Ultrasound-mediated nerve stimulation

Abstract

Various methods of stimulating neural activity in one or more target regions associated with one or more brain diseases or conditions include transmitting a first sequence of ultrasound pulses to the target regions; measuring a physiological parameter representative of neural activity at the target region generated by the ultrasound pulse; and adjusting, based at least in part on the measurement, a parameter value associated with at least one of the transducer elements in order to achieve a target of neural activity.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62 / 722,509, filed on August 24, 2018, and incorporates the entire contents of this application by reference. Technical Field

[0003] The present invention relates generally to systems and methods for neural stimulation and, more particularly, to neural stimulation using focused ultrasound. Background Art

[0004] Deep brain stimulation (DBS) is a neurosurgical procedure in which electrical pulses are sent to specific targets in the brain associated with a disease or condition. These signals regulate abnormal impulses or beneficially affect certain cells and chemicals within the brain, thereby alleviating neurological diseases or conditions (e.g., tremors, Parkinson's disease, dystonia, and obsessive-compulsive disorder). Typically, DBS involves the implantation of a neurostimulator with three medical components - an impulse generator (IPG) implanted in the patient's chest to control the electrical impulses, four electrodes located in one or two nuclei of the patient's brain to deliver the impulses thereto, and an extension that connects the electrodes to the IPG. However, implanting a neurostimulator requires surgery, which can be painful and creates a risk of infection. In addition, the neurostimulator may need to be replaced when the battery runs out or if the device malfunctions.

[0005] Furthermore, once implanted, the electrodes stimulate a maximum of two regions of the brain at fixed locations. However, it may be desirable to stimulate more regions associated with a disease / disorder to increase the efficacy of the treatment. Additionally, a patient may exhibit multiple diseases / disorders requiring brain stimulation in more than two regions for effective treatment. Therefore, there is a need for a non-invasive method that facilitates brain stimulation at multiple (e.g., more than two) target locations and is able to change the stimulated location as needed. Summary of the invention

[0006] The present invention provides systems and methods for non-invasively stimulating multiple (e.g., more than two) regions of the brain using transcranial focused ultrasound (i.e., sound waves having a frequency greater than about 20 kilohertz) applied by an ultrasound transducer array. The transducer array may include a plurality of transducer elements that are "tiled" to form a flat or curved surface; by driving different elements with different phases of a driver signal, the beams from the elements can be directed to the target region and converged centrally to the focus. The acoustic pressure at the focus, provided at a low intensity that does not cause a clinically significant temperature increase, can effectively modulate excitability and stimulate the ultrasound-treated region of the brain with high spatial selectivity. Therefore, multiple ultrasound treatments (e.g., one hour per week for four weeks) may affect the target region (e.g., modulation of electrical pulses, changes in certain cells or chemicals therein, etc.) in a manner comparable to that of conventional neurostimulators (e.g., IPG and implanted electrodes).

[0007] In various embodiments, the relative phase of the sound waves or pulses emitted from the transducer elements is dynamically adjusted to manipulate the focus of the acoustic beam. This allows ultrasound-mediated neural stimulation to be applied to multiple regions (e.g., multiple sub-regions within a target region or multiple target regions) if desired. In addition, the transducer elements can be grouped into multiple subarrays; the settings (e.g., relative phase, frequency, and / or amplitude) of the transducer elements in each subarray can be independently and separately determined to produce a focus at a desired brain region. Thus, the subarrays can produce multiple focuses to stimulate multiple regions in the brain substantially simultaneously or sequentially (with very short delays). The method can advantageously increase the stimulated volume of a brain region for a disease / disorder, thereby enhancing the efficacy of the treatment. Alternatively, the method can allow multiple brain regions associated with different diseases / disorders to be stimulated during the same ultrasound procedure, thereby enabling the simultaneous treatment of multiple diseases / disorders.

[0008] In various embodiments, during ultrasound-mediated neural stimulation, neural activity or other therapeutic effects of the ultrasound-treated brain region are monitored in real time using a measurement system (e.g., functional magnetic resonance imaging (fMRI) and / or electroencephalography (EEG)). The settings of the transducer elements can then be adjusted based on the real-time feedback to ensure that the target therapeutic goal (e.g., desired blood flow changes) is achieved.

[0009] Thus, various embodiments provide non-invasive, focused ultrasound-mediated neural stimulation that allows multiple (e.g., more than two) target areas to be stimulated substantially simultaneously or sequentially for treatment. In addition, effective and efficient treatment can be achieved by monitoring neural activity in the target area during application of ultrasound and providing real-time feedback for ultrasound treatment adjustment based thereon.

[0010] Thus, in one aspect, the present invention relates to a system for stimulating neural activity in one or more target areas associated with one or more brain diseases or conditions using focused ultrasound. In various embodiments, the system includes an ultrasonic transducer having a plurality of transducer elements; and a controller configured to (a) send a first sequence of ultrasonic pulses / bursts to the target area; (b) measure physiological parameters representing neural activity at the target area generated by the ultrasonic pulses / bursts (e.g., changes in blood flow at the target area or changes in chemicals in the tissue); and (c) adjust a first parameter value associated with one or more transducer elements (e.g., frequency, phase, amplitude, and / or transducer activation duration) based at least in part on the measurements to achieve a target objective of the neural activity. In one embodiment, the system further includes a monitoring system (e.g., fMRI, ASL MRI, EEG, and / or fNIRS) for measuring physiological parameters at the target area.

[0011] In addition, the controller is further configured to cause the sequence of ultrasound pulses / pulse trains to produce a focus at a target area; measure a temperature at the focus; and adjust a second parameter value (e.g., frequency, phase, amplitude, and / or activation duration) associated with the transducer element based at least in part on the measured temperature to avoid damaging the target area. In one embodiment, the controller is further configured to manipulate the focus at multiple sub-areas of the target area. In another embodiment, the controller is further configured to sequentially control the focus at multiple target areas, each target area being associated with a brain disease or condition, and different target areas being associated with different brain diseases or conditions.

[0012] In some embodiments, the ultrasound transducer comprises a plurality of subarrays, each subarray having a plurality of transducer elements. The controller may be further configured to cause the first and second different subarrays of the transducer to respectively transmit a plurality of ultrasound pulse sequences to first and second different subregions of the target region sequentially or substantially simultaneously. Additionally or alternatively, the controller may be further configured to cause the first and second different subarrays of the transducer to respectively transmit a plurality of ultrasound pulse sequences to first and second different target regions sequentially or substantially simultaneously; the first and second target regions are associated with different brain diseases or conditions. In some embodiments, the controller is further configured to compare the measured physiological parameters with the target objective; and repeat steps (a)-(c) until the target objective is met.

[0013] In another aspect, the present invention relates to a method for stimulating neural activity in one or more target areas associated with one or more brain diseases or conditions. In various embodiments, the method includes transmitting a first sequence of ultrasonic pulses / bursts from an ultrasonic transducer having a plurality of transducer elements to a target area; measuring a physiological parameter representing neural activity at the target area generated by the ultrasonic pulses / bursts (e.g., a change in blood flow or a change in a chemical substance in the tissue at the target area) and adjusting a parameter value associated with one or more transducer elements (e.g., frequency, phase, amplitude, and / or transducer activation duration) based at least in part on the measurement to achieve a target goal of neural activity. In one embodiment, the method further includes causing the sequence of ultrasonic pulses / bursts to generate a focus at the target area; measuring a temperature at the focus; and adjusting a second parameter value associated with the transducer element (e.g., frequency, phase, amplitude, and / or activation duration) based at least in part on the measured temperature to avoid damaging the target area.

[0014] In various embodiments, the ultrasound transducer comprises a plurality of subarrays, each subarray having a plurality of transducer elements; the method further comprises causing first and second different subarrays of the transducer to transmit a plurality of ultrasound pulse sequences to first and second different subregions of the target region, respectively, sequentially or substantially simultaneously. Additionally or alternatively, the method further comprises causing first and second different subarrays of the transducer to transmit a plurality of ultrasound pulse sequences to first and second different target regions, respectively, sequentially or substantially simultaneously; the first and second target regions are associated with different brain diseases or conditions.

[0015] As used herein, the term "clinically significant" means that, for example, before inducing damage to the tissue, the clinician believes that the undesirable (and sometimes undesirable) effect on the tissue is significant. In addition, the terms "approximately", "about", "sufficiently" and "substantially" refer to ±10%, in some embodiments ±5%. Throughout the specification, references to "an example", "an example", "an embodiment" or "an embodiment" refer to references to specific features, structures or characteristics described in conjunction with the example included in at least one example of the technical solution of the present invention. Therefore, the phrases "in an example", "in an example", "an embodiment" or "an embodiment" appearing throughout the specification do not necessarily all refer to the same example. In addition, specific features, structures, routines, steps or characteristics can be combined in any suitable manner in one or more examples of the technical solution of the present invention. The titles provided herein are for convenience only and are not intended to limit or interpret the scope or meaning of the claimed technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In the accompanying drawings, the same reference numerals in different views generally represent the same parts. Moreover, the drawings are not necessarily drawn to scale, but the emphasis is generally placed on illustrating the principles of the invention. In the following description, various embodiments of the invention are described with reference to the following drawings, in which:

[0017] Figure 1A schematically illustrates an exemplary ultrasound system according to various embodiments of the present invention;

[0018] Figure 1B shows an exemplary configuration of transducer elements for producing multiple focal points at multiple target areas according to various embodiments;

[0019] Figure 1C shows an exemplary configuration of transducer elements for producing multiple focal points at multiple sub-regions within a target region according to various embodiments;

[0020] Figure 2 schematically illustrates an exemplary MRI system according to various embodiments of the present invention;

[0021] Figure 3A shows one or more brain regions stimulated by ultrasound waves / pulses in order to treat one or more brain diseases / disorders according to various embodiments;

[0022] Figure 3B shows application of ultrasound pulses / waves to a target region and measurement of tissue in the target region in response to ultrasound application according to various embodiments;

[0023] Figure 4 Flowchart showing an exemplary method of stimulating neural activity in one or more brain regions associated with one or more diseases / disorders, according to various embodiments. DETAILED DESCRIPTION

[0024] Figure 1A An exemplary ultrasound system 100 is shown for generating and transmitting a focused beam of acoustic energy to a target region 101 in a patient's brain to stimulate neural activity therein and thereby treat a neurological disease or condition. In various embodiments, the system 100 includes a phased array 102 of transducer elements 104, a beamformer 106 that drives the phased array 102, a controller 108 that communicates with the beamformer 106, and a frequency generator 110 that provides input electronic signals to the beamformer 106.

[0025] The array 102 can have a curved (e.g., spherical or parabolic) shape suitable for surrounding the patient's head, or can include one or more flat or other shaped portions. Its size can vary from millimeters to tens of centimeters. The transducer elements 104 of the array 102 can be made of any material, such as piezoelectric ceramics, piezoelectric composites, or generally any technology capable of converting electrical energy into acoustic energy, and can be mounted in silicone rubber or other materials (including air) suitable for mechanical connection between damping elements 104. To ensure maximum power transmission to the transducer elements 104, the elements 104 can be configured for electrical resonance of 50Ω, matching the input connector impedance.

[0026] The transducer array 102 is coupled to a beamformer 106, which drives the individual transducer elements 104 so that they collectively produce a focused ultrasound beam or field. For n transducer elements, the beamformer 106 may include n driver circuits, each driver circuit including or consisting of an amplifier 118 and a phase / time delay circuit 120; each driver circuit drives one of the transducer elements 104. The beamformer 106 receives a radio frequency (RF) input signal, typically in the range of 0.1 MHz to 10 MHz, from a frequency generator 110, which may be, for example, a DS345 generator available from Stanford Research Systems. For the n amplifiers 118 and delay circuits 120 of the beamformer 106, the input signal may be split into n channels. In some embodiments, the frequency generator 110 is integrated with the beamformer 106. The RF 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.

[0027] The amplification or attenuation factor α1-α applied by the beamformer 106 n and phase shift a1-a n For transmitting and focusing ultrasound energy onto a target area 101, and causing wave distortion to be induced in tissue located between the transducer element 104 and the target area 101. For example, a method for compensating for beam aberrations caused by intervening tissue and producing a focus with desired characteristics at a desired location is provided in International Application PCT / IB2017 / 000990 filed on July 19, 2017, which is incorporated herein by reference.

[0028] The amplification factor and phase shift are calculated by the controller 108, and the calculation function can be provided by software, hardware, firmware, hard wiring or any combination of the above. For example, the controller 108 can utilize a general or special digital data processor programmed with software in a conventional manner, and without excessive experimentation, in order to determine the phase shift and amplification factor required to obtain the desired focus or any other desired spatial acoustic field pattern at the target area 101. In some embodiments, the calculation is based on detailed information about the characteristics (e.g., structure, thickness, density, etc.) of the tissue located between the transducer elements 104 and their effects on the propagation of acoustic energy. Such information can be obtained from the imager 122. The imager 122 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 ultrasonic scanning device. The image acquisition can be three-dimensional (3D), or the imager 122 can provide a set of two-dimensional (2D) images suitable for reconstructing a three-dimensional image of the target area and / or its surrounding area. The imager 122 may be operated using the same controller 108 that facilitates operation of the transducer; alternatively, the imager 122 may be separately controlled by a separate controller that is in communication with the controller 108 .

[0029] In some embodiments, the transducer array 102 can be configured to mechanically or electrically generate an ultrasonic manipulation beam to sequentially stimulate multiple target areas or multiple sub-areas within a target area. This can advantageously increase the stimulated volume of the area for a disease / disorder, thereby enhancing its therapeutic efficacy. In addition or alternatively, the method can stimulate various brain areas associated with different diseases / disorders, thereby providing treatment for multiple diseases / disorders with the same procedure. In one embodiment, the transducer element 104 is mechanically manipulated, that is, physically moved relative to the target area. When the transducer array 102 is substantially larger than the skull (e.g., about 30 cm or more in diameter), mechanical manipulation is particularly suitable to provide sufficient freedom of movement. Alternatively, the beam can be electronically manipulated by adjusting the relative phase of the sound waves / pulses emitted from the transducer elements 104. The degree of control provided by such electronic manipulation is inversely proportional to the size of each transducer element 104. For example, it is generally desirable to make the size of the transducer element 104 on the order of the wavelength of the acoustic energy emitted by the array, and preferably as small as half the wavelength, in order to effectively manipulate the ultrasound beam. Thus, for acoustic energy having a wavelength on the order of two millimeters (2 mm), as is commonly used in focused ultrasound systems, effective steering would require transducer elements 104 of similar size, i.e., approximately 2 mm or less in cross-section. Electronic steering is preferred because no physical movement of the transducer array 102 is required and steering occurs rapidly.

[0030] In some embodiments, the transducer array 102 is configured to generate multiple focal points substantially simultaneously. Figure 1B , the controller 108 can dynamically group the transducer elements 104 into a plurality of sub-arrays 150-154; each sub-array includes, or is composed of, a one-dimensional or two-dimensional array (i.e., a row or matrix) of transducer elements 104. The transducer sub-arrays 150-154 can be individually controllable, i.e., each of them can emit ultrasound waves at a frequency, amplitude, and / or phase that is independent of the frequency, amplitude, and / or phase of the other sub-arrays. For example, each sub-array can produce a focus on one of the target regions 156-160 by adjusting the relative phase of the elements 104. Thus, multiple target regions 156-160 can be stimulated subsequently or substantially simultaneously by focused ultrasound. Similarly, referring to Figure 1C , each subarray can be independently controlled to produce a focus on one of the subregions 162-166 within a single target region. The grouping of the subarrays 150-154 can be dynamically determined by one or more targeting criteria that specify the geometric relationship (e.g., steering angle and / or aiming line) between the elements 104 and / or between the elements 104 and the subregions / target regions. The targeting criteria can also take into account the physical location of the subregions / target regions, the number of subregions / target regions, the anatomical features of the tissue intervening the subregions / target regions, and the elements 104, etc. It should be noted that the configuration of the transducer subarrays provided herein is for illustration only, and the present invention is not limited to such configurations. One of ordinary skill in the art will appreciate that many variations are possible and are therefore within the scope of the present invention.

[0031] In order to perform ultrasound-mediated neural stimulation, it is necessary to accurately determine the location of the target area prior to the ultrasound procedure. Therefore, in various embodiments, the imager 122 is first activated to acquire an image of the target area and, in some cases, to acquire an image of the surrounding non-target area. For example, the tissue volume can be represented as a set of 3D voxels (i.e., volume pixels) based on a 3D image or a series of 2D image slices, and can include a target area and / or a non-target area. Figure 2An exemplary imager, namely an MRI device 202, is shown. The device 202 may include a cylindrical electromagnet 204 that generates a necessary static magnetic field within a bore 206 of the electromagnet 204. During a medical procedure, a patient is positioned within the bore 206 on a movable support bracket 208. A target region 210 within the patient's body (e.g., the patient's head) may be positioned within an imaging region 212, wherein the electromagnet 204 generates a substantially uniform field. A set of cylindrical magnetic field gradient coils 213 may also be disposed within the bore 206 and around the patient. The gradient coils 213 generate magnetic field gradients of predetermined amplitudes at predetermined times and in three mutually orthogonal directions. Using the field gradients, different spatial locations may be associated with different precession frequencies, thereby providing the MR image with its spatial resolution. An RF transmitter coil 214 surrounding the imaging region 212 transmits RF pulses into the imaging region 212, causing the patient's tissue to emit a magnetic resonance (MR) response signal. The raw MR response signals are sensed by the RF coil 214 and passed to the MR controller 216, which then computes an MR image that can be displayed to a user. Alternatively, separate MR transmitter and receiver coils may be used. Images acquired using the MRI device 202 can provide radiologists and physicians with visual contrast between different tissues and detailed internal views of the patient's anatomical structures that cannot be visualized with conventional X-ray technology. The acquired images are then analyzed by the controller executing conventional image analysis software to determine the location and / or anatomical features (e.g., type, properties, structure, thickness, density, etc.) of target / non-target tissue.

[0032] The MRI controller 216 can control the pulse sequence, i.e., the relative timing and intensity of the magnetic field gradient and RF excitation pulses and the response detection period. The MR response signals are amplified, conditioned, and digitized into raw data using a conventional image processing system, and further converted into an image data array by methods known to those of ordinary skill in the art. Based on the image data, the target area to be stimulated is identified. The image processing system can be part of the MRI controller 216, or can be a separate device (e.g., a general-purpose computer containing image processing software) that communicates with the MRI controller 216.

[0033] In some embodiments, the focused ultrasound transducer system 100 is disposed within the bore 206 of the MRI device 202. In addition, the ultrasound system 100 may include MR tracking coils or other markers for determining the position and orientation of the transducer relative to the target region in the MR image. Based on the calculation of the required transducer element phase and amplitude, the transducer array is driven to focus the ultrasound at the target.

[0034] In various embodiments, the MRI device 202 is used in conjunction with a blood oxygen level dependent (BOLD) contrast agent to detect changes in blood flow at target / non-target areas in real time during ultrasound-mediated stimulation (this technique is often referred to as "functional magnetic resonance imaging" or "fMRI"). Typically, when a target area is stimulated, neural activity therein increases, which then causes additional blood to be oxygenated, resulting in changes in blood flow. Changes in blood flow can cause changes in the BOLD signal that can be detected by fMRI. Thus, fMRI can provide feedback on the effects of stimulation on target / non-target areas when ultrasound is applied.

[0035] For example, refer to Figure 3A In order to treat Parkinson's disease, focused ultrasound can be applied to one or more specific target areas (e.g., the subthalamic nucleus 302 and / or the globus pallidus internalis 304). fMRI can be activated to obtain images of areas where blood flow increases during the ultrasound procedure. The images can be used to verify that neural activity in the target area has been sufficiently stimulated to cause changes in blood flow (e.g., more than 10%), while neural activity in non-target areas remains sufficiently unchanged (e.g., less than 5%) to avoid adverse effects. In addition, the BOLD signal can be analyzed to determine whether the intensity of the stimulation reaches the desired goal. For example, before applying focused ultrasound, the change in the BOLD signal at the target area produced by deep brain stimulation that successfully treats Parkinson's disease can first be obtained from, for example, known literature; and the BOLD signal change can be stored in a memory and set as the target goal of the ultrasound treatment. Reference Figure 3B , during the application of a sequence of ultrasound pulses / waves 302 to a target, a BOLD signal 304 at the target can be measured in real time. As shown, during the sonication, the amplitude of the BOLD signal 306 is greater than the amplitude of the BOLD signal 308 measured between two sonication pulses / waves / pulse trains. Therefore, in one embodiment, the amplitude of the BOLD signal 308 between two pulses / waves / pulse trains is first averaged to obtain a baseline level; then, the amplitude of the BOLD signal 306 during the sonication is compared to the baseline level to determine the change 310 therebetween. The measured BOLD change 310 can then be compared to a target target, such as determined from the literature as described above. If the measured BOLD change is less than the target target, the amplitude, frequency, and / or duration of the sonication in subsequent pulses may be increased. Alternatively, the ultrasound focus can be directed to different sub-regions of the target (e.g., in some embodiments, during continuous manipulation between different sub-regions of the target); this can effectively increase the change in the BOLD signal at the target region, thereby achieving the desired goal.

[0036] If the BOLD change measured at the target region and / or non-target region is greater than the target target, the amplitude and / or duration of the ultrasound treatment in subsequent pulses can be maintained unchanged, or in some embodiments, reduced to ensure safety. Of course, it should be emphasized that this exemplary use of fMRI to adjust the ultrasound amplitude and / or application duration is for illustrative purposes only, and any signal representing a physiological condition associated with neural activity can be used as feedback to adjust any ultrasound parameter (e.g., amplitude, activation and deactivation, frequency, steering angle, etc.) applicable to the application.

[0037] In some embodiments, the temperature of the target area during ultrasound treatment is monitored in real time using, for example, an MRI device 202 to avoid damage to it. Based on the measured temperature, the relative phase and / or amplitude of the ultrasound waves / pulses emitted from the element 104 can be adjusted so that the temperature rise caused by the acoustic energy at the focus does not exceed a predetermined threshold. Among the various methods that can be used for nuclear magnetic resonance temperature measurement, the proton resonance frequency (PRF) shift method is usually the preferred method because it has excellent linearity with respect to temperature changes, is almost unaffected by tissue type, and the acquisition of temperature maps has high spatial and temporal resolution. The PRF shift method utilizes the phenomenon that the MR resonance frequency of protons in water molecules changes linearly with temperature. Since the frequency change with temperature is very small, only -0.01ppm / ℃ in bulk water and about -0.0096 to -0.013ppm / ℃ in tissue, the PRF shift is usually detected using a phase-sensitive imaging method that performs imaging twice: first, a baseline PRF phase image is acquired before the temperature change, and then a second phase image is acquired after or during the temperature change, thereby capturing small phase changes proportional to the temperature change. A temperature map can then be calculated from the MR images by determining the phase difference between the baseline image and the processed image on a voxel-by-voxel basis and converting the phase difference into a temperature difference based on the temperature dependence of the PRF, taking into account imaging parameters such as static magnetic field strength (typically 1.5T or 3T) and echo time (TE) (e.g., gradient echo). Various alternative or advanced methods can be used to compensate for patient motion, magnetic field drift, and other factors that affect the accuracy of PRF-based temperature measurements; suitable methods known to those skilled in the art include, for example, multiple baseline and reference-free thermometry methods, and can be implemented without undue experimentation.

[0038] Additionally or alternatively, arterial spin labeling (ASL) MRI using magnetically labeled arterial blood water protons as endogenous tracers can be implemented to directly measure blood flow changes. Arterial blood water can be magnetically labeled by applying RF pulses that reverse or saturate the water protons in the flowing blood supplying the target / non-target area of ​​imaging. After a period of delay, the labeled blood flows into the imaging area; the reverse spins flowing into the labeled blood water can change the total magnetization of the tissue, thereby changing the MR signal and image intensity. During this time, MR signals and images (called labeling images) can be acquired. By subtracting the labeling image from the control image (in which no arterial blood is labeled), the amount of arterial blood delivered to each voxel in the target / non-target area during the elapsed time can be determined. Therefore, this method allows ASL (arterial spin labeling) to qualitatively measure blood flow changes caused by ultrasound-mediated stimulation.

[0039] Similar to the measurement of the BOLD signal described above, the amplitude of the ASL signal at the target area corresponds to the effective treatment produced by conventional deep brain stimulation, which can be acquired prior to the ultrasound procedure; this amplitude is set as the target target. During the ultrasound treatment, the ASL signal at the target area can be measured in real time and compared to the target target. Similarly, if the amplitude of the measured ASL signal is less than the target target, the amplitude and / or duration of the ultrasound treatment in the next pulse can be increased. Additionally or alternatively, the ultrasound focus can be directed to different sub-areas of the target (for example, in some embodiments, as described above, during manipulation between different sub-areas of the target) to enhance neural activity and thereby enhance the ASL signal. If the measured ASL signal at the target area is greater than the target target, the amplitude and / or duration of the ultrasound treatment can remain unchanged, or in some embodiments can be reduced to ensure safety.

[0040] fMRI and / or ASL can be used in conjunction with other brain physiological measures. For example, again referring to Figure 2 , multiple electrodes 216 can be placed along the patient's scalp to monitor the brain's electrical activity during ultrasound-mediated neurostimulation (this technology is often referred to as "electroencephalography" or "EEG"). Alternatively, functional near-infrared spectroscopy (fNIRS) can be used. Similarly, EEG signals, fNIRS signals, alone or in combination with fMRI and / or ASL, can be compared to target targets determined using other methods (e.g., conventional deep brain stimulation); and on this basis, ultrasound parameters (e.g., amplitude, application duration, phase, frequency, steering angle, etc.) can be adjusted to ensure therapeutic effectiveness and safety. In some embodiments, as described above, these feedback signals are used to determine whether to stimulate multiple sub-regions of the target and / or multiple target regions sequentially or substantially simultaneously.

[0041] Typically, ultrasound-mediated neurostimulation can effectively treat a disease / condition after a few sessions (e.g., one hour per week for four weeks) (although in some embodiments, more sonication sessions may be required); thus, the method advantageously avoids the invasive implantation of a neurostimulator required by traditional deep brain stimulation methods. In addition, by adjusting the relative phase of the sound waves / pulses emitted from the transducer elements, the focused ultrasound beam can be dynamically steered to various locations in one or more target areas. This can improve the efficacy of treatment of a disease / condition or enable multiple diseases / conditions to be treated in the same procedure. Further, by grouping the transducer elements into multiple sub-arrays, multiple sub-regions of the target and / or multiple target areas can be stimulated substantially simultaneously or sequentially. Likewise, the method can advantageously improve the efficacy of treatment and / or allow different diseases / conditions to be treated in the same ultrasound procedure.

[0042] Figure 4 4 is a flowchart showing a method for stimulating neural activity in one or more brain regions associated with one or more diseases / disorders according to various embodiments. In a first step 402, information (such as location, anatomical features, and / or material features) of a target region and / or non-target region for neural stimulation is first acquired using, for example, an imager (e.g., MRI) 122. In a second step 404, based on the target / non-target information acquired in step 402, ultrasound parameters (e.g., amplitude, phase, frequency, steering angle, application duration, etc.) are determined so as to generate one or more focuses at one or more sub-regions of the target region or at one or more target regions. Multiple focuses may be generated sequentially or substantially simultaneously. The acoustic pressure at the target region may cause stimulation without causing damage thereto. For example, the temperature increase caused by ultrasound may drop below a threshold corresponding to clinical significance. In a third step 406, an ultrasound transducer element is activated based on the parameters determined in step 404. In a fourth step 408, a measurement system (e.g., fMRI, EGG, ASL MRI, fNIRS) is activated to monitor the effects of stimulation (e.g., blood flow changes) at the target / non-target region during the ultrasound procedure. In a fifth step 410, based on the measurement results, the ultrasound parameters are adjusted if necessary. For example, the measurement results can be compared with the desired target target determined using other methods (e.g., conventional deep brain stimulation). If the measurement result is less than the target target, the amplitude and / or duration of the ultrasound treatment in the next ultrasound pulse can be increased. Additionally or alternatively, the ultrasound focus can be directed to different sub-areas of the target to enhance neural activity. If the measurement results at the target area and / or non-target area exceed the target target, the amplitude and / or duration of the ultrasound treatment can remain unchanged, or in some embodiments can be reduced to ensure safety. Steps 406-410 can be repeated until the desired target target is reached.

[0043] Typically, functionality for stimulating neural activity in one or more sub-regions or one or more target regions within a target region associated with one or more brain diseases / disorders may be built into one or more modules, implemented in hardware, software, or a combination of both, whether integrated within a controller of the imager 122 and / or administration system 124 of the ultrasound system 100, or provided by a separate external controller or other computing entity. Such functionality may include, for example, analyzing imaging data of target and / or non-target areas acquired using imager 122; determining the location and / or anatomical features (e.g., type, properties, structure, thickness, density, etc.) of target / non-target tissue; causing an ultrasonic transducer to transmit a series of waves / pulses / pulse trains to the target area; measuring temperature and / or physiological parameters representing neural activity at the target area caused by the ultrasonic pulses / pulse trains; adjusting parameter values ​​associated with transducer elements based at least in part on the measurements; manipulating focus at multiple sub-areas within the target area or at multiple target areas; dynamically grouping transducer elements into multiple sub-arrays; causing different sub-arrays to sequentially or substantially simultaneously transmit multiple ultrasonic pulse sequences to different sub-areas or different target areas of the target area; comparing the measured physiological parameters with desired target objectives; and / or iteratively performing temperature and / or physiological parameter measurements and adjustments to ultrasonic parameter values ​​until the above-mentioned target objectives are met.

[0044] In addition, the values ​​of the ultrasound parameters used to drive the transducer elements 104 in the transducer array 102 or various sub-arrays as described above can be determined in the ultrasound controller 108, which can be separate from the control device in the imager 122 or combined with the control device in the imager 122 into an integrated system control device. The controller 108 may include 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, the programs may be written in any of a number of high-level languages, such as PYTHON, FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scripting languages, and / or HTML. In addition, the software may be implemented in an assembly language directed to a microprocessor resident on a target computer; for example, if the software is configured to run on an IBM PC or PC clone, it may be implemented in Intel 80x86 assembly language. The software may be implemented on an article of manufacture, including but not limited to a floppy disk, a flash disk, a hard disk, an optical disk, a tape, a PROM, an EPROM, an EEPROM, a field programmable gate array, or a CD-ROM. Embodiments using hardware circuitry may be implemented using, for example, one or more FPGA, CPLD, or ASIC processors.

[0045] In addition, the term "controller" used herein broadly includes all necessary hardware components and / or software modules for performing any functions described above; the controller may include multiple hardware components and / or software modules, and the functions may be distributed among different components and / or modules.

[0046] The terms and expressions used herein are used as descriptive rather than limiting terms and expressions, and when using these terms and expressions, it is not intended to exclude any equivalents of the features shown and described or parts thereof. In addition, certain embodiments of the present invention have been described, and it is obvious to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the present invention. Therefore, the described embodiments should be considered to be illustrative of the present invention in all aspects only and not limiting.

Claims

1. A system for stimulating neural activity in at least one target region associated with at least one brain disease or disorder using focused ultrasound, the system comprising: an ultrasonic transducer comprising a plurality of transducer elements; as well as The controller is configured as: (a) sending a first sequence of ultrasound pulses to a target area; (b) measuring changes in blood flow indicative of neural activity at the target area produced by the ultrasound pulses; and (c) based at least in part on the measurements, adjusting a frequency, phase, amplitude, or activation duration associated with at least one of the transducer elements to induce a change in blood flow at the target area that corresponds to a target goal for stimulation of neural activity.

2. The system of claim 1, further comprising a monitoring system for measuring physiological parameters at the target area.

3. The system according to claim 2, wherein: The monitoring system includes at least one of fMRI, ASL MRI, EEG, or fNIRS.

4. The system according to claim 1, wherein: The controller is further configured to: Focusing the sequence of ultrasound pulses at a target area; measuring the temperature at the focus; and Based at least in part on the measured temperature, a second parameter value associated with at least one of the transducer elements is adjusted to avoid damage to the target area.

5. The system according to claim 4, wherein: The controller is further configured to manipulate focus at a plurality of sub-areas of the target area.

6. The system according to claim 4, wherein: The controller is further configured to sequentially manipulate focus at a plurality of target regions, each target region being associated with a brain disease or condition, different target regions being associated with different brain diseases or conditions.

7. The system according to claim 4, wherein: The second parameter value includes at least one of frequency, phase, amplitude, or activation duration.

8. The system according to claim 1, wherein: The ultrasound transducer includes a plurality of sub-arrays, each sub-array including a plurality of transducer elements.

9. The system according to claim 8, wherein: The controller is further configured to cause first and second different sub-arrays of transducers to sequentially transmit a plurality of ultrasound pulse sequences to first and second different sub-regions of the target region, respectively.

10. The system according to claim 8, wherein: The controller is further configured to cause first and second different sub-arrays of transducers to transmit the plurality of ultrasound pulse sequences substantially simultaneously to first and second different sub-regions of the target region, respectively.

11. The system according to claim 8, wherein: The controller is further configured to cause first and second different sub-arrays of the transducer to sequentially transmit a plurality of ultrasound pulse sequences to first and second different target regions, respectively, wherein the first and second target regions are associated with different brain diseases or disorders.

12. The system according to claim 8, wherein: The controller is further configured to cause first and second different subarrays of the transducer to transmit the plurality of ultrasound pulse sequences substantially simultaneously to first and second different target regions, respectively, wherein the first and second target regions are associated with different brain diseases or disorders.

13. The system of claim 1, wherein: The controller is further configured to: comparing the measured physiological parameters to target values; and Repeat steps (a)-(c) until the target is reached.

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