System and method for low intensity focused ultrasound brain stimulation

Abstract

A system and method for treating a patient with stroke-related deficiencies. The treatment includes modulating discrete cortical or deep sub-cortical regions of the patient's brain. The modulation is provided by low-intensity focused ultrasound (LIFU) as it can be configured to be selective, targeted, reversible, and non-invasive with millimeter precision across the entire human brain.

Description

Attorney Docket No.028193-0058-WO01 SYSTEM AND METHOD FOR LOW INTENSITY FOCUSED ULTRASOUND BRAIN STIMULATION CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a non-provisional of and claims the benefit of U.S. Provisional Patent Application No. 63 / 681,516, filed on August 9, 2024, the entire contents of which are incorporated herein by reference. BACKGROUND

[0002] There are 800,000 new strokes per year in the United States and 12 million worldwide, and stroke remains a leading cause of adult disability.

[0003] Among many post-stroke devastating complications, post-stroke motor impairment (i.e., arm and / or leg weakness) is the most common complication after stroke affecting nearly 40% of stroke patients or 35 million stroke survivors with this complication worldwide in total), and it negatively impacts the quality of life of stroke survivors. Effective evidence-based treatment for post-stroke motor impairment is still lacking. Intensive therapy, such as constraint- induced movement therapy has certain evidence in benefiting a subgroup of stroke patients with preserved distal hand movement. When it comes to neuromodulation, only the invasive vagus nerve stimulation device is used for treating moderate-to-severe upper extremity motor deficits in chronic ischemic stroke survivors, but it requires surgery and is costly.

[0004] Central post-stroke pain (CPSP) is another disabling complication that is under- diagnosed and difficult to treat. CPSP is referred to as chronic neuropathic pain caused by stroke lesions of the somatosensory pathway, as defined by the International Association for the Study of Pain. Overall, about 8% of stroke patients will develop CPSP, which translates to 65,000 new patients in the U.S. or 1.2 million worldwide per year. The primary symptoms are various types of spontaneous or evoked pain (dysesthesia, hyperesthesia, allodynia), or decreased or loss of sensation, usually in the face, arm, and / or leg, contralateral to the side of the brain with stroke. It can be worsened by exposure to heat / cold, or by emotional distress. It can interfere with rehabilitation therapy, impair sleep, affect mood, and negatively impact quality of life.Attorney Docket No.028193-0058-WO01

[0005] CPSP is typically associated with lesions at various anatomical locations disrupting function and structural Spinothalamocortical tract (STCT), commonly seen in thalamic stroke. A classic stroke affecting the ventroposterior lateral (VPL) nucleus in the thalamus can lead to CPSP; however, the resulting functional changes also occur in the medial emotional pathway involving the amygdala, anterior cingulate cortex, and insular cortex (see FIG. 1). Many drugs have been attempted to treat CPSP without good evidence and effect. None of them received approval from the FDA for this indication. Alternative options for treating CPSP have been considered. For example, non-invasive neuro-modulatory approaches, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), can induce transient plastic changes in the human cortex and have significantly contributed to understanding of the human brain for several clinical applications. However, these technologies have critical limitations, including poor spatial resolution and an inability to stimulate deep neural structures.

[0006] Accordingly, there is an unmet medical need for a neuromodulation system and method that can non-invasively modulate discrete cortical or deep sub-cortical regions to treat stroke-related deficiencies, such as post-stroke motor impairment and central post-stroke pain. SUMMARY

[0007] In some embodiments, the present disclosure provides a system and method for treating a patient with either post-stroke motor impairment or CPSP. In some aspects, the treatment includes modulating discrete cortical or deep sub-cortical regions of the patient’s brain. In some aspects, the modulation is provided by low-intensity focused ultrasound (LIFU) as it can be configured to be selective, targeted, reversible, and non-invasive with millimeter precision essentially across the entire human brain.

[0008] In one embodiment, the disclosure provides a method of delivering low-intensity ultrasound stimulation to a patient. The method comprises applying a head-worn device to the patient, coupling an ultrasound transducer to the head-worn device, applying the ultrasound transducer to a scalp of the patient, moving the ultrasound transducer relative to the head-worn device to align delivery of a low intensity focused ultrasound (LIFU) beam emitted from the ultrasound transducer to a target area within a brain of the patient, and delivering the LIFU beamAttorney Docket No.028193-0058-WO01 to the target area to modulate the target area, wherein parameters of the LIFU beam are configured to provide a therapeutic effect of alleviating stroke-related deficiencies of the patient.

[0009] In another embodiment, the present disclosure provides a system for treating post- stroke pain in a patient. The system comprises a head-worn device configured to be fitted to a scalp of the patient, an ultrasound transducer coupled to the helmet, the ultrasound transducer configured to deliver a low intensity focused ultrasound (LIFU) beam to a target area in the patient, a passive cavitation detector coupled to the ultrasound transducer, the passive cavitation detector configured to monitor cavitation activity caused by delivery of the LIFU beam, a temperature sensor coupled to the ultrasound transducer, the temperature sensor configured to monitor temperature between the scalp of the patient and the ultrasound transducer, wherein the ultrasound transducer is adjustable relative to the head-worn device to align delivery of a low intensity focused ultrasound (LIFU) beam emitted from the ultrasound transducer to a target area within a brain of the patient, wherein the ultrasound transducer is adjusted based on position data provided by a tracking sensor to a navigation system and displayed to a user.

[0010] Other aspects of the present disclosure will become apparent by consideration of the detailed description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG.1 is a schematic illustrating the pathophysiological mechanism of CPSP as presently understood.

[0012] FIG.2 is a schematic illustrating a system for treating stroke-related deficiencies according to an embodiment of the present disclosure.

[0013] FIG.3 is a block diagram of the system for treating stroke-related deficiencies according to an embodiment of the present disclosure.

[0014] FIG.4 is a flow chart of a method for treating stroke-related deficiencies according to an embodiment of the present disclosure.Attorney Docket No.028193-0058-WO01

[0015] FIG.5 illustrates experimental procedures; A) study visit activities; B) concurrent neuronavigated-LIFUS and MSL setup during the LIFUS administration; C) system component schematic of the neuronavigated-LIFUS; D) concurrent MSL-LIFUS protocol.

[0016] FIG.6 illustrates topical apparent diffusion coefficient variations; A) sample mean diffusivity map (Participant 11) overlaid with region of interest outline (red); B) individual (white circle) and within-intensity mean (gray circles connected with line) variation of apparent diffusion coefficient against intensity. m2 / ms: square micrometers per millisecond; W / cm2: Watts per square centimeter.

[0017] FIG.7 illustrates behavioral and neurophysiological outcomes; A) percentage MSL improvements against intensities. Positive indicates faster response time.67% (6 / 9) of participants in HIGH improved 20% on the MSL, whereas no participant (0 / 9) in LOW did (p=0.009). Similarly, percentage MSL improvements in LOW are significantly different from the HIGH, p=0.014; B) percentage MEP changes against intensities. Positive indicates greater corticospinal excitability. 67% (6 / 9) in HIGH had 20% enhanced corticospinal excitability as compared to 44% (4 / 9) in LOW (p=0.67). Similarly, percentage MEP changes in LOW are not significantly different from HIGH, p = 0.53; A and B) Horizontal dashed lines identify a 20% change in MSL / MEP amplitude, both the likely minimal clinically meaningful change, horizontal dotted lines indicate group medians for HIGH and LOW, and circles are individual data points. DETAILED DESCRIPTION

[0018] Before any implementations are explained in detail, it is to be understood that the implementations are not limited in application to the details of the configurations and arrangements of components set forth in the following description or illustrated in the accompanying drawings. The implementations are capable of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein are for the purpose of description and should not be regarded as limiting.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, theAttorney Docket No.028193-0058-WO01 present document, including definitions, will control. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. Methods and materials similar or equivalent to those described herein can be used in practice or testing of the disclosed invention. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.

[0020] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0021] Unless specified or limited otherwise, the terms “mounted,” “connected,” “supported,” and “coupled” and variations thereof are used broadly and encompass both direct and indirect mountings, connections, supports, and couplings.

[0022] Unless the context of their usage unambiguously indicates otherwise, the articles “a,” “an,” and “the” should not be interpreted as meaning “one” or “only one.” Rather these articles should be interpreted as meaning “at least one” or “one or more.” Likewise, when the terms “the” or “said” are used to refer to a noun previously introduced by the indefinite article “a” or “an,” “the” and “said” mean “at least one” or “one or more” unless the usage unambiguously indicates otherwise.

[0023] For the recitation of numeric ranges herein, each intervening number therebetween with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are contemplated, and for the range 1.5-2, the numbers 1.5, 1.6, 1.7, 1.8, 1.9, and 2 are contemplated.

[0024] Relative terminology, such as, for example, “about,” “approximately,” “substantially,” etc., used in connection with a quantity or condition would be understood by those of ordinary skill to be inclusive of the stated value and has the meaning dictated by the context (e.g., the term includes at least the degree of error associated with the measurement accuracy, tolerances [e.g., manufacturing, assembly, use, etc.] associated with the particularAttorney Docket No.028193-0058-WO01 value, etc.). To illustrate, the term “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The term “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9- 1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0025] In addition, it should be understood that implementations may include hardware, software, and electronic components or modules that, for purposes of discussion, may be illustrated and described as if the majority of the components were implemented solely in hardware. However, one of ordinary skill in the art, and based on a reading of this detailed description, would recognize that, in at least one implementation, the electronic-based aspects may be implemented in software (e.g., stored on non-transitory computer-readable medium) executable by one or more processing units, such as a microprocessor and / or application specific integrated circuits (“ASICs”). As such, it should be noted that a plurality of hardware and software-based devices, as well as a plurality of different structural components, may be utilized to implement the implementations. For example, “servers,” “computing devices,” “controllers,” “processors,” etc., described in the specification can include one or more processing units, one or more computer-readable medium modules, one or more input / output interfaces, and various connections (e.g., a system bus) connecting the components.

[0026] It should be understood that although certain drawings illustrate hardware and software located within particular devices, these depictions are for illustrative purposes only. Functionality described herein as being performed by one component may be performed by multiple components in a distributed manner. Likewise, functionality performed by multiple components may be consolidated and performed by a single component. In some implementations, the illustrated components may be combined or divided into separate software, firmware and / or hardware. For example, instead of being located within and performed by a single electronic processor, logic and processing may be distributed among multiple electronic processors. Regardless of how they are combined or divided, hardware and software componentsAttorney Docket No.028193-0058-WO01 may be located on the same computing device or may be distributed among different computing devices connected by one or more networks or other suitable communication links. Similarly, a component described as performing particular functionality may also perform additional functionality not described herein. For example, a device or structure that is “configured” in a certain way is configured in at least that way but may also be configured in ways that are not explicitly listed.

[0027] Accordingly, in the claims, if an apparatus, method, or system is claimed, for example, as including a controller, control unit, electronic processor, computing device, logic element, module, memory module, communication channel or network, or other element configured in a certain manner, for example, to perform multiple functions, the claim or claim element should be interpreted as meaning one or more of such elements where any one of the one or more elements is configured as claimed, for example, to make any one or more of the recited multiple functions, such that the one or more elements, as a set, perform the multiple functions collectively.

[0028] FIG.2 illustrates a system 10 for treating stroke-related deficiencies, including but not limited to post-stroke motor impairment, central post-stroke pain syndrome (or post thalamic pain syndrome, a subgroup of CPSP) in a patient according to an embodiment of the present disclosure. It is further envisioned that the disclosed system and related methods can be used with other similar deficits and disorders that are not necessarily stroke-related.

[0029] The system 10 includes a head-worn device, such as a helmet 14, which is adjustably configured to fit onto the patient’s head and scalp. The head-worn device 14 is flexible and includes an adjustable strap or headband 18 to fit a curvature of the patient’s head. The headband 18 is adjustable to fit various-sized heads of patients receiving treatment. The headband 18 is comfortably fitted to the patient’s head such that it remains in position without moving. The head-worn device 14 includes a track 22 coupled to the headband 18. The track 22 is configured to receive a housing 26 supporting an ultrasound transducer 30. The housing 26 is configured to move along the track 22 to position the ultrasound transducer 30 so that delivery of a low intensity focused ultrasound (LIFU) beam emitted from the ultrasound transducer 30 is aligned to a target area within a brain of the patient. In some aspects, the housing 26 includes aAttorney Docket No.028193-0058-WO01 universal ball joint that moves along the track 22 to position the ultrasound transducer 30. The head-worn device 14 can include a cooling water bolus coupled to the housing 26 to provide air- bubble free acoustic coupling to the patient’s scalp and to prevent temperature rise at the scalp. In some aspects, the target area is in the cortical or deep sub-cortical region within the patient’s brain. For example, the target area is a motor cortex of the brain or a thalamus of the brain.

[0030] The system 10 includes the ultrasound transducer 30 configured to deliver a LIFU beam to a target area in the patient. LIFU uses low intensity acoustic energy to reversibly modulate neural activity in the target area. The ultrasound transducer 30 is in communication with a controller 32 (e.g., a pulse generator) configured to drive the transducer according to prescribed ultrasound parameters. The ultrasound transducer 30 includes a piezoelectric element, which is driven by the controller 32 to generate the LIFU beam. The controller 32 generates an electrical waveform, which is amplified and transferred to the ultrasound transducer 30. This amplified electrical signal excites the piezoelectric element, causing the active face of the transducer to oscillate and produce ultrasound waves. The ultrasound waves reflect off tissues in the target area (e.g., brain) and are received by the transducer 30 and can be processed to generate an ultrasound image of the anatomical area.

[0031] In some aspects, the ultrasound transducer 30 includes one or more piezoelectric elements. In one aspect, the ultrasound transducer 30 includes a single piezoelectric element. The piezoelectric element provides focality with a specific associated focal length (measured in mm) that defines a three-dimensional zone of maximum applied ultrasound. The treatment plan for the patient includes one or more of the following prescribed ultrasound parameters: (1) fundamental frequency, (2) pulse repetition frequency (PRF), (3) duty cycle, (4) sonication duration and sonication period, (5) intensity (ISPPAand ISPTA), and (6) mechanical index. The fundamental frequency is the number of oscillations over time and is inversely proportional to wavelength. The PRF is the rate at which acoustic pulses are delivered, and duty cycle is the proportion of each pulse filled with cycles of ultrasound at the fundamental frequency (or the ratio of “on time” to total time). Sonication duration refers to the total length of time a sample is exposed to ultrasonic waves, while sonication period typically refers to the duration of each individual pulse or cycle when using pulsed sonication. The spatial-peak temporal average (ISPTA) measures the average intensity during an entire sonication and the spatial-peak pulseAttorney Docket No.028193-0058-WO01 average (ISPPA) measures the average intensity over a single pulse. Mechanical index refers to the local variation in pressure within a medium caused by the passage of sound waves. The treatment plan is provided to the controller 32 to generate signals in accordance with the ultrasound parameters to drive the ultrasound transducer 30 to deliver the LIFU beam to the target area of the patient.

[0032] In some embodiments, the system 10 includes a passive cavitation detector 34 (e.g., hydrophone transducer) coupled to the ultrasound transducer 30. A passive cavitation detector is a type of hydrophone specifically designed to provide optimum signal to noise ratio in the measurement of cavitation induced acoustic signals. The passive cavitation detector 34 is configured to monitor and detect transcranial cavitation activity caused by delivery of the LIFU beam to the target area. In some aspects, after the ultrasound transducer 30 is placed on the scalp of the patient, a small amplitude ultrasound pulse can be transmitted to the target area to measure acoustic reflections. Those acoustic reflections assess whether there is proper acoustic coupling to avoid cavitation on the scalp. In some aspects, the ultrasound transducer 30 is configured to deactivate the LIFU beam if cavitation is detected by the passive cavitation detector 34.

[0033] In some embodiments, the system 10 includes a temperature sensor 42, for example, a thermocouple, coupled to the ultrasound transducer 30. The temperature sensor 42 is configured to monitor temperature between the scalp of the patient and the ultrasound transducer 30. In some aspects, the ultrasound transducer 30 is configured to deactivate the LIFU beam if the temperature detected by the temperature sensor 42 rises to a pre-specified point or exceeds a pre- set threshold. For example, the threshold may be set at a 3°C increase over the treatment period. In some aspects, the treatment period may be about 12 minutes, but may vary based on a treatment plan developed for the patient.

[0034] In some embodiments, a tracking sensor 46 is coupled to the ultrasound transducer 30. The tracking sensor 46 is associated with a navigation system 50 (e.g., Brainsight® navigation system) and is configured to determine the position of the ultrasound transducer 30 relative to the scalp of the patient. The navigation system 50 is configured to display an image of the patient’s brain, and the tracking sensor 46 indicates the position (e.g., roll, pitch, and yaw) of the ultrasound transducer 30 on the image. In this way, the trajectory of the LIFU beam to theAttorney Docket No.028193-0058-WO01 target area can be visually assessed and the position of the ultrasound transducer 30 can be modified or adapted by the user to ensure the LIFU beam reaches the target area for effective modulation of the target area. The neuroimage is typically acquired by a magnetic resonance imaging (MRI) system, and provided to the navigation system 50 for precise stimulation.

[0035] With reference to FIG.3, in some embodiments, the system 10 includes a computing device 54 configured to provide electronic communications between the ultrasound transducer and the navigation system 50. The computing device 54 includes an electronic processor 58 (for example, a microprocessor, application specific integrated circuit, etc.), a memory 62, a communication interface 66, an output device 70, and an input device 74. The memory 62 may be made up of one or more non-transitory computer-readable media. The memory 62 may include combinations of different types of memory, such as read-only memory (“ROM”), random access memory (“RAM”), electrically erasable programmable read-only memory (“EEPROM”), flash memory, or other suitable memory devices. The electronic processor 58 is coupled to the memory 62, the communication interface 66, the output device 70, and the input device 74. The electronic processor 58 sends and receives information (for example, from the memory 62 and / or the communication interface 66) and processes the information by executing one or more software instructions or modules, capable of being stored in the memory 62, or another non-transitory computer readable medium. The software can include firmware, one or more applications, program data, filters, rules, one or more program modules, and other executable instructions. In some examples, the electronic processor 58 is configured to retrieve from the memory 62 and execute, among other things, software for performing methods as described herein. The communication interface 66 may transmit information to and receive information from devices external to the computing device 54 (for example, the controller 32 and the navigation system 50). The output device 70 may be a speaker and / or a display device such as a liquid crystal display (LCD), a touchscreen display, a light-emitting diode (LED) display, an organic light-emitting diode (OLED) display, or the like. In some implementations, the output device 70 may be a light, for example, an LED light. The input device 74 may be a touch screen, a microphone, a keyboard, a mouse, a combination of the foregoing, or the like.

[0036] FIG.4 is an example flowchart of a method 100 for delivering ultrasound stimulation to a patient. At block 104, the head-worn device 14 is applied to the patient and adjusted forAttorney Docket No.028193-0058-WO01 proper fit. At block 108, the ultrasound transducer 30 is coupled to the head-worn device 14. For example, the ultrasound transducer 30 may be positioned within the housing 26 on the head- worn device 14. Next, at block 112, the ultrasound transducer 30 is positioned to be in contact with the patient’s scalp. At block 116, the ultrasound transducer 30 is positioned to align delivery of the LIFU beam emitted from the ultrasound transducer to the target area. For example, the ultrasound transducer 30 may be moved along the track 22 to properly position the ultrasound transducer 30. In some aspects, once the LIFU transducer is placed on the scalp, a small amplitude ultrasound pulse can be emitted to measure acoustic reflections. These reflections are used to measure proper acoustic coupling to avoid cavitation on the scalp. After alignment of the ultrasound transducer 30, at block 120, the controller 32 receives the treatment plan with prescribed ultrasound parameters to generate signals in accordance with the ultrasound parameters that will drive the ultrasound transducer 30 to deliver the LIFU beam to the target area of the patient. At block 124, the ultrasound transducer 30 delivers the LIFU beam to the target area to modulate the target area to provide a therapeutic effect to the patient. In some examples, the therapeutic effect is alleviating pain associated with central post-stroke pain syndrome and / or post thalamic pain syndrome. In other examples, the therapeutic effect is providing post-stroke motor recovery.

[0037] During delivery of the LIFU beam to the target area, the passive cavitation detector 34 monitors, at block 128, for transcranial cavitation activity caused by delivery of the LIFU beam to the target area. The passive cavitation detector 34 is in communication with the computing device 54, and if cavitation is detected by the passive cavitation detector 34, the computing device 54 will communicate with the controller 32 to send a signal to the ultrasound transducer 30 to deactivate, at block 136, the LIFU beam. Also, during delivery of the LIFU beam to the target area, the temperature sensor 46 monitors the scalp, at block 132, to determine if temperature has increased to a value that exceeds a predetermined threshold. For example, the predetermined threshold may be 3°C over the treatment period. In some aspects, the treatment period may be about 12 minutes. The temperature sensor 46 is in communication with the computing device 54, and if the temperature exceeds the predetermined threshold, the computing device 54 will communicate with the controller 32 to send a signal to the ultrasound transducer 30 to deactivate, at block 136, the LIFU beam.Attorney Docket No.028193-0058-WO01 EXAMPLE – APPLICATION OF LIFU TREATMENT IN STROKE PATIENTS

[0038] Thirty stroke participants were screened and 18 participants (6 females, aged 52±14 years) met the eligibility criteria and participated in the study. Stroke participants were included only if they: 1) were 21 years old of any race or gender; 2) had a first-ever ischemic or hemorrhagic stroke more than one month ago; 3) had a unilateral limb weakness with a Fugl Meyer-Upper Extremity (FM-UE) score 62 (out of 66); and 4) had transcranial magnetic stimulation (TMS)-elicitable motor-evoked potentials (MEPs) on the paretic abductor pollicis brevis (APB). Participants were excluded if they had: 1) any concomitant neurological disorder(s) affecting arm functions; 2) a documented history of severe dementia with or without medications before the stroke; or 3) any contraindication(s) to MRI / TMS / low-intensity focused ultrasound stimulation (LIFUS).

[0039] The study included one baseline visit and one testing visit (see FIG.5 (at A)). At the baseline visit, participants gave their written informed consent, followed by determining eligibility and collecting vital signs and clinic-demographic information. A licensed physical therapist assessed upper extremity motor impairment using the FM-UE scale, after which participants were tested for their TMS-MEP status. If eligible, participants underwent anatomical and diffusion MRIs.

[0040] For the testing visit, participants were instructed to wash their hair prior to their arrival. The testing visit began with a navigation-guided, single-pulse TMS for APB MEPs in a seated position and proceeded with one block of a baseline motor sequence learning (MSL) task. Then, a 12-minute continuous and neuronavigated LIFUS was administered (see FIG.5 (at B and C)). In parallel, participants completed three practice blocks of the same MSL task, interleaved with 1-2 minutes breaks (FIG.5 (at D)). After the LIFUS, a study team member first inspected the scalp for any burn / injury. Then participants performed a post-stimulation MSL assessment, followed by a TMS assessment, and lastly another MRI.

[0041] LIFU beam protocol: a custom-made, 500 kHz single-element focused ultrasound transducer with a 30 mm focal depth for stimulations (e.g., Blatek Industries, Inc., PA, USA) was employed in the study. Two function generators (e.g., 33210A, Keysight Technologies, Inc., CA, USA) were utilized to generate the desired electrical waveform (FIG. 5 (at C)).Attorney Docket No.028193-0058-WO01 Specifically, function generator (FG) A delivered 500 pulses at a 1000 Hz pulse repetition frequency (PRF) to trigger FG B, while FG B provided 100 cycles of a 500 kHz sine wave per pulse. Overall, the electrical waveform consisted of a 200 s tone burst duration (TBD), a 500 ms sonication duration (SD), and a 1 s inter-stimulus interval (FIG. 5 (at D)). A radio frequency power amplifier (e.g., 50A250, Amplifier Research Corporation, PA, USA) amplified the electrical waveform from FG B to drive the ultrasound transducer. The measured ISPPA in free water was set to 40 W / cm2, providing the estimated transcranial 8 W / cm2ISPPA considering skull attenuations. Other estimated in-vivo parameters included a 0.69 mechanical index (MI) and a 533 mW / cm2averaged spatial-peak temporal-average intensity (ISPTA).

[0042] For precise stimulations, a tracking sensor (e.g., Brainsight® CT-913 tracking sensor (Rouge Research Inc., Quebec, Canada)) was mounted to the ultrasound transducer and the participants’ MRI was co-registered with a TMS coil (FIG.5 (at B and C)). Ultrasound gel (e.g., Aquasonic 100, Parker Laboratories, Inc., NJ, USA) was applied between the transducer and the scalp “hot-spot” – the optimal spot where TMS elicited the largest MEP on the contralateral APB. The ultrasound transducer location was monitored online, adjusted its position if necessary, and retrospectively assessed transducer locations offline.

[0043] Neuroimaging protocol: neuroimaging was collected on a 3-Tesla GE Signa UHP MRI scanner. Three-dimensional T1 magnetization-prepared rapid acquisition gradient-echo (MPRAGE) and T2-weighted fluid attenuated inversion recovery (FLAIR) images (1 mm isotropic spatial resolution) were acquired, along with a DTI sequence (dual spin-echo echo- planar imaging acquisitions, 2 mm isotropic spatial resolution, b factor = 1000 s / mm2).

[0044] MSL protocol: the discrete sequence production task was utilized to examine motor sequence learning. The MSL task was created in-house (e.g., E-Prime 3.0, Psychology Software Tools, PA, USA), and placed a five-button keyboard (1 cm-diameter round buttons, horizontally equidistant) in front of participants, at a location where participants confirmed comfortable reach with their affected hand. In addition, participants saw five horizontally equidistant, 2 cm x 2 cm boxes on a computer screen, each corresponding to one keyboard button. With a circle appearing in one of the boxes, participants were cued to hit the corresponding button using their stroke- affected hand (FIG.5 (at D)). The circle appeared uniquely within a sequence, e.g., box numberAttorney Docket No.028193-0058-WO01 4-1-3-5-2. Each participant was assigned a sequence randomly and received this same sequence on their pre-LIFUS assessment (one block), practices during LIFUS (three blocks), and their post-LIFUS assessment (one block) MSL. Each block consisted of twelve repetitions of the participant’s assigned sequence. All MSL tasks were delivered without mentioning “a sequence” in any form, and only asked participants to complete the task as quickly and accurately as possible using just their affected hand.

[0045] TMS protocol: Identical TMS-MEP procedures were performed across participants for a neurophysiological assessment of their corticospinal excitability. Participants sat in a comfortable position with arms and hands at rest. Using the navigation system (e.g., Brainsight® 2.4.10 (Rouge Research Inc., Quebec, Canada), participants had their physical anatomical landmarks co-registered to the MNI ICBM 152 template for the baseline screening, and to their T1 neuroimages in the testing session. Electrodes (e.g., Kendall™ H124SG, Cardinal Health 200, LLC, IL, USA) were applied to participants’ paretic APB in a belly-tendon montage and were connected to the CED1902 amplifier (e.g., Cambridge Electronic Design Limited, Cambridge, UK). A MICRO4 analog-to-digital converter (e.g., Cambridge Electronic Design Limited, Cambridge, UK) was used, and the Signal 7.05a (x86) software (e.g., Cambridge Electronic Design Limited, Cambridge, UK) for data acquisitions. The TMS stimulator (e.g., BiStim2, Magstim Inc, MN, USA) was set to the BiStim mode, and had the 70 mm figure-of-eight coil oriented for posteroanterior intracranial currents. Single monophasic TMS pulses were bilaterally applied over motor cortical areas to elicit MEPs larger than 50 V peak-to-peak on the contralateral APB while it was at rest. After the detection of a coil setup that best elicited contralateral APB MEPs, the resting motor threshold (RMT) and testing motor threshold (TMT) with this coil setup (the “hot-spot”) using the adaptive parameter estimation by sequential testing method (MTAT 2.1) was determined. RMT and TMT were defined as the percentage of maximum stimulator output (MSO) required to attain 50 V and 1 mV MEP, respectively. When a 50 V MEP was attainable but a 1 mV was not, 100% MSO was used. Then, twenty single pulses spaced over 10 seconds apart were applied over the “hot-spot” using either the TMT or 100% MSO when the TMT could not be determined. TMS assessments were collected both before and after the LIFUS. The post-stimulation TMS started 12 minutes after LIFUS, for a transducer removal, safety assessments and TMS preparations.Attorney Docket No.028193-0058-WO01

[0046] DATA ANALYSIS

[0047] ADC calculation: To assess topical ADC changes, DTI images were corrected for movements and eddy currents, fitted voxel-wise diffusion tensors, and took the voxel-wise mean diffusivity (MD) to obtain ADC maps. Region of interest (ROI) for ADC readout was drawn on b0 DTI images (directly beneath the scalp location where the LIFUS transducer was placed) and masked with both grey-matter and white-matter segments (obtained from steps below) to maintain only the intersection. The mean MD was used in this masked ROI to calculate the percentage ADC change, and recorded occurrences of ADC dropping equal or more than the minimal clinically significant 20%.

[0048] The segmentation and co-registration step started with lesion delineations, performed on FLAIR images under the supervision of a stroke neurologist (WF). A lesion was defined as areas of abnormal signal intensities standing out against the surrounding normal tissue, and using our previously described procedures. These lesion masks were paired with T1 images for segmentations by cost-function non-linear registration to an elderly template using the Clinical Toolbox24 in Statistical Parametric Mapping 12 (e.g., SPM12, University College London, London, UK). The resultant segments were co-registered into the participant’s diffusion space using the normalized mutual information pipeline in SPM12, and these co-registered segments were fed to the ADC calculation above.

[0049] MSL response time: motor learning improvements were quantified by calculating the percentage change in the within-block median response time. The response time was defined as the time from a cue presentation (circle appearance) to a motor response (button pressing). The median response time was calculated for the five key presses in each sequence repetition (one response time for each repetition) and took the median of these twelve within-repetition medians as the overall median response time for that MSL block. Next, the percentage post-minus-pre change in the within-block median response time was calculated and the number of participants who improved 20% on MSL was recorded.

[0050] Corticospinal excitability assessment: In the TMS-MEP, MEPs were first identified as signals that had a biologically plausible latency between the stimulus artifact and the first prominent post-stimulus deflection. Next, the peak-to-peak amplitude of each MEP was taken.Attorney Docket No.028193-0058-WO01 After sorting these values from low to high, the four outliers were removed from both tails and calculated the mean of the middle twelve (5th – 16th) values. The mean amplitude of these twelve MEPs was used as the measure of corticospinal excitability. The percentage post-minus- pre change was calculated and the number of participants who improved 20% on MEP was recorded.

[0051] Statistical Analyses: participant demographics were summarized with descriptive statistics, mean±standard deviation (SDev). To test the effect of intensity on MSL and TMS measures, participants were lumped 0 / 1 / 2 W / cm2in one dose group (LOW), and 4 / 6 / 8 W / cm2participants in another dose group (HIGH). Metrics of comparison, which were presented median±SDev, were a) the percentage improvement in MSL response time and b) the percentage variation in the peak-to-peak amplitude of MEPs. Given the sample size of eighteen participants, we performed the non-parametric Fligner-Policello robust rank order test with bootstrapping to not assume data normality or symmetry. For categorical analysis, a Fisher’s Exact test was used to compare the two groups. Tests were performed in MATLAB (e.g., R2020a, MathWorks, Inc., MA, USA), significance level = 0.05.

[0052] RESULTS

[0053] Each participant received one stimulation dose / intensity, with three participants at each dose as the intensity was escalated to 8 W / cm2without meeting pre-defined stopping rules. No participant had a 2nd-degree scalp burn or clinical seizure, visible lesion on the DTI,clinically significant ( 20% reduction) ADC reduction (FIG. 6), and discontinuation (Table 1).Since no major response occurred at any intensity, the trial was completed with eighteen participants. TABLE 1:Attorney Docket No.028193-0058-WO01

[0054] MSL: Sixty-seven percent of participants (6 / 9) in HIGH improved 20% on the MSL, whereas no participant (0 / 9) in LOW did, p=0.009. Similarly, the median percentage MSL improvement of HIGH (24.7±13.3%) was statistically significantly higher than that in LOW (13.2±10.9%), p=0.014 (FIG.7 (at A)).

[0055] TMS: Sixty-seven percent of participants (6 / 9) in HIGH, compared to forty-four percent (4 / 9) in LOW, had enhanced corticospinal excitability 20%, p=0.67. The median percentage increase in MEP amplitude for HIGH (32.0±34.3%) was not statistically significantly higher than that in LOW (12.9±48.0%), p=0.53 (FIG.7 (at B)).

[0056] DISCUSSION

[0057] This study was believed to be the first one to test the potential application of LIFUS in stroke patients for motor implications. The data was instrumental for the stroke recovery field to further establish the efficacy of LIFUS in stroke population. There were zero occurrences of pre-defined major adverse events. All participants tolerated LIFUS well and completed all studyAttorney Docket No.028193-0058-WO01 procedures. ADC was used qualitatively and quantitatively to ensure safety at subclinical safety level. Qualitatively, there was no participant with visible lesion on the DTI sequence. Quantitively, there was no participant with ADC reduction 20% or absolute ADC threshold 620×10 6 mm2 / s. One participant had a mild first-degree scalp burn, but symptoms went awaythe next day without seeking medical attentions. An insufficient amount of ultrasound gel was likely the cause. Simulation data suggests that the intensity / dose range should have minimal scalp temperature rises. However, this highlighted the need to further monitor safety issues in future studies with multiple sessions.

[0058] A traditional 3+3 dose-escalation trial design (the modified Fibonacci method) was used and demonstrated that single-session, 12-minute LIFUS up to 8 W / cm2ISPPAwas safe and tolerable in stroke participants. The outcome of 3+3 trials was that the maximum tolerable dose (intensity) was the intensity / dose at which 1 / 3 or more of participants experience predefined dose (intensity)-limiting major response(s) (i.e., meeting the stopping dose). This design was simple, clear, and has been accepted and widely used in drug trials, although the selection of one-third or more for stopping rule is admittedly arbitrary. The alternative was the accelerated titration design which started at a low dose, assesses its toxicity degree, and uses that extent to determine the next dose. This accelerated titration design is suitable for wide dose range and no initial approximate endpoint. Adhering the FDA and the International Electrotechnical Commission guidelines, the maximum ISPPAfor LIFUS is around 8 W / cm2. Therefore, the modified Fibonacci method was deemed appropriate.

[0059] In addition to determining the safety of LIFUS in stroke patients, the effects of LIFUS on motor learning and corticospinal excitability was observed in the stroke population. LIFUS at ipsilesional M1 during a motor practice can enhance motor skill learning, with more significant effects at higher intensities – 67% (6 / 9) participants in HIGH had 20% improvement in MSL while no participant (0 / 9) in LOW did. Corticospinal excitability showed the same direction as the motor learning effect, but the magnitude is relatively small and does not reach significance. There are several potential explanations. This study was not powered to detect a significance in corticospinal excitability variations. MEPs are known to have a huge variability in both healthy controls and in stroke patients with an injured corticospinal tract, even though several mitigating approaches were incorporated. For example, over ten secondsAttorney Docket No.028193-0058-WO01 transpired between TMS pulses, which is known to reduce MEP variabilities. The huge individual variability requires a large sample size to detect a significant change in MEPs. It was reported that, to reliably detect a 20% difference in MEP amplitudes, each group requires thirty participants. Nevertheless, what really matters is that corticospinal excitability moved in the same direction as the motor learning effect.

[0060] In this study, it was demonstrated that a 12-minute session of 500 kHz LIFUS up to 8 W / cm2ISPPA is feasible, safe, and tolerable in stroke participants. Also, stroke participants receiving higher intensity LIFUS (HIGH) performed significantly better on the MSL task and showed signs of greater LIFUS-induced corticospinal excitability, compared to participants receiving lower intensity LIFUS (LOW).

[0061] Additional features and advantages of the present disclosure are set forth in the following claims.

Claims

Attorney Docket No.028193-0058-WO01 CLAIMS What is claimed is:

1. A method of delivering low intensity ultrasound stimulation to a patient, the method comprising: applying a head-worn device to the patient; coupling an ultrasound transducer to the head-worn device; applying the ultrasound transducer to a scalp of the patient; moving the ultrasound transducer relative to the head-worn device to align delivery of a low intensity focused ultrasound (LIFU) beam emitted from the ultrasound transducer to a target area within a brain of the patient; and delivering the LIFU beam to the target area to modulate the target area, wherein parameters of the LIFU beam are configured to provide a therapeutic effect of alleviating stroke- related deficiencies of the patient.

2. The method of claim 1, wherein the target area is a motor cortex within the brain of the patient.

3. The method of claim 1, wherein the target area is a thalamus within the brain of the patient.

4. The method of claim 1, wherein a first one of the parameters is acoustic intensity (spatial- peak pulse average intensity, ISPPA, estimated in-vivo transcranial value), and wherein the acoustic intensity is less than or equal to about 38 W / cm2.

5. The method of claim 4, wherein the acoustic intensity is between about 4 W / cm2and about 8 W / cm2.

6. The method of claim 1, wherein a second one of the parameters is frequency, and wherein the frequency is between about 150 kHz to about 1.5 MHz.Attorney Docket No.028193-0058-WO01 7. The method of claim 6, wherein the frequency is between about 250 kHz to about 750 kHz.

8. The method of claim 7, wherein the frequency is 500 kHz.

9. The method of claim 1, wherein a third one of the parameters is beam width, and wherein the beam width is between about 2 mm to about 5 mm.

10. The method of claim 1, wherein a fourth one of the parameters is mechanical index, and wherein the mechanical index is equal to or less than about 1.

9.

11. The method of claim 1, wherein the ultrasound transducer is flexible with an adjustable curvature to comply with the scalp of the patient.

12. The method of claim 1, wherein the parameters of the LIFU beam account for attenuation associated with a skull of the patient.

13. The method of claim 1, further comprising monitoring a temperature of the scalp of the patient.

14. The method of claim 13, further comprising deactivating the LIFU beam if the temperature of the scalp increases 3 °C over a treatment period.

15. The method of claim 14, wherein the treatment period is about 12 minutes per session.

16. The method of claim 1, wherein the therapeutic effect includes an increase in cortical excitability and an increase in motor learning.

17. The method of claim 1, wherein the stroke-related deficiencies is central post-stroke pain or post-stroke motor impairment.Attorney Docket No.028193-0058-WO01 18. A system for treating post-stroke pain in a patient, the system comprising: a head-worn device configured to be fitted to a scalp of the patient; an ultrasound transducer coupled to the head-worn device, the ultrasound transducer configured to deliver a low intensity focused ultrasound (LIFU) beam to a target area in the patient; a passive cavitation detector coupled to the ultrasound transducer, the passive cavitation detector configured to monitor cavitation activity caused by delivery of the LIFU beam; and a temperature sensor coupled to the ultrasound transducer, the temperature sensor configured to monitor temperature between the scalp of the patient and the ultrasound transducer; wherein the ultrasound transducer is adjustable relative to the head-worn device to align delivery of a low intensity focused ultrasound (LIFU) beam emitted from the ultrasound transducer to a target area within a brain of the patient, wherein the ultrasound transducer is adjusted based on position data provided by a tracking sensor to a navigation system and displayed to a user.

19. The system of claim 18, wherein the tracking sensor is coupled to the ultrasound transducer, the tracking sensor configured to determine position of the ultrasound transducer relative to the scalp of the patient.

20. The system of claim 18, further comprising a computing device in communication with a controller of the ultrasound transducer, the temperature sensor, and the passive cavitation detector, and wherein the computing device is configured to send a signal to the ultrasound transducer to deactivate the LIFU beam if the temperature sensor detects a temperature that exceeds a threshold or if the passive cavitation detector detects cavitation.

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