Systems and methods for personalized noninvasive brain therapies

Abstract

A method for treating a neurological or psychiatric disorder in a subject is provided, including sequentially delivering low-intensity focused ultrasound (LIFU) neuromodulation to a plurality of brain targets while measuring one or more disease-related metrics, selecting, based on the measured metrics, a subset of brain targets exhibiting improvement satisfying a predefined selection criterion, and delivering high-intensity focused ultrasound (HIFU or sustained LIFU) neuromodulation to the selected subset to produce durable reduction of one or more disease signs or symptoms.

Description

SYSTEMS AND METHODS FOR PERSONALIZED NONINVASIVE BRAIN THERAPIESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 720,278 filed on November 14, 2024, and titled “Systems and Methods for Ultrasound Neuromodulation-Guided Ultrasound Brain Therapies,” United States Provisional Patent Application 63 / 737,725, filed 12 / 22 / 2024, and titled “Systems and Methods for Personalized Noninvasive Brain Therapies,” United States Provisional Patent Application No. 63 / 743,600 filed January 9, 2025, and titled “Systems and Methods for Ultrasound Neuromodulation-Guided Ultrasound Brain Therapies,” United States Provisional Patent Application 63 / 772,532 filed on March 15, 2025 and titled “Systems and Methods for Personalized Noninvasive Brain Therapies,” and United States Provisional Patent Application 63 / 886,634 filed on September 23, 2025, and titled “System for Controlled Mechanical Therapies of the Brain,” which are hereby incorporated by reference in their entirety.TECHNICAL FIELD

[0002] The present disclosure relates to systems and methods for systematically applying low-intensity, reversible ultrasound neuromodulation to a set of brain targets to determine an optimal subset for subsequent high-intensity ultrasound brain therapy for treatments of neurological, psychological, and mental disorders.BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0003] The embodiments disclosed herein will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings. The drawings depict only typical embodiments, which embodiments will be described with additional specificity and detail in connection with the drawings in which:

[0004] FIG. 1 illustrates a schematic drawing of a wearable ultrasound device positioned on a head of a subject and to target a target region in the head of a subject, according to embodiments herein.

[0005] FIG. 2A illustrates a front view of a wearable ultrasound device being worn by a subject, according to embodiments described herein.

[0006] FIG. 2B illustrates an isometric top front view of the wearable ultrasound device of FIG.2A, according to embodiments described herein.

[0007] FIG. 2C illustrates a top view of the wearable ultrasound device of FIG. 2A, according to embodiments described herein.

[0008] FIG. 3A illustrates a side view of a wearable ultrasound device being worn by a subject, according to embodiments described herein.

[0009] FIG. 3B illustrates an isometric top rear view of the wearable ultrasound device of FIG.3A being worn by the subject, according to embodiments described herein

[0010] FIG. 4 illustrates a flow diagram of a method of stimulating a target region of a brain of a subject, according to embodiments disclosed herein.14921-1718-5658 1

[0011] FIG. 5 illustrates a flow diagram of a method summarizing the concept for an ultrasound neuromodulation-guided ultrasound-based therapy, according to embodiments disclosed herein.

[0012] FIG. 6 instantiates the method of FIG. 5, according to embodiments described herein.

[0013] FIG. 7 illustrates a perspective view of a setup for a transducer array, according to embodiments described herein.

[0014] FIG. 8 illustrates an alternate view of a single transducer array of FIG. 7, according to embodiments described herein.

[0015] FIG. 9A-1 illustrates an orthogonal slice of a focusing capacity of a system, according to embodiments described herein.

[0016] FIG. 9A-2 illustrates an orthogonal slice of a focusing capacity of a system, according to embodiments described herein.

[0017] FIG. 9A-3 illustrates an orthogonal slice of a focusing capacity of a system, according to embodiments described herein.

[0018] FIG. 9B-1 illustrates an orthogonal slice of a focusing capacity of the system, according to embodiments described herein.

[0019] FIG. 9B-2 illustrates an orthogonal slice of a focusing capacity of the system, according to embodiments described herein.

[0020] FIG. 9B-3 illustrates an orthogonal slice of a focusing capacity of the system, according to embodiments described herein.

[0021] FIG. 10 illustrates a plot of the pressure output at the geometric focus as a function of input voltage.

[0022] FIG. 11A illustrates a plot characterizing the electronic steering capacity, according to embodiments described herein.

[0023] FIG. 11 B illustrates a plot characterizing the electronic steering capacity, according to embodiments described herein.

[0024] FIG. 11C illustrates a plot characterizing the electronic steering capacity, according to embodiments described herein.

[0025] FIG. 12A illustrates a plot characterizing ultrasound attenuation through ex-vivo human skulls at 325 kHz, according to embodiments described herein.

[0026] FIG. 12B illustrates a plot characterizing ultrasound attenuation through ex-vivo human skulls at 325 kHz, according to embodiments described herein.

[0027] FIG. 12C illustrates a plot characterizing ultrasound attenuation through ex-vivo human skulls at 325 kHz, according to embodiments described herein.

[0028] FIG. 13 illustrates a plot illustrating the percent pressure loss due to attenuation versus aberration, according to embodiments described herein.

[0029] FIG 14A illustrates a plot characterizing the normalized peak pressure based on skull demographic data, according to embodiments described herein

[0030] FIG. 15 illustrates a plot characterizing the focusing ability of the system through human skulls, according to embodiments described herein.24921-1718-5658\1

[0031] FIG. 16 illustrates a plot characterizing the effects of the skull on focal volume, according to embodiments described herein.

[0032] FIG. 17A illustrates a plot of the ultrasound pressure field produced by the Beam through an ex-vivo human skull at a location corresponding to the ventral intermediate nucleus, according to embodiments described herein.

[0033] FIG. 17B illustrates a plot of the ultrasound pressure at the target as a function of the voltage applied to the transducers, according to embodiments described herein

[0034] FIG. 18A illustrates a focusing capacity through human skulls, according to embodiments described herein.

[0035] FIG. 18B illustrates a focusing capacity through human skulls, according to embodiments described herein.

[0036] FIG. 18C illustrates a focusing capacity through human skulls, according to embodiments described herein.

[0037] FIG. 18D illustrates a focusing capacity through human skulls, according to embodiments described herein.

[0038] FIG. 18E illustrates a focusing capacity through human skulls, according to embodiments described herein.

[0039] FIG. 18F illustrates a focusing capacity through human skulls, according to embodiments described herein.

[0040] FIG. 18G illustrates a focusing capacity through human skulls, according to embodiments described herein.

[0041] FIG. 18H illustrates a focusing capacity through human skulls, according to embodiments described herein.DETAILED DESCRIPTION

[0042] Mental and neurological disorders affect nearly one fifth of the world's population. Approximately one third of patients across mental and neurological conditions are treatmentresistant. Neuromodulation has the potential to provide a targeted reset of the malfunctioning circuits, but current state-of-the-art approaches, detailed below, have significant limitations. These limitations leave millions of patients in the United States and worldwide not adequately treated.

[0043] Mental and neurological disorders involve neural networks situated deep in the brain, including limbic, basal ganglia, memory, and brain stem networks. Progress in treatments of these has been hampered by the lack of tools to effectively and safely modulate and reset these circuits. Deep brain stimulation (DBS) has shown promise in providing a selective reset of the involved deep brain circuits, but the surgical implantation of stimulating leads is associated with high costs and risks, including brain hemorrhage, infection, and in some cases, death.

[0044] On the other hand, current noninvasive neuromodulation modalities do not have the necessary intensity or spatial resolution at depth. Electroconvulsive therapy (EOT) resets the deep brain structures using large currents that induce brain-wide seizures. This broad activation often results in cognitive side effects such as memory loss. Transcranial magnetic stimulation34921-1718-5658\1(TMS) can modulate cortical regions, but its fields decay rapidly with depth and remain too weak to reach subcortical targets effectively.

[0045] Neuromodulation with transcranial low-intensity focused ultrasound (LIFU) combines the depth and precision of DBS with the noninvasiveness of TMS. However, the effects of ultrasonic neuromodulation have been reported to be transient, lasting on the order of several hours or several days. The effects of low-intensity focused ultrasound depend on exposure duration. Brief, second-scale exposures typically yield transient changes. Longer sonications lasting minutes can induce therapeutic effects that persist for hours or days.

[0046] Transcranial high-intensity focused ultrasound (HIFU) is emerging as a noninvasive neurosurgical approach that has the potential to provide durable relief in disease signs and symptoms. Unlike LIFU, which applies to a brain target limited amount of ultrasound energy, typically within the 510k Track FDA levels (FDA, 2019), HIFU applies to the brain substantial amount of energy that is sufficient to dampen the function of the target region and thus mitigate disease signs or symptoms in a durable manner, with the benefits lasting months to years. HIFU is FDA approved for treatments of essential tremor and tremor and symptoms associated with Parkinson's disease. HIFU also shows promise in treatments of obsessive-compulsive disorder, depression, and chronic pain.

[0047] HIFU is currently FDA-approved only for movement disorders. This is because the neural targets involved in movement disorders, such as essential tremor, are relatively invariant from patient to patient. To scale the approach to other indications, including chronic pain and epilepsy, in which the variability in neural networks is considerable, it is necessary to equip the approach with a mechanism for effective and personalized guidance based on each patient’s symptoms.

[0048] Because the effects of HIFU are long-term or permanent, it is paramount to apply HIFU to appropriate regions and targets in the brain. In this regard, a major limitation of current HIFU applications is that the neural regions and targets associated with many disorders are either poorly understood, vary from individual to individual, or there are multiple possible targets.

[0049] Previous work on ultrasound-based neuromodulation (LIFU) has shown that low-intensity focused ultrasonic waves can substantially decrease the amplitude of essential tremor, the intensity of chronic pain, and depressive symptoms. Because low-intensity ultrasound only provides transient effects, lasting on the order of 10-20 minutes, it is uniquely suited for systematic guidance. Specifically, by systematically and sequentially perturbing candidate brain targets involved in a given disorder, the approach identifies the region most strongly implicated in the pathology, as demonstrated in recent studies

[0050] At present, only one HIFU device — the Insightec Exablate Neuro — is available for brain therapies The platform is optimized and approved for surgical ablation and is risky and impractical to be used for low-intensity neuromodulation

[0051] The systems and methods presented in the examples below provide a noninvasive neuromodulatory system that may be used, for example, for treatment and / or diagnosis of neurological and mental disorders. The system is applied to the head using key anatomical44921-1718-5658\1landmarks, such as the nasion, facial features, or other landmarks of the head. The positioning allows the system to deliver the neuromodulation from one or a plurality of ultrasonic transducers into a specified deep brain target.

[0052] Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways.

[0053] The systems and methods presented in the examples below provide an approach that may be used, for example, for treatment of neurological and mental disorders, including essential tremor, Parkinson’s disease, chronic pain, epilepsy, post-traumatic stress disorder, obsessive compulsive disorder, and the like.

[0054] In some implementations, the systems are configured to correct for the ultrasound aberration of the skull using a procedure described in PCT / US2023 / 010095, filed January 4, 2023, and PCT / US2025 / 042155, filed August 15, 2025, both of which are incorporated by reference in their entirety. This procedure is applicable for single-element and multi-element transducers.

[0055] The phrases “coupled to” and “in communication with” refer to any form of interaction between two or more entities, including mechanical, electrical, magnetic, electromagnetic, fluid, and thermal interaction. Two components may be coupled to or in communication with each other even though they are not in direct contact with each other. For example, two components may be coupled to or in communication with each other through an intermediate component.

[0056] Embodiments may be understood by reference to the drawings, wherein like parts are designated by like numerals throughout. It will be understood by one of ordinary skill in the art having the benefit of this disclosure that the components of the embodiments, as generally described and illustrated in the figures herein, could be arranged and designed in a wide variety of different configurations Thus, the following, more detailed description of various embodiments, as represented in the figures, is not intended to limit the scope of the disclosure but is merely representative of various embodiments. While the various aspects of the embodiments are presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.

[0057] It will be appreciated that various features are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure. Many of these features may be used alone and / or in combination with one another.

[0058] In many embodiments, an ultrasound system (e.g., ultrasound-based neuromodulation system) for at-home or outpatient use is disclosed. An ultrasound system may comprise a controller and one or more transducers operably coupled to the controller and configured to selectively generate ultrasonic waves at a low frequency (e.g., about 100 kHz to about 650 kHz) effective to stimulate a target region of a body of a subject without ablating the target region.54921-1718-5658\1

[0059] As used herein, “stimulation” of the brain target region (or other target regions) may include a modulation of activity of excitable cells, such as neurons, glial cells, pancreatic cells, or other cell types that are responsive to the mechanical pressure waves associated with ultrasound. As used herein, “stimulation” is broad enough to include delivery of mechanical pressure waves at any degree, energy level, or amount configured to induce a therapeutic response from the target cell.

[0060] In many embodiments, the frequency of the ultrasonic waves generated by the transducers may be about 100 kHz to about 650 kHz, about 100 kHz to about 300 kHz, about 200 kHz to about 650 kHz, about 100 kHz to about 200 kHz, about 150 kHz to about 250 kHz, about 200 kHz to about 300 kHz, about 250 kHz to about 350 kHz, about 300 kHz to about 650 kHz, less than about 500 kHz, less than about 450 kHz, less than about 650 kHz, less than about 350 kHz, less than about 300 kHz, less than about 250 kHz, less than about 200 kHz, or less than about 150 kHz.

[0061] FIG. 1 illustrates a schematic drawing of a wearable ultrasound device 100 (e.g., wearable neuromodulation device) positioned on a head 10 of a subject and to target a target region 20a in the head 10 of a subject, according to embodiments herein. The wearable ultrasound device 100 may be configured to provide deep brain therapy. Moreover, embodiments of the wearable ultrasound device 100 and related methods of use may be configured to deliver ultrasonic neuromodulation for repeated use at home. The wearable ultrasound device 100 and related methods of use do not require the conventional steps for precision targeting of a region of the brain and thus enable in-home use of the wearable ultrasound device 100. More particularly, the wearable ultrasound device 100 and related methods of use may be utilized without the need for MRI images of the head or other precision neuronavigational tools. Moreover, the wearable ultrasound device 100 and related methods of use enable repeated and reproducible use, including in in-home settings.

[0062] As shown in FIG. 1, the ultrasonic waves 115 generated by the two transducers 102 have a focal width 120 larger than the brain target region 20a in the head 10 (e.g., brain) of the subject. For example, the focal width 120 may be larger than the diameter of deep brain nuclei in the brain of the subject. By generating ultrasonic waves 115 having a larger focal width 120 than the brain target region 20a, the configuration of the ultrasound device 100 increases the likelihood or even ensures that the brain target region 20a is engaged by the ultrasonic waves 115 (e.g., modulated or stimulated).

[0063] The wearable ultrasound device 100 may be coupled to the head 10 at multiple points or regions. For example, the transducers 102 may be secured to a head support 103 that is configured to support the transducers 102 in a position that allows the head 10 of the subject to be disposed between the two transducers 102. The head support 103 may be configured to position the head 10 and / or the transducers 102 such that the transducers 102 provide maximal intensity of the ultrasonic waves 115 at the intended brain target region 20a.

[0064] The transducers 102 may be held by the head support 103 in a position that focuses the ultrasonic waves 115 into the desired brain target region 20a. Accordingly, the head support 10364921-1718-5658\1may hold the transducers 102 in a position or orientation that aims the ultrasonic waves 115 at the selected brain target region 20a given the stabilized position of the head 10 in the head support 103. In many embodiments, the two opposing transducers 102 are positioned such that the focal regions including the focal width 120 of each of the transducers 102 are proximate or overlapping with one another. The head support 103 may be configured or adjusted such that the brain target region 20a may be positioned within this area or region where the focal regions including the focal width 120 of each of the transducers 102 overlap or are proximate to one another, as shown in FIG. 1.

[0065] The ultrasonic waves 115 may be delivered into the head 10 of the subject from the transducers 102 using a coupling medium 104. The coupling medium 104 may comprise any material that conducts the ultrasonic waves 115, such as a cryogel. In some embodiments described in greater detail below, the transducers 102 are configured to adjust to the head 10 of the subject such that the transducers 102 and / or the coupling medium 104 contact the head 10 of the subject. In some embodiments, the transducers 102 are selectively steerable and the controller 101 includes a steering control configured to steer the transducers 102 to direct the ultrasonic waves 115 at the brain target region 20a when the head 10 of the subject is positioned between the transducers 102 Thus, the wearable ultrasound device 100 may provide the ability for an operator to steer the ultrasonic waves 115 into the brain target region 20a using the controller 101 (e.g., an electronic controller) coupled to the wearable ultrasound device 100. In some embodiments, ultrasound aberrations by the head may be compensated for using an ultrasound through-transmit procedure described by Riis, et al. in the publication of “Controlled noninvasive modulation of deep brain regions in humans,” Communications Engineering, 3(1), 13 (2024), which is hereby incorporated by reference in its entirety.

[0066] The positioning of the transducers 102 allow the wearable ultrasound device 100 and related methods of use to deliver ultrasonic waves 115 from one or more transducers 102 into specified deep brain target regions (e.g., the brain target region 20a) of the subject. The targeting of the ultrasonic waves 115 into specific brain regions (e.g., the brain target region 20a) for a given condition or disorder may be mediated using fixed transducer holders, such that the ultrasonic waves 115 are aimed specifically into the desired brain target region 20a.

[0067] An ultrasound system of this disclosure comprising the wearable ultrasound device 100 coupled to the controller 101 may be configured to treat a variety of conditions or disorders in the brain. In some embodiments, an ultrasound system of this disclosure may be configured to treat a condition of the brain including at least one of cognitive decline or Alzheimer’s disease, and the target region 20a may include one or more of a region of the brain associated with memory functions, a hippocampus of the brain, an entorhinal cortex of the brain, an amygdala of the brain, or a nucleus basalis of Meynert of the brain. In some embodiments, an ultrasound system of this disclosure may be configured to treat a condition of the brain including depression, and the target region 20a may include one or more of a cingulate cortex of the brain or a subcallosal cingulate cortex of the brain. In some embodiments, an ultrasound system of this disclosure may be configured to treat a condition of the brain including chronic pain, and the target region 20a may74921-1718-5658\1include one or more of an anterior cingulate cortex of the brain, a medial cingulate cortex of the brain, a subcallosal cingulate cortex, a ventral posterolateral nucleus, or a ventral posteromedial nucleus. In some embodiments, an ultrasound system of this disclosure may be configured to treat a condition of the brain including addiction, and the target region 20a may include one or more of a nucleus accumbens of the brain, a subcallosal cingulate cortex of the brain, or an anterior cingulate cortex of the brain. In some embodiments, an ultrasound system of this disclosure may be configured to treat a condition of the brain including food cravings, and the target region 20a may include one or more of a nucleus accumbens of the brain or a nucleus accumbens shell of the brain. In some embodiments, an ultrasound system of this disclosure may be configured to treat a condition of the brain including anxiety, and the target region 20a may include one or more of an amygdala of the brain or a stria terminalis of the brain. In some embodiments, an ultrasound system of this disclosure may be configured to treat a condition of the brain including post-traumatic brain disorder, and the target region 20a may include one or more of an amygdala of the brain or a bed nucleus of a stria terminalis of the brain.

[0068] The controller 101 may be configured to provide voltages of specific waveforms to the transducers 102. In some embodiments, the voltages and wave forms may be defined by the required stimulation parameters for the brain target region. Generally, low-intensity ultrasound should be safe and thus the stimulation parameters would ideally comply with the FDA 510k guidelines on safe ultrasound exposure, i.e., not exceeding peak intensity of 190W / cm2and not exceeding time-average intensity of 0.72 W / cm2. The controller 101 can drive either a single channel (for single-element transducer) or multiple channels (for ultrasound arrays).

[0069] The controller 101 may be configured to implement any of the example methods disclosed herein, such as the method 400 described below. Moreover, the controller 101 may be configured to coordinate or otherwise direct the transducers 102 to emit the ultrasonic waves 115 at a selected frequency The controller 101 may include at least one computing device configured to perform one or more of the acts described herein. The at least one computing device of the controller 101 can include one or more servers, one or more computers (e.g., desk-top computer, lap-top computer), or one or more mobile computing devices (e.g., smartphone, tablet, etc.) The computing device of the controller 101 can comprise at least one processor, memory, a storage device, an input / output (“I / O”) device / interface, and a communication interface. Additional or alternative components may be used in some examples. Further, in some examples, the controller 101 or the computing device can include fewer components.

[0070] In some examples, the processor(s) of the controller 101 includes hardware for executing instructions (e.g., instructions for carrying out one or more portions of any of the methods disclosed herein), such as those making up a computer program For example, to execute instructions, the processor(s) may retrieve (or fetch) the instructions from an internal register, an internal cache, the memory, or a storage device and decode and execute them In particular examples, processor(s) of the controller 101 may include one or more internal caches for data. As an example, the processor(s) of the controller 101 may include one or more instruction caches, one or more data caches, and one or more translation lookaside buffers (TLBs). Instructions in84921-1718-5658\1the instruction caches may be copies of instructions in memory or storage device. In some examples, the processor of the controller 101 may be configured (e.g., include programming stored thereon or executed thereby) to carry out one or more portions of any of the example methods or acts disclosed herein. In some examples, the processor of the controller 101 is configured to perform any of the acts disclosed herein (such as in the method 400) or cause one or more portions of the computing device or the controller 101 to perform at least one of the acts disclosed herein. Such configuration can include one or more operational programs (e.g., computer program products) that are executable by the at least one processor of the controller 101.

[0071] The at least one computing device (e.g., a server) of the controller 101 may include at least one memory storage medium (e.g., memory and / or storage device). The computing device of the controller 101 may include memory, which is operably coupled to the processor(s) of the controller 101. The memory may be used for storing data, metadata, and programs for execution by the processor(s). The memory of the controller 101 may include one or more of volatile and non-volatile memories, such as Random Access Memory (RAM), Read-Only Memory (ROM), a solid-state disk (SSD), Flash, Phase Change Memory (PCM), or other types of data storage The memory of the controller 101 may be internal or distributed memory.

[0072] The computing device of the controller 101 may include the storage device having storage for storing data or instructions. The storage device may be operably coupled to the at least one processor. In some examples, the storage device of the controller can comprise a non-transitory memory storage medium, such as any of those described above. The storage device (e.g., non-transitory storage medium) of the controller 101 may include a hard disk drive (HDD), a floppy disk drive, flash memory, an optical disc, a magneto-optical disc, magnetic tape, or a Universal Serial Bus (USB) drive or a combination of two or more of these. The storage device of the controller 101 may include removable or non-removable (or fixed) media. The storage device of the controller 101 may be internal or external to the computing device. In some examples, the storage device of the controller 101 may include non-volatile solid-state memory. In some examples, the storage device of the controller 101 may include read-only memory (ROM). Where appropriate, this ROM may be mask-programmed ROM, programmable ROM (PROM), erasable PROM (EPROM), electrically erasable PROM (EEPROM), electrically alterable ROM (EAROM), or flash memory or a combination of two or more of these In some examples, one or more portions of the memory and / or the storage device (e.g , memory storage medium(s)) may store one or more databases thereon.

[0073] The computing device of the controller 101 also may include one or more I / O devices / interfaces, which are provided to allow a user to provide input to, receive output from, and otherwise transfer data to and from the computing device. These I / O devices / interfaces of the controller 101 may include a mouse, keypad or a keyboard, a touch screen, camera, optical scanner, network interface, web-based access, modem, a port, other known I / O devices, or a combination of such I / O devices / interfaces. The touch screen may be activated with a stylus or a finger. The I / O devices / interfaces of the controller 101 may include one or more devices for94921-1718-5658\1presenting output to a user, including, but not limited to, a graphics engine, a display (e.g., a display screen or monitor), one or more output drivers (e.g., display drivers), one or more audio speakers, and one or more audio drivers.

[0074] The computing device of the controller 101 also may include a communication interface. The communication interface may include hardware, software, or both. The communication interface of the controller 101 may provide one or more interfaces for communication (such as, for example, packet-based communication) between the computing device and one or more additional computing devices or one or more networks. For example, communication interface of the controller 101 may include a network interface controller (NIC) or network adapter for communicating with an Ethernet or other wire-based network or a wireless NIC (WNIC) or wireless adapter for communicating with a wireless network, such as a WI-FI Any suitable network and any suitable communication interface of the controller 101 may be used. For example, the computing device of the controller 101 may communicate with an ad hoc network, a personal area network (PAN), a local area network (LAN), a wide area network (WAN), a metropolitan area network (MAN), or one or more portions of the Internet or a combination of two or more of these. One or more portions of one or more of these networks may be wired or wireless. As an example, one or more portions of controller 101 may communicate with a wireless PAN (WPAN) (such as, for example, a BLUETOOTH WPAN), a WI-FI network, a WI-MAX network, a cellular telephone network (such as, for example, a Global System for Mobile Communications (GSM) network), or other suitable wireless network or a combination thereof. The computing device of the controller 101 may include any suitable communication interface for any of these networks, where appropriate.

[0075] The computing device of the controller 101 may include a bus. The bus can include hardware, software, or both that couples components of computing device of the controller 101 to each other. For example, the bus of the controller 101 may include an Accelerated Graphics Port (AGP) or other graphics bus, an Enhanced Industry Standard Architecture (EISA) bus, a front-side bus (FSB), a HYPERTRANSPORT (HT) interconnect, an Industry Standard Architecture (ISA) bus, an INFINIBAND interconnect, a low-pin-count (LPC) bus, a memory bus, a Micro Channel Architecture (MCA) bus, a Peripheral Component Interconnect (PCI) bus, a PCI-Express (PCIe) bus, a serial advanced technology attachment (SATA) bus, a Video Electronics Standards Association local (VLB) bus, or another suitable bus or a combination thereof.

[0076] In many embodiments, the frequency of the ultrasonic waves 115 generated by the transducers 102 may be about 100 kHz to about 650 kHz, about 100 kHz to about 300 kHz, about 200 kHz to about 650 kHz, about 100 kHz to about 200 kHz, about 150 kHz to about 250 kHz, about 200 kHz to about 300 kHz, about 250 kHz to about 350 kHz, about 300 kHz to about 650 kHz, less than about 500 kHz, less than about 450 kHz, less than about 650 kHz, less than about 350 kHz, less than about 300 kHz, less than about 250 kHz, less than about 200 kHz, or less than about 150 kHz.

[0077] FIGS. 2A-2C are various views of a wearable ultrasound device 200 being worn by a subject and will be described in tandem. FIG. 2A illustrates a front view of a wearable ultrasound104921-1718-5658\1device 200 being worn by a subject, FIG. 2B illustrates an isometric top front view of the wearable ultrasound device 200, and FIG. 2C illustrates a top view of the wearable ultrasound device 200, according to embodiments described herein. The wearable ultrasound device 200 is configured to be use in systems and methods that allow for reproducible positioning of the wearable ultrasound device 200 with respect to the head 10. For example, the wearable ultrasound device 200 may include a head support assembly 203 comprising a first member 205 and an eyeglasses frame 207 secured to the first member 205. The head support assembly 203 allows the wearable ultrasound device 200 to be fitted on the head 10 of the subject while providing reproducible positioning of the wearable ultrasound device 200 (e.g., the transducers 202a, 202b) on the head 10 of subject(s) across multiple treatment sessions and / or multiple subjects. The wearable ultrasound device 200, using the head support assembly 203, positions the ultrasonic transducers 202a, 202b ultrasonic transducers to aim the ultrasonic waves 115 (shown in FIG. 1) into the desired brain target region 20a (shown in FIG. 1) for each specific indication (e.g., brain condition or disorder)

[0078] Unless otherwise noted or specified, the ultrasound device 200 may include any aspect of the ultrasound device 100 described above. Accordingly, like features are designated with like reference numerals with the leading digits incremented to “2.” For example, the ultrasound device 200 may include a controller 201, a head support assembly 203, one or more transducers 202a, 202b secured to the head support assembly 203 and configured to emit ultrasonic waves, and a coupling medium 204 that may, in some respects, resemble the controller 101, the head support 103, the transducer 102 secured to the head support 103 and configured to emit the ultrasonic waves 115, and the coupling medium 104 of the ultrasound device 100.

[0079] The wearable ultrasound device 200 comprises the head support assembly 203 having the two transducers 202a, 202b secured thereto and configured to support the two transducers 202a, 202b on the head 10 of the subject with the head 10 of the subject positioned between the two transducers 202a, 202b, according to embodiments. The head support assembly 203 may comprise the first member 205 positioned to extend across the forehead of the subject and the eyeglasses frame 207 configured to rest on at least one of a nose 12 or an ear of the subject The head support assembly 203 is configured position the two transducers 202a, 202b on the head 10 of the subject to deliver ultrasonic waves at a target region in the brain of the subject without ablating the target region. The first member 205 may be shaped to wrap at least partially around the forehead of the subject. For example, the first member 205 may be generally U-shaped or C-shaped In some embodiments, the first member 205 may be configured to adjust to the head 10 of the subject. For example, the first member 205 may be configured to bend and then retain the shape to which the first member 205 is bent around the forehead of the subject. In some embodiments, the transducers 202a, 202b are secured to opposing end regions of the first member 205

[0080] In some embodiments, the head support assembly 203 further comprises an arm 212 secured to the first member 205 and the eyeglasses frame 207 effective to secure the eyeglasses frame 207 to the first member 205. At least one of the eyeglasses frames 207 or the first member114921-1718-5658\1205 may be adjustably secured to the arm 212 to allow the subject or other individual to adjust the wearable ultrasound device 200 to the fit the head 10 of the subject.

[0081] The eyeglasses frame 207 may comprise at least one (e.g., both) of a nasal support member 209 configured to rest on the nose 12 of the subject and one or more ear support members 211 configured to rest on one or more ears of the subject effective to support the wearable ultrasound device 200 in a selected position on the head 10 of the subject. The nasal support member 209 may comprise, for example, nose pads or nose pieces secured to the eyeglasses frame 207. In some embodiments, the nasal support member 209 is adjustably secured to the eyeglasses frame 207 to allow repositioning of the eyeglasses frame 207 in a particular position on the head 10 of the subject dependent on the selected target region in the brain of the subject and / or the unique shape of the head 10 of the subject. In some embodiments, the nasal support member 209 comprises a portion of the eyeglasses frame 207 or is otherwise integrally formed with the eyeglasses from 207. The one or more ear support members 211 may be shaped to extend over and / or bend or otherwise curve at least partially around one or more ears of the subject. In many embodiments, the one or more ear support members 211 are adjustable to allow repositioning of the eyeglasses frame 207 in a particular position on the head 10 of the subject depending on the selected target region in the brain of the subject and / or the unique shaped of the head 10 of the subject. For example, the one or more ear support members 211 may be configured to bend and then retain the shape to which the one or more ear support members 211 are bent.

[0082] The head support assembly 203 may further comprise a strap 206 secured or securable to the eyeglasses frame 207. The strap 206 may be adjustable and configured to selectively tighten or loosen the head support assembly 203 around the head 10 of the subject effective to support the wearable ultrasound device 200 in a selected position on the head 10 of the subject In many embodiments, the strap 206 is detachably or fixedly secured to the one or more ear support members 211 of the eyeglasses frame 207. In some embodiments, the strap 206 may be detachably secured to the first member 205 or the transducers 202a, 202b.

[0083] Similar to the wearable ultrasound device 100, an ultrasound system of this disclosure comprising the wearable ultrasound device 200 coupled to the controller 201 may be configured to treat a variety of conditions or disorders in the brain. The transducers 202a, 202b may be positioned or selectively positionable to treat the variety of conditions or disorders in the brain. For example, an ultrasound system including the wearable ultrasound device 200 and the controller 201 may be configured to treat a condition of the brain including at least one of cognitive decline or Alzheimer’s disease, and the target region 20a may include one or more of a region of the brain associated with memory functions, a hippocampus of the brain, an entorhinal cortex of the brain, an amygdala of the brain, or a nucleus basalis of Meynert of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 200 and the controller 201 may be configured to treat a condition of the brain including depression, and the target region 20a may include one or more of a cingulate cortex of the brain or a subcallosal cingulate cortex of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 200 and124921-1718-5658\1the controller 201 may be configured to treat a condition of the brain including chronic pain, and the target region 20a may include one or more of an anterior cingulate cortex of the brain, a medial cingulate cortex of the brain, a subcallosal cingulate cortex, a ventral posterolateral nucleus, or a ventral posteromedial nucleus. In some embodiments, an ultrasound system including the wearable ultrasound device 200 and the controller 201 may be configured to treat a condition of the brain including addiction, and the target region 20a may include one or more of a nucleus accumbens of the brain, a subcallosal cingulate cortex of the brain, or an anterior cingulate cortex of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 200 and the controller 201 may be configured to treat a condition of the brain including food cravings, and the target region 20a may include one or more of a nucleus accumbens of the brain or a nucleus accumbens shell of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 200 and the controller 201 may be configured to treat a condition of the brain including anxiety, and the target region 20a may include one or more of an amygdala of the brain or a stria terminalis of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 200 and the controller 201 may be configured to treat a condition of the brain including post-traumatic brain disorder, and the target region 20a may include one or more of an amygdala of the brain or a bed nucleus of a stria terminalis of the brain.

[0084] FIGS. 3A and 3B illustrate a wearable ultrasound device 300 being worn by a subject and will be described in tandem. FIG. 3A illustrates a side view of a wearable ultrasound device 300 being worn by a subject and FIG. 3B illustrates an isometric top rear view of the wearable ultrasound device 300 being worn by the subject, according to embodiments described herein.

[0085] The wearable ultrasound device 300 is configured to be use in systems and methods that allow for reproducible positioning of the wearable ultrasound device 300 with respect to the head 10. For example, the wearable ultrasound device 300 may include a head support assembly 303 comprising a first member 305 shaped and dimensioned to fit around the head 10 of the subject. The head support assembly 303 allows the wearable ultrasound device 300 to be fitted on the head 10 of the subject while providing reproducible positioning of the wearable ultrasound device 300 (e.g., the transducers 302a, 302b) on the head 10 of subject(s) across multiple treatment sessions and / or multiple subjects The wearable ultrasound device 300, using the head support assembly 303, positions the ultrasonic transducers 302a, 302b ultrasonic transducers to aim the ultrasonic waves 115 (shown in FIG. 1 ) into the desired brain target region 20a (shown in FIG. 1) for each specific indication (e.g., brain condition or disorder).

[0086] Unless otherwise noted or specified, the ultrasound device 300 may include any aspect of the ultrasound devices 100, 200 described above Accordingly, like features are designated with like reference numerals with the leading digits incremented to “3.” For example, the ultrasound device 300 may include a controller 301, a head support assembly 303, one or more transducers 302a, 302b secured to the head support assembly 303 and configured to emit ultrasonic waves, and a coupling medium 304 that may, in some respects, resemble the controller 101, 202, the head support 103, 203, the transducer 102, 202a-b secured to the head support 103, 203 and134921-1718-5658\1configured to emit the ultrasonic waves 115, and the coupling medium 104, 204 of the ultrasound device 100, 200.

[0087] As provided above, the first member 305 of the head support assembly 303 may be shaped and dimensioned to fit around the head 10 of the subject. More specifically, the first member 305 of the head support assembly 303 may comprise a front region 321 positioned to extend across the forehead of the subject, a rear region 322 positioned generally opposite to the front region 321, and two side regions 323a, 323b extending at least partially between the front region 321 and the rear region 322.

[0088] The two transducers 302a, 302b may be secured to a different one of the two side regions 323a, 323b In other words, a first transducer 302a is secured or securable to a first side region 323a of the first member 305 and a second transducer 302a is secured or securable to a second side region 323b of the first member 305, according to embodiments herein. The two transducers 302a, 302b may be selectively movable and / or repositionable on the two side regions 323a, 323b of the first member 305. For example, the two transducers 302a, 302b may include or otherwise be secured to a transducer body 344a, 344b, respectively, and the side regions 323a, 323b may each include an elongated slot 345a, 345b. The head support assembly 303 also may include fasteners 343a, 343b selectively secured or securable to a respective transducer body 344a, 344b. For example, the fastener 343a, 343b may be threadedly fastened or fastenable to the transducer body 344a, 344b. At least one of the transducer body 344a, 344b or the fastener 343a, 343b may include an extension member (not visible) secured thereto or extending therefrom that is movably positioned or positionable in the elongated slot 345a, 345b. Each transducer 302a, 302b may be moved to adjust to the head 10 of the subject and / or the selected target region in the brain by loosening the fastener 343a, 343b, sliding the extension member within the slot 345a, 345b to move the transducer 302a, 302b to a selected position, and then tightening the fastener 343a, 343b to the transducer body 344a, 344b within the side region 323a, 323b therebetween. When the fastener 343a, 343b is tightened sufficiently, the transducer 302a, 302b becomes locked in a selected position on the head 10 to allow the transducer 302a, 302b to target the selected target region of the brain.

[0089] In some embodiments, the transducers 302a, 302b may be disposed substantially parallel to each other on either side of the head support assembly 303. Further the transducers 302a, 302b may be aligned with each other across the head support assembly 303 The head support assembly 303 may be configured as a substantially rigid member, configured to maintain the relative positions of the transducers 302a, 302b. Additionally, it is within the scope of this disclosure to configured other embodiments, including the embodiment of Figs. 2A-2C with parallel transducers, a rigid frame, and / or alignment of the transducers from side to side.

[0090] In some embodiments, the head support assembly 303 includes a front projection 331 extending inwardly from the front region 321 of the first member 305 and positioned to interface the forehead of the subject. The front projection 331 may include a pad to cushion against the head 10 of the subject. In some embodiments, the front projection 331 is adjustable and configured increase or decrease a distance between the front projection 331 and the rear region144921-1718-5658\1322 effective to tighten or loosen the first member 305 on the head 10 of the subject and support the wearable ultrasound device 300 in a selected position on the head 10 of the subject. Said another way, the front projection 331 may be adjustable to increase or decrease a distance between the forehead of the subject and the front region 321 of the first member 305. The head support assembly 303 also may include a front fastener 341 selectively secured or securable to the front projection 331. Adjustment (e.g., rotation) of the front fastener 341 moves the front projection 331 inward towards an axis of the first member 305 or outward away from the axis of the first member 305 to adjust an inner diameter or circumference of the first member 305.

[0091] In some embodiments, the head support assembly 303 includes a rear projection 332 extending inwardly from the front region 322 of the first member 305 and positioned to interface the rear of the head 10 of the subject. The rear projection 332 may include a pad to cushion against the head 10 of the subject. In some embodiments, the rear projection 332 is adjustable and configured increase or decrease a distance between the rear projection 332 and the front region 321 effective to tighten or loosen the first member 305 on the head 10 of the subject and support the wearable ultrasound device 300 in a selected position on the head 10 of the subject. Said another way, the rear projection 332 may be adjustable to increase or decrease a distance between the forehead of the subject and the rear region 322 of the first member 305. The head support assembly 303 also may include a rear fastener 342 selectively secured or securable to the rear projection 332. Adjustment (e.g., rotation) of the rear fastener 342 moves the rear projection 332 inward towards an axis of the first member 305 or outward away from the axis of the first member 305 to adjust an inner diameter or circumference of the first member 305.

[0092] In many embodiments, the head support assembly 303 includes a nasal support member 309 extending from at least one of the front projection 331 or the front region 321 of the first member 305. The nasal support member 309 is configured to rest on the nose 12 of the subject effective to support the wearable ultrasound device 300 in a selected position on the head 10 of the subject. The nasal support member 309 may be Y- or V-shaped and configured to rest on the nose 12 of the subject.

[0093] In many embodiments, the head support assembly 303 comprises one or more ear support members 311 configured to rest on one or more ears 14 of the subject effective to support the wearable ultrasound device 300 in a selected position on the head 10 of the subject. In some embodiments, the one or more ear support members 311 extend inward from the rear region 322 of the first member 305

[0094] Similar to the wearable ultrasound device 100, 200 an ultrasound system of this disclosure comprising the wearable ultrasound device 300 coupled to the controller 301 may be configured to treat a variety of conditions or disorders in the brain. The transducers 302a, 302b may be positioned or selectively positionable to treat the variety of conditions or disorders in the brain For example, an ultrasound system including the wearable ultrasound device 300 and the controller 301 may be configured to treat a condition of the brain including at least one of cognitive decline or Alzheimer’s disease, and the target region 20a may include one or more of a region of the brain associated with memory functions, a hippocampus of the brain, an entorhinal cortex of154921-1718-5658\1the brain, an amygdala of the brain, or a nucleus basalis of Meynert of the brain In some embodiments, an ultrasound system including the wearable ultrasound device 300 and the controller 301 may be configured to treat a condition of the brain including depression, and the target region 20a may include one or more of a cingulate cortex of the brain or a subcallosal cingulate cortex of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 300 and the controller 301 may be configured to treat a condition of the brain including chronic pain, and the target region 20a may include one or more of an anterior cingulate cortex of the brain, a medial cingulate cortex of the brain, a subcallosal cingulate cortex, a ventral posterolateral nucleus, or a ventral posteromedial nucleus. In some embodiments, an ultrasound system including the wearable ultrasound device 300 and the controller 301 may be configured to treat a condition of the brain including addiction, and the target region 20a may include one or more of a nucleus accumbens of the brain, a subcallosal cingulate cortex of the brain, or an anterior cingulate cortex of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 300 and the controller 301 may be configured to treat a condition of the brain including food cravings, and the target region 20a may include one or more of a nucleus accumbens of the brain or a nucleus accumbens shell of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 300 and the controller 301 may be configured to treat a condition of the brain including anxiety, and the target region 20a may include one or more of an amygdala of the brain or a stria terminalis of the brain. In some embodiments, an ultrasound system including the wearable ultrasound device 300 and the controller 301 may be configured to treat a condition of the brain including post-traumatic brain disorder, and the target region 20a may include one or more of an amygdala of the brain or a bed nucleus of a stria terminalis of the brain.

[0095] In some cases, the transducers 302a and 302b are positioned symmetrically with respect to the mid-sagittal plane of the head of the subject. In some implementations, exemplified in FIGS.3A-3B, the wearable ultrasound device 300 is configured to correct for the ultrasound aberration of the head 10 and coupling medium 304. The system can compensate for the attenuation of ultrasound by the respective segment of the head 10 and the coupling medium 304. Such compensation takes into account all obstacles positioned between transducers. These include the skull, the scalp, the ultrasound coupling, any air pockets between the scalp and the transducers, and inner parts of the head including the dura and the brain.

[0096] In some embodiments, the system can compensate for attenuation of ultrasound using an Analytical Relative Through-Transmit (ARTT) procedure that determines transmission coefficients between each transducer and a target region of the brain. Such an ARTT procedure can include obtaining reference signal amplitude measurements while the system (e.g., the transducers) is immersed in a liquid medium (e.g., degassed water), and then obtaining corresponding measurements with the transducers positioned on the head of the subject Based on a comparison between the measured amplitudes (e.g., between the reference and in-vivo measurements) the system or controller can compute a scaling factor and adjust driving voltages to the transducers to compensate for the attenuation of ultrasonic energy.164921-1718-5658\1

[0097] Thus, in some cases, the system is configured to compensate for skull-induced aberrations to maintain a focal precision at the intended deep brain region. In some cases, the system can be configured to compensate for skull-induced aberrations via a distinct, separable, or a portion of the overall controller, so as to be conceptualized as a dedicated feedback controller. Otherwise stated, in some cases, such a (feedback) controller is configured to compensate for skull-induced attenuation and phase aberration to maintain a consistent pressure profile across multiple or varying skull specimens. Thus, in some cases, the system is configured to compensate for skull-induced aberrations to maintain a focal precision at the intended deep brain region using an ultrasound through-transmit procedure.

[0098] FIG. 4 illustrates a flow diagram of a method 400 of stimulating a target region of a brain of a subject, according to embodiments disclosed herein. The method 400 may utilize any of the ultrasound devices 100, 200, 300 disclosed herein. In many embodiments, the method 400 comprises providing 405 a wearable ultrasound device comprising two transducers and a head support assembly having the two transducers secured thereto. The method 400 also may comprise positioning 410 the two transducers of the wearable ultrasound device on a head of the subject with the head positioned between the two transducers and a first member of the head support assembly extending across a forehead of the subject. The method 400 also may comprise supporting 415 the two transducers in a selected position on the head of the subject by positioning one or more members of the head support assembly on at least one of a nose or an ear of the subject to support the wearable device. The method 400 also may comprise, with a controller coupled to the two transducers, activating 420 the two transducers to generate ultrasonic waves effective to stimulate the target region of the brain of the subject without ablating the target region of the brain of the subject.

[0099] In particular embodiments, the wearable ultrasound device 300 may be used in the method 400. Accordingly, positioning 410 the two transducers of the wearable ultrasound device on the head of the subject with the head positioned between the two transducers and a first member of the head support assembly extending across a forehead of the subject may comprise positioning the first member of the head support assembly around the head of the subject with a front region of the first member extending across the forehead of the subject, a rear region of the first member positioned generally opposite to the front region, and two side regions of the first member extending between the front region and the rear region. The two transducers being secured to a different one the two side regions with the head of the subject between the two transducers.

[0100] In these embodiments of the method 400 using the wearable ultrasound device 300, as well as other embodiments, the method 400 may further comprises at least one (e.gr, both) of (1) interfacing a front projection of the head support assembly with the forehead of the subject, the front projection extending inwardly from the front region of the first member or (2) interfacing a rear projection of the head support assembly with a rear of the head of the subject, the rear projection extending inwardly from the rear region of the first member. The method 400 may further comprise adjusting at least one of the front projection or the rear projection to increase or decrease174921-1718-5658\1a distance between the front projection and the rear projection effective to tighten or loosen the first member on the head of the subject and support the wearable ultrasound device in the selected position on the head of the subject.

[0101] In these embodiments of the method 400 using the wearable ultrasound device 300, as well as other embodiments, supporting 415 the two transducers in the selected position on the head ofthe subject by positioning one or more members of the head support assembly on at least one of a nose or an ear ofthe subject to support the wearable device may comprise at least resting a nasal support member on the nose of the subject, the nasal support member extending from at least one the front projection or the front region of the first member.

[0102] In these embodiments of the method 400 using the wearable ultrasound device 300, as well as other embodiments, supporting the two transducers in the selected position on the head of the subject by positioning one or more members of the head support assembly on at least one of a nose or an ear of the subject to support the wearable device may comprise at least resting one or more ear support members on one or more ears ofthe subject. The one or more ear support members extend inward from the rear region of the first member. In these embodiments of the method 400 using the wearable ultrasound device 300, as well as other embodiments, the method may further comprise moving the two transducers on the two side regions of the first member to a selected transducer position for the subject.

[0103] In particular embodiments, the wearable ultrasound device 200 may be used in the method 400. In these embodiments of the method 400 using the wearable ultrasound device 200, as well as other embodiments, positioning 410 the two transducers of the wearable ultrasound device on the head of the subject with the head positioned between the two transducers and a first member of the head support assembly extending across a forehead of the subject may comprise positioning the two transducers of the wearable ultrasound device on the head of the subject with the head positioned between the two transducers, the first member of the head support assembly extending across a forehead of the subject, a nasal support member of an eyeglasses frame of the head support assembly resting on the nose of the subject, and one or more ear support members of the head support assembly resting on one or more ears of the subject, the eyeglasses frame being secured to the first member of the head support assembly. In these embodiments of the method 400 using the wearable ultrasound device 200, as well as other embodiments, the method 400 may further comprise adjusting a strap of the head support assembly to tighten or loosen the head support assembly around the head of the subject.

[0104] In many embodiments of the method 400, activating 420 the two transducers to generate ultrasonic waves effective to stimulate the target region ofthe brain of the subject without ablating the target region of the brain of the subject comprises activating the two transducers to generate ultrasonic waves at a frequency of about 200 kHz to about 650 kHz effective to stimulate the target region of the brain of the subject without ablating the target region of the brain of the subject The ultrasonic waves generated by the two transducers in the method 400 may have a focal width that is at least two times larger than the target region in the brain of the subject.184921-1718-5658\1

[0105] In some embodiments of the method 400, the target region may comprise a region of the brain that is associated with at least one of cognitive decline or Alzheimer’s disease. In these and other embodiments of the method 400, the target region may include one or more of a region of the brain associated with memory functions, a hippocampus of the brain, an entorhinal cortex of the brain, an amygdala of the brain, or a nucleus basalis of Meynert of the brain.

[0106] In some embodiments of the method 400, the target region may comprise a region of the brain associated with depression. In these and other embodiments of the method 400, the target region may include one or more of a cingulate cortex of the brain or a subcallosal cingulate cortex of the brain

[0107] In some embodiments of the method 400, the target region may comprise a region of the brain associated with chronic pain. In these and other embodiments of the method 400, the target region may include one or more of an anterior cingulate cortex of the brain, a medial cingulate cortex of the brain, a subcallosal cingulate cortex, a ventral posterolateral nucleus, or a ventral posteromedial nucleus.

[0108] In some embodiments of the method 400, the target region may comprise a region of the brain associated with addiction In these and other embodiments of the method 400, the target region may include one or more of a nucleus accumbens of the brain, a subcallosal cingulate cortex of the brain, or an anterior cingulate cortex of the brain.

[0109] In some embodiments of the method 400, the target region may comprise a region of the brain associated with food craving. In these and other embodiments of the method 400, the target region may include one or more of a nucleus accumbens of the brain or a nucleus accumbens shell of the brain.

[0110] In some embodiments of the method 400, the target region may comprise a region ofthe brain associated with anxiety. In these and other embodiments of the method 400, the target region may include one or more of an amygdala of the brain or a stria terminalis of the brain.

[0111] In some embodiments of the method 400, the target region may comprise a region ofthe brain associated with post-traumatic brain disorder. In these and other embodiments of the method 400, the target region may include one or more of an amygdala of the brain or a bed nucleus of a stria terminalis of the brain.

[0112] Similar to the method 400, also disclosed herein is a method of treating a condition of a brain of a subject. This method may comprise providing wearable ultrasound device comprising two transducers and a head support assembly having the two transducers secured thereto. This method also may comprise positioning the two transducers of the wearable ultrasound device on a head of the subject with the head positioned between the two transducers and a first member of the head support assembly extending across a forehead of the subject. This method also may comprise supporting the two transducers in a selected position on the head of the subject by positioning one or more members of the head support assembly on at least one of a nose or an ear of the subject to support the wearable device. This method also may comprise, with a controller coupled to the two transducers, activating the two transducers to generate ultrasonic194921-1718-5658\1waves effective to stimulate a target region of the brain of the subject without ablating the target region of the brain of the subject, the target region being associated with the condition ofthe brain.

[0113] This method of treating a condition of a brain of a subject may use the wearable ultrasound devices 200, 300 and controllers 201 , 301 as described above in relation to the method 400. In some embodiments of this method of treating a condition of a brain of a subject, the condition of the brain may include at least one of cognitive decline or Alzheimer’s disease and the target region may include one or more of a region of the brain associated with memory functions, a hippocampus of the brain, an entorhinal cortex of the brain, an amygdala of the brain, or a nucleus basalis of Meynert of the brain.

[0114] FIG. 5 illustrates a flow diagram of a method 500 summarizing the concept for an ultrasound neuromodulation-guided ultrasound-based therapy, according to embodiments disclosed herein. As seen in the illustrated embodiment, method 500 comprises of three steps. In the proposed approach, ultrasound neuromodulation is sequentially applied, one by one, to multiple brain targets. Disease signs, such as tremor amplitude, numerical rating scale of pain intensity, changes in mood, or the frequency of interictal epileptic events, is measured during (and immediately after) the neuromodulation of each target by one or more sensors.

[0115] In the first step (e.g., at block 502), low-intensity focused ultrasound (LIFU) neuromodulation is sequentially applied to multiple predetermined brain targets. Each target is stimulated individually for a duration of about 30 to 120 seconds while disease signs such as tremor amplitude, pain intensity, mood scale, or interictal epileptic event frequency are measured. The measurement period typically lasts from about 1 to 30 minutes per target

[0116] In the second step (e.g., at block 504), an operator or algorithm identifies one or more brain targets that yield maximum improvement or meet a predefined threshold of therapeutic benefit.

[0117] In the third step (e.g., at block 506), high-intensity focused ultrasound (HIFU) or sustained low-intensity focused ultrasound (LIFU) therapy is applied to the subset of selected targets. This high-energy intervention enhances the therapeutic effect and provides durable relief of the disease signs.

[0118] In practice, the system can operate at a relatively low frequency of 325 kHz (bandwidth 270-380 kHz) to accentuate mechanical effects and minimize the shift of the focal point, field distortion, and acoustic attenuation.

[0119] Evaluation through 21 ex-vivo human skulls demonstrated a mean focal shift of 1.2 mm (maximum 2.6 mm), a mean focal volume increase of 18%, and an average pressure attenuation of 67%, all achieved without phase correction. These results confirm that low-frequency systems are less susceptible to skull-induced aberrations and support their feasibility for combined neuromodulation and mechanical therapy applications.

[0120] Thus, transient low-intensity ultrasound offers reversibility, while high-intensity ultrasound or sustained low-intensity ultrasound provides long-lasting therapeutic outcomes. Combining these modalities enables individualized treatment by identifying the most therapeutically relevant brain regions through low-intensity neuromodulation before applying high-204921-1718-5658\1intensity or high-energy therapy Neuromodulation and cavitation-related mechanisms (e.g., blood-brain barrier modulation, localized drug release) are more efficient at lower frequencies, which also reduce dephasing and attenuation. Accordingly, next-generation mechanical therapy systems should operate at low frequencies sufficient to preserve focus at the scale of individual brain nuclei (e.g., the ventral intermediate nucleus, approximately 4 mm in diameter).

[0121] FIG. 6 instantiates the method 500 of FIG. 5, according to embodiments described herein. As seen in the illustrated embodiment, low-intensity ultrasound neuromodulation (LIFU) is sequentially applied (e.g., at sequences 602A, 602B), one by one, to five brain targets 600 (e.g., target 1, target 2, target 3, target 4, and target 5). In some embodiments, LIFU constitutes a low-energy intervention to cause transient changes, on the order of several (e.g., 1-30) minutes, in signs or symptoms. In some embodiments, the LIFU peak intensity and average intensity comply with the indices of the FDA 510(k) Track 3 guidelines (FDA, 2019), i.e. , ISPPA (spatial-peak, pulse-average intensity) < 190 W / cm2and ISPTA (intensity spatial-peak temporal average) < 720 mW / cm2. The typical duration of LIFU for each target is 30-120 seconds.

[0122] Disease signs, such as tremor amplitude, numerical rating scale of pain intensity, mood scale, or the frequency of interictal epileptic events, is measured during and immediately after the neuromodulation of each target by one or more sensors. Otherwise stated, a disease-related metric can be gathered, measured, or collected that includes a symptom score or electrophysiologic biomarker associated with a disease or disorder. Otherwise stated, the system can sequentially deliver low-intensity focused ultrasound (LIFU) neuromodulation to any number of brain targets while measuring one or more disease-related metrics. The typical duration of the measurements may be 1-30 minutes per target.

[0123] As seen in FIG. 6, changes in measured values are indicated as arrows with certain length (e.g., a longer upward arrow is associated with worse signs or symptoms; a longer downward arrow is associated with better signs or symptoms). The continuous lines (e.g., lines 605A, 605B, 605C) provide a baseline state of disease signs (no change) prior to any intervention. The dotted lines (e.g., line 608B) provide a threshold state of disease signs after intervention.

[0124] In some embodiments, such as for essential tremor or Parkinson's disease, the measure of the disease signs is the tremor amplitude In some embodiments, the tremor amplitude is measured using a dataglove or other device that quantifies the hand oscillations caused by tremor. In some embodiments, such as for chronic pain, the measure of the disease symptoms is pain intensity. In some embodiments, the pain intensity is measured using the numerical rating scale or the visual analog scale of pain intensity. In some embodiments, such as for intractable epilepsy, the measure of the disease signs are interictal spike events recorded using electroencephalography. In some embodiments, the interictal spikes are quantified through the frequency of their occurrence In some embodiments, such as major depression, the measure of the disease symptoms is Beck's Depression Inventory. In some embodiments, such as post-traumatic stress disorder (PTSD), the measure of the disease symptoms is the PTSD Checklist for DSM-5 (PCL-5 scores).214921-1718-5658\1

[0125] Next (e.g., at the second step, or block 504 as described with respect to FIG. 5), an operator or an algorithm selects a target or a plurality of targets that minimizes the disease signs or exceeds a predefined threshold of improvement. The dashed threshold 608b exemplifies a threshold for the selection or satisfies a selection criterion. Otherwise stated, in some cases, this step selects a target or a plurality of targets that reduce the signs most strongly. In some embodiments, this selection is performed by an operator. In other embodiments, this selection is performed by an algorithm. In some embodiments, the selection rests on a predefined sign or symptom improvement threshold. In such embodiments, only the targets that show an improvement greater than this threshold are selected for the subsequent HIFU or sustained LIFU treatment. In this instantiation, target 3 and target 4 are selected (seen in rectangle 604).

[0126] Finally (e.g., at the third step, or block 506 as described with respect to FIG. 5), sequence 602C applies therapeutic ultrasound or HIFU to the selected targets 3 and 4. This high-energy intervention improves the signs even more (longer downward arrows) and also provides a relief that is durable and / or non-reversible.

[0127] In some embodiments, HIFU delivers into the target substantially more energy than LIFU to cause durable changes. In some embodiments, HIFU substantially exceeds the peak intensity and average intensity, spatial peak pulse average (SPPA or ISPPA) or spatial peak temporal average (SPTA or ISPTA) indices of the FDA 510(k) Track 3 guidelines (FDA, 2019). In some embodiments, the targets are treated with HIFU in the order of their relative benefit determined in the selection step. This high-energy intervention is aimed at substantially improving the disease signs or symptoms (long downward arrows) for a durable time period, on the order of 2 or more weeks.

[0128] In some embodiments, the treatment is provided using LIFU itself, but of substantial longer duration than the transient LIFU used to evaluate the relative contribution of each brain target. The therapeutic LIFU complies with the peak intensity and average intensity, spatial peak pulse average (SPPA or ISP A) and spatial peak temporal average (SPTA or IS TA) indices of the FDA 510(k) Track 3 guidelines (FDA, 2019), but is delivered for durations that can range from 3 minutes to several hours per day. Several hours may be 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, or more. This high-energy intervention is aimed at substantially improving the disease signs or symptoms (long downward arrows) for a durable time period, on the order of 2 or more weeks.

[0129] In some embodiments, the brain targets are situated in deep brain regions, whereas in other embodiments, they are situated in shallow, cortical regions of the brain. In some embodiments, the individual brain targets are sub-regions of a brain region. In some embodiments, the typical duration of the transient LIFU neuromodulation for each target is 30-120 seconds.

[0130] FIG 6 illustrates five targets to be stimulated in sequence However, in some embodiments, less, more, or any number of individual brain targets as is feasible may be targeted via the system and / or method.224921-1718-5658\1

[0131] In some embodiments, the first and second step (e.g., blocks 502 and 504 as described with respect to FIG. 5), can correspond to, or be considered as a screening or a scanning mode in which the phased-array transducer configured to operate in low-intensity screening mode that produces transient neuromodulation The third step (e.g., block 506 as described with respect to FIG. 5), can correspond to, or be considered as a high-intensity and / or therapeutic mode that produces durable neuromodulation effects. A controller can be configured to switch between modes according to data acquired during the screening mode.

[0132] FIG. 7 illustrates a perspective view of a setup for a transducer array 700, according to embodiments described herein. As seen in the illustrated embodiment, the transducer array 700 includes arrays 702 placed in custom frame, a skull cap 704, magnets 706 securing the skull cap 704 to a positioning system, and a fiber optic hydrophone 708 connected to a micro manipulator 710. In some embodiments, a single array contains a 10 x 13, 13x 13 mm square PZT elements in a spherical configuration with a radius of about 100 mm.

[0133] FIG. 8 illustrates an alternate view of a single transducer array 700 of FIG 7, according to embodiments described herein.

[0134] An MRI-compatible ultrasonic neuromodulation device, referred to as Diadem, has been previously developed and deployed in human studies. Diadem comprises two 126-element phased arrays that enable electronic focusing of ultrasound into a specified brain target via a software-controlled interface. Safety of operation is ensured by maintaining both peak and timeaverage ultrasound intensities within the FDA 510(k) T rack 3 guidelines.

[0135] A next-generation device, termed High Beam, extends the Diadem platform by integrating neuromodulation (LIFU) and neurosurgical functionality (HIFU) within a single system. HighBeam incorporates several major improvements, including a high-power driving system (Prodigy HIFU256), enhanced focal precision, and lower-frequency operation (325 kHz) to mitigate phase distortions induced by the skull.

[0136] The Prodigy HIFU256 platform provides up to 11.5 W per channel, yielding a total power capacity of approximately 2,898 W across 252 channels. This output enables both low-intensity neuromodulatory applications and high-intensity therapeutic interventions, including mechanical therapies. The system is fully programmable, allowing precise control over acoustic output, waveform parameters, and treatment sequencing for combined neuromodulation and focused ultrasound therapy

[0137] FIGS. 9A-1 through 9A-3 and 9B-1 through 9B-3 illustrate a focusing capacity of the system, according to embodiments described herein. As seen in the illustrated embodiment, FIGS 9A-1 through 9A-3 illustrate orthogonal slices through the acoustic intensity field measured in free field at a 30V after transcranial propagation through a sample human skull FIGS. 9B-1 through 9B-3 illustrate orthogonal slices through the acoustic intensity field measured in free field at a 30 V FIGS 9A-1 and 9B-1 illustrate sagittal (YZ) slices FIGS 9A-2 and 9B-2 illustrate coronal (XY) slices, and FIGS. 9A-3 and 9B-3 illustrate transverse (XZ) slices, all respectively centered at the acoustic focus.234921-1718-5658\1

[0138] As shown with respect to FIGS. 7 and 8, a 256-element hemispherical array operating at 325 kHz was evaluated to quantify its suitability for mechanical therapies through the skull. Free-field pressure output and steering were characterized, followed by measurements of attenuation, focal shift, and focal-volume change through 21 ex-vivo human skulls. Simulations indicated that two 128-element hemispherical arrays offset by 30 degrees create a compact focus and support through-transmit calibration. This configuration guided fabrication of two custom 128-element arrays with 1 mm kerf and 100 mm radius, mounted in mirrored orientation and powered by the Verasonics Vantage NXT-256 platform In some cases, each element of the 128-element arrays can be independently driven via a driving voltage configured and / or controlled by a controller (e.g , as described with respect to FIG. 1)

[0139] Pressure fields were acquired with a fiber-optic hydrophone in a degassed water tank using a three-axis scanning system. Transmission, acquisition, and spatial mapping were coordinated via a custom MATLAB interface. Peak negative pressure was recorded at the geometric focus using 40-cycle bursts across 5 to 80 V input levels. To avoid hydrophone overload, element-level emissions were acquired separately and numerically summed. Steering performance was mapped through three 80 x 80 mm plane scans with 0.5 mm step size, and intensities were normalized to the geometric focus. Complementary simulations extended the field of view to identify peripheral lobes.

[0140] Ex-vivo skulls were prepared by isolating the cranial vault and removing air content through extended degassing. A geometric alignment protocol matched each skull’s interior reference point to the free-field focus, ensuring reproducible positioning. A 15 x 15 x 15 mm region centered at the free-field focus was raster-scanned at 0.5 mm resolution under identical drive conditions for both free-field and transcranial measurements.

[0141] At 325 kHz, the array produced a well-confined focus with full-width-half-maximum dimensions of roughly 6 mm (X), 3 mm (Y), and 3 mm (Z) Across the skull set, mean focal shift was approximately 1.1 mm and focal volume increased by about 17 %. Peak pressure decreased by an average of 67 % relative to free field. These values align with general trends in the 300-400 kHz range, which consistently show reduced aberration and improved focus preservation compared with higher-frequency operation. A dorsal-ventral bias in focal displacement was observed, attributable to skull curvature. T ransmission efficiency did not differ by sex, and age showed a modest correlation with transmitted pressure

[0142] Measurements indicate that attenuation within the bone dominates the total transmission loss, whereas aberration contributions remain comparatively small at this frequency. These findings are consistent with earlier low-frequency reports showing that operation below 400 kHz lowers inter-skull variability, decreases focal displacement, and limits spatial degradation relative to higher-frequency systems that typically exhibit higher attenuation and larger uncorrected shifts

[0143] Thus, the present results complement prior low-frequency investigations by quantifying focal behavior through intact human skulls rather than post-craniectomy conditions. Collectively, the data identify 300-400 kHz as a practical operating window for transcranial mechanical244921-1718-5658\1therapies and neuromodulation due to improved transmission and reduced distortion without phase correction.

[0144] Low-frequency operation further ensures minimal targeting deviation. As shown in FIGS 9A-1 through 9B-3, the acoustic focus remains closely aligned with the intended target coordinates (0, 0), with observed focal shifts typically below 1 mm and never exceeding 2 mm. This precision level is sufficient for high-accuracy therapeutic interventions in deep brain structures.

[0145] FIG. 10 illustrates a plot 1000 of the pressure output at the geometric focus as a function of input voltage. The measurements were performed in a free field, and the dashed line represents a quadratic fit.

[0146] As shown, the prototype system demonstrated broad operational versatility, supporting both low-intensity (LIFU) and high-intensity (HIFU) transcranial ultrasound applications. In free-field conditions, the system generated peak negative pressures of up to approximately 35 MPa, a magnitude comparable to that required for histotripsy, with the potential for further increases through elevated drive voltages. Accordingly, operation at a relatively low frequency (325 kHz) facilitates the induction of mechanical effects while minimizing phase aberrations and acoustic attenuation.

[0147] In some embodiments, the system supports electronic beam steering with an effective range of approximately ±25 mm along the medial-lateral axis, ±17 mm along the dorsal-ventral axis, and ±14 mm along the anterior-posterior axis. This coverage can be further extended through mechanical adjustment of head position relative to the array assembly.

[0148] FIG. 11 A-11C illustrate plots 1100A, 1100B, 1100C characterizing the electronic steering capacity, according to embodiments described herein. Normalized intensity relative to that at the geometric focus is presented. The steering extent is shown in each direction from the geometric focus. Plot 1100A corresponds to AX, or medial-lateral direction, plot 1100B corresponds to AY or dorsal-ventral, plot 1100C corresponds to AZ or anterior-posterior. Measured intensity loss values are compared with simulated results, and data are plotted until the intensity falls below half of the maximum intensity observed at the geometric focus.

[0149] The system demonstrated a broad electronic steering range while maintaining stable focal intensity. The maximum steering range preserving at least 50% of the peak intensity was approximately ±25 mm in the medial-lateral direction, ±17 mm in the dorsal-ventral direction, and ±14 mm in the anterior-posterior direction. Beyond these limits, focal distortion and attenuation increased progressively. The steering envelope can be further expanded through controlled adjustment of head position relative to the transducer arrays.

[0150] FIG. 12A-12B illustrate plots 1200A, 1200B illustrating ultrasound attenuation through ex-vivo human skulls at 325 kHz, according to embodiments described herein Histograms are shown for the distributions of normalized pressure (plot 1200A) and normalized intensity (plot 1200B) through ex-vivo human skulls (n = 21), relative to free-field measurements.

[0151] Ex-vivo human skulls were placed within the ultrasound propagation path to quantify transcranial attenuation. Focal peak pressure and intensity were measured for each skull and254921-1718-5658\1normalized to tree-field conditions. On average, skulls reduced peak pressure by approximately 67%, with a range of 50-80%, and reduced acoustic intensity by approximately 87%, with a range of 65-95%. Attenuation accounted for the majority of transmission loss — approximately 95% on average — while phase aberration contributed the remaining 5%, with inter-subject variability of ±3%. These findings confirm attenuation as the primary mechanism of transmission loss at 325 kHz.

[0152] The total focal volume change was obtained by comparing skull-transmitted and free-field volumes To differentiate attenuation and aberration effects, individual transducer element waveforms at the geometric focus were compared to their free-field counterparts. Attenuation was estimated as the average reduction in waveform amplitude, while aberration was quantified as the residual pressure loss due to destructive interference arising from phase misalignment. This decomposition enabled separate assessment of material absorption and phase distortion contributions to total transmission loss.

[0153] Finally, demographic effects on transmission were evaluated using multiple linear regression, treating donor age as a continuous variable and sex as a categorical factor (ANCOVA model). This analysis permitted assessment of skull-specific influences on acoustic propagation efficiency across the ex-vivo sample cohort.

[0154] FIG. 13 illustrates a plot 1300 illustrating the percent pressure loss due to attenuation versus aberration, according to embodiments described herein. Violin plots depict the pressure loss through the skull attributable to attenuation and aberration when individual elements are compared with free-field conditions. The average pressure loss due to attenuation was determined to be 95 + 3%.

[0155] FIG. 14A and 14B illustrate plots 1400A, 1400B characterizing the normalized peak pressure based on skull demographic data, according to embodiments described herein. Plot 1400A illustrates a scatter plot shows skull donor age versus normalized pressure, indicating a modest correlation between skull age and transmitted pressure (p = 0.035). Plot 1400B illustrates a bar graph presenting the average normalized pressure for male and female skulls (p = 0.23).

[0156] Statistical analysis was performed to assess the influence of donor age and sex on acoustic transmission efficiency. A multiple linear regression model revealed a positive relationship between age and transmitted pressure (p = 0.044 MPa / year), though this effect did not reach conventional significance (F(1 , 18) = 3.93, p = 0.063). A Pearson correlation analysis confirmed a modest but statistically significant association between age and transmitted pressure (r = 0.46, p = 0.035), indicating that older skulls may exhibit reduced attenuation.

[0157] Sex was not a significant predictor of transmission efficiency (F(1 ,18) = 1.53, p = 0.23), though male skulls exhibited slightly lower average transmitted pressure (-0.60 MPa) relative to female skulls. The overall regression model accounted for approximately 27.4% of the variance in transmitted pressure (R2= 0 274) These findings suggest that age-related changes in skull composition may modestly influence acoustic transmission, while sex-based differences are negligible.264921-1718-5658\1

[0158] FIG. 15 illustrates a plot 1500 characterizing the focusing ability of the system through human skulls, according to embodiments described herein. Violin plots 1500A, 1500B, 1500C, 1500D depict the distribution of focal shift across individual skulls and directions, showing displacement along each axis: plot 1500A corresponding to AX, or the medial-lateral direction, plot 1500B corresponding to AY or the dorsal-ventral direction, plot 15000 corresponding to AZ, or the anterior-posterior direction, as well as plot 1500D corresponding to the magnitude of the vector shift Points correspond to individual skulls and thick black lines indicate the median of each distribution.

[0159] Introduction of skull specimens into the ultrasound path resulted in measurable displacement of the acoustic focus relative to the free-field condition. The mean total focal shift was 1.2 ± 0.5 mm (range: 0.5-2.6 mm), a statistically significant deviation from zero (one-sided t-test, t_20 = 9.75, p < 0.001) The largest component of displacement occurred along the dorsal-ventral (Y) axis, with an average shift of 0 7 mm. Shifts along the medial-lateral (X) and anterior-posterior (Z) axes were minimal, averaging -0.02 mm and 0.07 mm, respectively.

[0160] Statistical testing confirmed that only the Y-axis shift differed significantly from zero (two-sided t-test, t_20 = 3.62, p = 0 002), while X-axis (t_20 = -0.29, p = 0.771) and Z-axis (t_20 = 0.57, p = 0.576) displacements were not significant. The consistent dorsal-ventral bias suggests refraction effects specific to skull morphology rather than mounting variability. The discrete structure of the violin distributions reflects the 0.5 mm raster-scan step size, corresponding to a localization uncertainty of ±0.25 mm per axis — small relative to the observed mean Y-axis displacement.

[0161] FIG. 16 illustrates a plot 1600 characterizing the effects of the skull on focal volume, according to embodiments described herein. Plot 1600 is a histogram presenting the focal volume within each skull. The dashed triangle indicates the focal volume obtained in free-field conditions; the solid triangle denotes the mean value.

[0162] Introduction of ex-vivo skulls into the ultrasound path resulted in a measurable alteration of focal geometry. Comparison of transcranial to free-field measurements revealed an average increase in focal volume of 18 ± 35% (mean ± s.d.). Visual inspection of orthogonal field slices across skulls confirmed that the primary focal shape was qualitatively preserved despite localized broadening. However, intermittent side lobes exceeding the half-maximum threshold produced irregular field boundaries, rendering axis-specific full-width-half-maximum (FWHM) analyses unreliable. Accordingly, focal volume was used as the principal quantitative descriptor of focusing performance.

[0163] FIG. 17A illustrates a plot 1700A of the ultrasound pressure field produced by the Beam through an ex-vivo human skull at a location corresponding to the ventral intermediate nucleus, according to embodiments described herein. FIG. 17B illustrates a plot 1700B of the ultrasound pressure at the target as a function of the voltage applied to the transducers, according to embodiments described herein. All measurements were obtained using a calibrated fiber-optic hydrophone.274921-1718-5658\1

[0164] The HP-6510K-126-DE arrays operate at half the frequency of the Diadem system (325 kHz versus 650 kHz). This reduction in frequency effectively mitigates phase distortions and defocusing that occur during ultrasound propagation through the skull. Lower-frequency operation thus enables improved transmission efficiency and focal stability for transcranial targeting.

[0165] The system produces a sharply confined focus in deep brain regions through ex-vivo human skulls, achieving a typical full-width-at-half-maximum (FWHM) intensity profile of approximately 3.3 x 3.4 * 3.8 mm. The arrays can deliver pressure amplitudes exceeding 5 MPa through skull specimens, surpassing the acoustic thresholds required for effective HIFU treatments.

[0166] FIGS. 18A through 18H illustrate the focusing capacity through human skulls, according to embodiments described herein. Ultrasound pressure fields produced by the beam are shown for eight different ex-vivo human skulls. All measurements were obtained using a calibrated fiber-optic hydrophone.

[0167] The low-frequency operation indeed circumvents the phase distortions. The system provides sharp focus through human ex-vivo skulls. Moreover the focus, which is aimed at the coordinate 0-0, is shifted from the intended target minimally, typically by less than 1 mm and in all cases less than 2 mm. This level of targeting accuracy is sufficient for precision therapies.

[0168] Any methods disclosed herein comprise one or more steps or actions for performing the described method. The method steps and / or actions may be interchanged with one another. In other words, unless a specific order of steps or actions is required for proper operation of the embodiment, the order and / or use of specific steps and / or actions may be modified.

[0169] References to approximations are made throughout this specification, such as by use of the term “substantially.” For each such reference, it is to be understood that, in some embodiments, the value, feature, or characteristic may be specified without approximation. For example, where qualifiers such as “about” and “substantially” are used, these terms include within their scope the qualified words in the absence of their qualifiers.

[0170] Similarly, in the above description of embodiments, various features are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure. This method of disclosure, however, is not to be interpreted as reflecting an intention that any claim require more features than those expressly recited in that claim Rather, as the following claims reflect, inventive aspects lie in a combination of fewer than all features of any single foregoing disclosed embodiment.

[0171] The claims following this written disclosure are hereby expressly incorporated into the present written disclosure, with each claim standing on its own as a separate embodiment. This disclosure includes all permutations of the independent claims with their dependent claims. Moreover, additional embodiments capable of derivation from the independent and dependent claims that follow are also expressly incorporated into the present written description

[0172] Without further elaboration, it is believed that one skilled in the art can use the preceding description to utilize the invention to its fullest extent. The claims and embodiments disclosed herein are to be construed as merely illustrative and exemplary, and not a limitation of the scope284921-1718-5658\1of the present disclosure in any way. It will be apparent to those having ordinary skill in the art, with the aid of the present disclosure, that changes may be made to the details of the abovedescribed embodiments without departing from the underlying principles of the disclosure herein. In other words, various modifications and improvements of the embodiments specifically disclosed in the description above are within the scope of the appended claims. Moreover, the order of the steps or actions of the methods disclosed herein may be changed by those skilled in the art without departing from the scope of the present disclosure. In other words, unless a specific order of steps or actions is required for proper operation of the embodiment, the order or use of specific steps or actions may be modified. The scope of the invention is therefore defined by the following claims and their equivalents.294921-1718-5658\1

Claims

CLAIMSWhat is claimed is:

1. A method for treating a neurological disorder in a subject, comprising:sequentially delivering low-intensity focused ultrasound (LIFU) neuromodulation to a plurality of brain targets while measuring one or more disease-related metrics;selecting, based on the measured metrics, a subset of brain targets exhibiting improvement satisfying a predefined selection criterion; anddelivering high-intensity focused ultrasound (HIFU) neuromodulation or sustained low-intensity focused ultrasound (LIFU) to the selected subset to produce durable reduction of one or more disease signs or symptoms.

2. The method of claim 1, wherein a spatial-peak, pulse-average intensity of the LIFU neuromodulation is less than 190 W / cm2and an intensity spatial-peak temporal average of the LIFU neuromodulation is less than 720 mW / cm2.

3. The method of claim 1 or 2, wherein a spatial-peak, pulse-average intensity of the HIFU neuromodulation exceeds 190 W / cm2or an intensity spatial-peak temporal average of the HIFU neuromodulation exceeds 720 mW / cm24. The method of any one of claims 1 to 3, wherein a duration of the LIFU neuromodulation for the identification of each target is 30-120 seconds, whereas the duration of the sustained LIFU neuromodulation for treatments ranges from 3 minutes to several hours.

5. The method of any one of claims 1 to 4, wherein the LIFU neuromodulation constitutes a low-energy intervention to cause reversible changes in symptoms that last between 1 and 30 minutes.

6. The method of any one of claims 1 to 5, where the individual brain targets are a sub-region of a brain region.

7. The method of claim 1, where a disease of the disease-related metric is essential or parkinsonian tremor and the disease-related metric is a tremor amplitude.

8. The method of claim 7, where the tremor amplitude is measured using a dataglove.

9. The method of claim 1, where a disease of the disease-related metric is chronic pain and the disease-related metric is pain intensity.

10. The method of claim 9, where the pain intensity is measured using a numerical rating scale or a visual analog scale of pain intensity.

11. The method of claim 1, where a disease of the disease-related metric is epilepsy and the disease-related metric is interictal spike events recorded using electroencephalography.

12. The method of claim 11, where the interictal spike events are quantified by a frequency of their occurrence.

13. The method of claim 1, where a disease of the disease-related metric is major depression and the disease-related metric is a Beck Depression Inventory14. The method of claim 1, where a disease of the disease-related metric is post-traumatic stress disorder (PTSD) and the disease-related metric is a PTSD Checklist for DSM-5 (PCL-5 scores).304921-1718-5658 115. A method for treating a neurological disorder in a subject, comprising:screening a plurality of brain targets to identify a subset of the plurality of brain targets that satisfies a selection criterion indicative of improvement based on a disease-related measurement; anddelivering therapeutic acoustic energy to the identified subset of brain targets to produce a durable neuromodulatory effect16. The method of claim 15, wherein screening the plurality of brain targets to identify a subset of the plurality of brain targets comprises operating a phased-array transducer in a low-intensity mode that produces transient neuromodulation at the plurality of brain targets while measuring one or more disease-related metrics.

17. The method of claim 15 or 16, wherein delivering therapeutic acoustic energy to the identified subset of brain targets comprises operating a phased-array transducer in a high-intensity or high-energy mode.

18. The method of any one of claims 15 to 17, wherein one or more sensor or an operator acquire the disease-related measurements during and immediately after the delivery of the therapeutic acoustic energy.

19. A method for delivering therapeutic ultrasound to a subject, comprising:driving an ultrasound array at a frequency between 250 kHz and 650 kHz; steering an acoustic focus of the ultrasound array within a brain of a subject; and delivering a therapeutic acoustic at the steered acoustic focus.

20. The method of claim 19, wherein steering the acoustic focus of the ultrasound array within the brain of the subject comprises steering the acoustic focus of the ultrasound array sequentially to a plurality of brain targets.

21. The method of claim 19 or 20, further comprising maintaining a focal displacement of less than 2 mm relative to a free-field focus of the ultrasound array.314921-1718-5658\1

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