic pulse; computationally estimating activity of the contrast agents at the target volume based on a comparison between values of a signal parameter in the reflection signal after successive acoustic pulses; controlling the application of the acoustic pulses based on the estimated activity to alter the tissue properties.

8. The method of claim 7, wherein the alteration of the tissue properties is: disrupting a tissue barrier to increase permeability of the barrier; ​ ​ neuro-modulating a tissue neuron; activating a sonodynamic therapy drug; activating a contrast agent carrier for drug and / or gene delivery; thrombolytic; and / or inducing an ischemic effect.

9. The method of claim 7, wherein: the change to the tissue property is disruption of a tissue barrier to increase permeability of the barrier, wherein the tissue barrier is a blood-brain barrier, a blood-retinal barrier, skin, a mucous membrane, a cell membrane, or a nuclear membrane; and the permeability is increased enough to allow a therapeutic agent to pass therethrough, wherein the therapeutic agent is selected to treat a tumor, a neurodegenerative disease, an enzyme deficiency, or a CNS infection.

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

11. The method of claim 7, wherein: the contrast agent comprises gas-filled bubbles or phase-shift 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 a degree of cavitation, wherein the degree of cavitation is estimated based on a difference between average measured amplitudes of consecutive pulses.

12. The method of claim 7, wherein: an interval between consecutive acoustic pulses is no more than 3 ms; the signal parameter is phase or amplitude; and the comparison between values of the signal parameter in the reflected signal is consistent with a first harmonic of a transmission spectrum of the consecutive 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 a target volume and causing cavitation of a suspension of contrast agent therein; a plurality of spatially distributed acoustic detectors for detecting ultrasonic reflected signals from the target volume after each acoustic pulse; and a controller configured to receive data from the acoustic detectors characterizing the detected reflected signals and to estimate a level of cavitation at least at a plurality of voxel locations spanning the target volume in space based on at least (i) the received data, (ii) locations of the acoustic detectors, and (iii) an acoustic speed between the acoustic detectors and the target volume.

14. A method of treating a nervous system disease or disorder in a subject in need thereof, wherein the nervous system disease or disorder is characterized by a site in the brain having abnormal production, aggregation, and / or deposition of a protein or other biological molecule, and wherein a therapeutic agent and / or a contrast agent composition is to be, is being, or has been administered to the subject, the method comprising: applying a sequence of acoustic pulses to a target volume, wherein the target volume encompasses the site and an adjacent blood-brain barrier (BBB); detecting reflected signals from the target volume after each acoustic pulse; computationally estimating the activity of the contrast agent at the target volume based on a comparison between values of signal parameters in the reflected signal following the continuous acoustic pulse; and controlling the application of the acoustic pulses based on the estimated activity to alter tissue properties without producing a clinically significant effect on non-target tissue, thereby increasing delivery of the level of the therapeutic agent to the site.

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

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

17. The method of claim 14, wherein the protein that exhibits abnormal production, aggregation, and / or deposition is selected from the group consisting of beta amyloid (Ab), Tau protein, TDP-43, alpha-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 to a protein or other biological molecule that exhibits abnormal production, aggregation, and / or deposition; and the therapeutic agent is a non-specific scavenger antibody, an anti-beta amyloid 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, inflammation reduction, neurotransmitter receptor modulation, and / or oxidative stress reduction; and the therapeutic agent is donepezil, galantamine, rivastigmine, memantine, safinamide, carbidopa-levodopa, selegiline, rasagiline, safinamide, entacapone, benztropine, tolcapone, opicapone, pimavanserin (nuplazid), istradefylline, and / or amantadine.

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

25. The method of any one of claims 14-23, wherein the nervous system 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 lobe disease, multiple system atrophy, a quadruple repeat tauopathy, or a prion disease.

26. The method of any one of claims 14-23, wherein: the nervous system disease or disorder is a tumor, and the therapeutic agent is selected to treat the tumor; the nervous system disease or disorder is a central nervous system infection, and the therapeutic agent comprises an antibiotic, an antiviral drug, an antiretroviral drug, and / or an antifungal drug; or the nervous system disease or disorder is a congenital enzyme deficiency disease, and the therapeutic agent comprises enzyme replacement therapy.

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