Systems and methods for combined surface and deep brain neuromodulation

Abstract

A system for noninvasive neuromodulation of brain regions is provided. The system includes, one or more ultrasound transducers configured to deliver ultrasonic stimulation energy to an intended deep brain region and a transcranial magnetic stimulation (TMS) coil configured to deliver magnetic stimulation energy to an intended superficial cortical region. The system is configured to deliver the ultrasonic stimulation to a deep brain region and the magnetic stimulation to a superficial brain region. The intended deep brain region and intended superficial cortical region are a pairing corresponding to a neurological or psychological disorder.

Description

SYSTEMS AND METHODS FOR COMBINED SURFACE AND DEEP BRAINNEUROMODULATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 706,575 filed on October 11 , 2024, and titled “Systems and Methods for Combined Surface and Deep Brain Neuromodulation” which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present disclosure relates to systems and methods for applying noninvasive neuromodulation methods to a shallow and a deep brain target in the human brain 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.

[0011] FIG. 5 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 described herein.

[0012] FIG. 6 illustrates a plot of a schema in which TMS and US are applied concurrently, according to embodiments described herein.

[0013] FIG 7 illustrates a plot of a schema in which TMS and US are applied sequentially according to a first order, according to embodiments described herein.

[0014] FIG. 8 illustrates a plot of a schema in which TMS and US are applied sequentially according to a second order, according to embodiments described herein.14928-3495-6655' 1

[0015] FIG. 9 illustrates a method for noninvasive neuromodulation of brain regions in a wearable ultrasound device, according to embodiments disclosed herein.DETAILED DESCRIPTION

[0016] Mental and neurological disorders affect nearly one fifth of the world's population (Ahrnsbrak et al., 2017; Lancet, 2017). Approximately one third of patients across mental and neurological conditions are treatment-resistant (Al-Harbi, 2012; Bystritsky, 2006; Ferguson, 2001 ; Freire et al., 2016; Hamner et al., 2004; Jaffe et al. , 2019; Lindenmayer, 2000; Posse and Nemeroff, 2012; Widge and Dougherty, 2015; World Health Organization, 2009).Neuromodulation has the potential to provide a targeted reset of the malfunctioning circuits (Arie and Shils, 2017; Perlmutter and Mink, 2006), 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.

[0017] Mental and neurological disorders involve neural networks situated deep in the brain, including limbic, basal ganglia, memory, and brain stem networks (Alexander et a / . , 2019;Bishop, 2007; Davidson, 2002; Johansen-Berg et al., 2008; Morris et al., 2020; Rodrfguez-Cano et al , 201 ; Tye et al , 2011 ) 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 (Kisely et al., 2018; Meeres and Hariz, 2022), but the surgical implantation of stimulating leads is associated with high costs and risks, including brain hemorrhage, infection, and in some cases, death.

[0018] On the other hand, current noninvasive neuromodulation modalities do not have the necessary intensity or spatial resolution at depth Electroconvulsive therapy (ECT) resets the deep brain structures using large currents that induce brain-wide seizures (Lisanby, 2007). This broad activation often results in cognitive side effects such as memory loss (Ingram et al., 2008).

[0019] Transcranial magnetic stimulation (TMS) can modulate cortical regions; the fields are weak at the deep brain regions involved in mental and neurological disorders. TMS can likely modulate deep brain networks via connections with the stimulated cortical regions. However, this indirect effect has contributed to variable response and the need for many repeated applications to induce beneficial effects (Nicolo et al , 2015)

[0020] Low-intensity transcranial focused ultrasound (US) combines the depth and precision of DBS with the noninvasiveness of TMS (Fini and Tyler, 2017; Kubanek, 2018; Naor et al., 2016). However, the effects of ultrasonic neuromodulation have been reported to be moderate (Ai et al., 2018; Badran et al. , 2020; Fomenko et al., 2020; Lee et al., 2015, 2016; Legon et al. , 2014, 2018a, b; Sanguinetti et al., 2020).

[0021] Thus, TMS and US are both noninvasive neuromodulation approaches and each has its strength: TMS can provide strong effects in shallow cortical regions, whereas US can access deep brain structures Methods and systems that combine these two modalities and their strengths are described herein to provide benefits to patients with mental and neurological disorders24928-3495-6655' 1

[0022] The present text describes methods and systems that apply TMS to a surface region and US to a deep brain region. Thus, this method combines the two key strengths of TMS (strong neuromodulation effects at surface) and US (neuromodulation at depth)

[0023] 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 anatomical landmarks, 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, and from one or a plurality of TMS coils into a specified surface target.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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

[0029] 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 to34928-3495-6655' 1selectively 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. The ultrasonic waves generated by the one or more transducers have a focal width that is at least about three millimeters and / or larger than the target region of the body of the subject. In some embodiments, the focal width may be determined solely in relation to the size of the target area, embodiments where there is no absolute minimize size of the focal width are within the scope of this disclosure. For example, embodiments wherein the target region is at least two times larger than the target region, regardless of the absolute size of the focal width are within the scope of this disclosure Similar focal widths at least three times, at least four times, at least 1 5 times, or greater than 5 times larger than the target region are all within the scope of this disclosure.

[0030] 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

[0031] 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

[0032] 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.

[0033] 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 likelihood44928-3495-6655' 1or even ensures that the brain target region 20a is engaged by the ultrasonic waves 115 (e.g., modulated or stimulated) — even in cases without precise guidance. The relatively large focal width 120 or volume may be produced by at least one of the relatively low frequencies of the ultrasonic waves 115 emitted by the transducers 102 and / or the multi-element arrays. In many embodiments, the focal width 120 is at least about three millimeters. In some embodiments, the focal width or volume of the transducers is about two to about three times larger than the brain target region 20a. This focal width 120 allows the brain target region 20a be stimulated or activated by the ultrasonic waves 115 even during in-home use in which precision guidance is not available. In some instances, deep brain nuclei or peripheral targets may span about 2 mm to about 5 mm For such targets, a focal width of an ultrasound beam may be from about 2 mm to about 15 mm, including from about 6 mm to about 15 mm, from about 5 mm to about 10 mm, from about 3 mm to about 8 mm, or may be less than 20 mm, less than 15 mm, less than 10 mm, and may be greater the 3 mm, greater than 6 mm, and / or greater than 9 mm. These ranges for focal widths may be applied to any embodiment described herein.

[0034] 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.

[0035] The transducers 102 may be held by the head support 103 in a position that focuses the ultrasonic waves 1 15 into the desired brain target region 20a. Accordingly, the head support 103 may 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

[0036] 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 the54928-3495-6655' 1controller 101 (e.gr, 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.

[0037] 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.

[0038] 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 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 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.

[0039] 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 510k64928-3495-6655' 1guidelines 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)

[0040] 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.

[0041] 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 in the 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.

[0042] 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.74928-3495-6655' 1

[0043] 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

[0044] 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 for presenting 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.

[0045] 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 wireless84928-3495-6655' 1PAN (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.

[0046] 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.

[0047] 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.

[0048] 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 ultrasound device 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)

[0049] 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 device94928-3495-6655' 1200 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.

[0050] 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.

[0051] 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 member 205 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.

[0052] 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 the104928-3495-6655' 1unique 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.

[0053] 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.

[0054] 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 and the 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 20a114928-3495-6655' 1may include one or more of an amygdala of the brain or a bed nucleus of a stria terminalis of the brain.

[0055] 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.

[0056] 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).

[0057] 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 and configured to emit the ultrasonic waves 115, and the coupling medium 104, 204 of the ultrasound device 100, 200.

[0058] 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.

[0059] 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 include124928-3495-6655' 1fasteners 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.

[0060] 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.

[0061] 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 region 322 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.

[0062] 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 distance134928-3495-6655' 1between 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.

[0063] 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.

[0064] 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

[0065] 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 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 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, an144928-3495-6655' 1ultrasound 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.

[0066] 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.

[0067] In some embodiments, the system can compensate for attenuation of ultrasound using an Analytical Relative Through-T ransmit (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.

[0068] 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. 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

[0069] 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 generate154928-3495-6655' 1ultrasonic waves effective to stimulate the target region of the brain of the subject without ablating the target region of the brain of the subject.

[0070] 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.

[0071] 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.g., 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 decrease a 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.

[0072] 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 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 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.

[0073] 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 of the 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

[0074] 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 ultrasound164928-3495-6655' 1device 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.

[0075] In many embodiments of the method 400, 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 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.

[0076] 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

[0077] 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

[0078] 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.

[0079] 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.

[0080] 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.174928-3495-6655' 1

[0081] In some embodiments of the method 400, the target region may comprise a region of the 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.

[0082] In some embodiments of the method 400, the target region may comprise a region of the 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.

[0083] 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 ultrasonic waves 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 of the brain.

[0084] 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.

[0085] FIG. 5 illustrates a schematic drawing of a wearable ultrasound device 500 (e.g., a wearable neuromodulation device) positioned on a head 510 of a subject and to target a target region 520a in the head 510 of a subject, according to embodiments described herein. As seen in the illustrated embodiment, a combined TMS-US ultrasound-based neuromodulation system can deliver stimulation energy to the head 510 of a subject for deep brain therapy. In some embodiments, TMS may be applied to a cortical brain region (e.g., superficial region 503) while ultrasound (US) may be applied to a deep brain region (e.g., 520a). TMS may be emitted from one or more coils, and US may be emitted from one or more ultrasonic transducers toward a selected deep brain target.

[0086] The wearable ultrasound device 500 includes one or more ultrasonic transducers (e.g., ultrasonic transducers 502a and 502b) and one or more TMS coils 505 In some embodiments, the transducers 502a-b are configured to deliver low-frequency ultrasonic stimulation, while the coils 505 are configured to deliver pulsed or repetitive magnetic stimulation. The voltages, waveforms, and timing applied to the transducers and magnetic coils may be defined by the184928-3495-6655' 1required stimulation parameters. These may include waveform type, intensity, frequency, duty cycle, and stimulation duration.

[0087] Unless otherwise noted or specified, the ultrasound system (e.g. , device 500) may include any aspect of the ultrasound devices 100, 200, and / or 300 described above. Accordingly, like features are designated with like reference numerals with the leading digits incremented to “5.” For example, the wearable ultrasound device 500 may include a controller 501, a head support assembly 507, one or more transducers 502a, 502b secured to the head support assembly 507 and configured to emit ultrasonic waves, and a coupling medium 504 that may, in some respects, resemble the controller, the head support, the transducers secured to the head support and configured to emit the ultrasonic waves, and the coupling medium of the ultrasound systems of any one of FIG. 1 , FIGS. 2A-2O, and / or FIGS. 3A-3B.

[0088] As illustrated in the example of FIG. 5, the system is placed on the head 510 such that the US transducer / s aim into a deep brain region 520a, and the TMS coil / s into a surface brain region 503. The ultrasonic waves 515 generated by the two transducers 502a-b have a focal width 520 larger than the brain target region 520a in the head 510 (e.g., brain) of the subject For example, the focal width 520 may be larger than the diameter of deep brain nuclei in the brain of the subject. In some embodiments, the controller is configured to selectively generate ultrasonic waves at a low frequency range of 200 kHz to 650 kHz. This can produce a focal width on the order of several millimeters and larger than the diameter of deep brain nuclei

[0089] In some embodiments, the head attachment mechanism for the ultrasonic transducers 502a and 502b can comprise glasses The head attachment mechanism attaches to key anatomical landmarks on the head, including the nasion and the ears. For instance, glasses are reproducibly placed on the tip of the nose (nasion), and on the ears This enables reproducible positioning across stimulation sessions and across subjects.

[0090] As illustrated in the example of FIG. 5, the ultrasound is delivered into the head from the ultrasound transducers 502a and 502b. The coupling medium 504 can be a gel or other material that conducts ultrasound As illustrated in the example of FIG. 5, the TMS is delivered into the head 510 from the TMS coil(s) 505. TMS does not require any coupling beyond air.

[0091] Accordingly, the combination of TMS and US engages both superficial and deep brain regions In some cases, a specific pairing, or coupling, of a superficial brain region and deep brain region can be targeted. In some cases, a specific pairing can be dependent or reliant on an indication to be treated. Otherwise stated, for a given indication to be treated, specific pairings or areas of both superficial and deep brain regions can be targeted simultaneously. The specific regions for individual indications are provided in rows in the table below, separately for the TMS and US target.194928-3495-6655' 1Table 1. Pairs of brain regions to be modulated with US and TMS for individual indications.

[0092] For each listed indication above (rows), the table provides the brain regions to be modulated by US (left column) and TMS (right column). Abbreviations are as follows, SCC: subcallosal cingulate cortex. ACC: anterior cingulate cortex. MCC: medial cingulate cortex. Nac: Nucleus accumbens. Nacs: Nucleus accumbens shell. BNST: Bed nucleus of stria terminalis. DLPFC: Dorsolateral prefrontal cortex. M1 : Primary motor cortex. Hipp: Hippocampus. ERC: Entorhinal cortex. VPL: Ventral posterolateral nucleus of the thalamus. VPM: Ventral posteromedial nucleus of the thalamus. NBM: Nucleus Basalis of Meynert.

[0093] Accordingly, cognitive decline can be treated via simultaneous stimulation of the Hippocampus, Entorhinal cortex, Amygdala, or Nucleus Basalis of Meynert, and the Dorsolateral prefrontal cortex. Alzheimer's disease can be treated via simultaneous stimulation of the Hippocampus, Entorhinal cortex, Amygdala, or Nucleus Basalis of Meynert, and the Dorsolateral prefrontal cortex. Major depression can be treated via simultaneous stimulation of the subcallosal cingulate cortex or anterior cingulate cortex, and the Dorsolateral prefrontal cortex. For any given indication, stimulation pairings can continue so on and so forth, as provided for by Table 1 above.

[0094] FIG. 6 through FIG. 8 illustrate plots 600, 700, 800 plotting stimulation energy delivery for both TMS and US as a function of time and will be described in tandem. Accordingly, plot 600 of FIG. 6 illustrates a schema in which TMS and US are applied concurrently (e.g., overlapping in time). Plot 700 of FIG. 7 illustrates a schema in which TMS and US are applied sequentially, according to a first order where TMS precedes US. Plot 800 of FIG. 8 illustrates a schema in which TMS and US are applied sequentially, according to a second order in which US precedes TMS. Thus, each plot illustrates a schema in which a TMS pulse pattern or pulse train (e.g., 602, 702, 802) and a US pulse pattern or pulse train (e.g., 604, 704, 804) are plotted against time (e.g., 606, 706, 806) The illustrated pulses may be representative of a repeating pattern or train of pulses in some embodiments.

[0095] In some embodiments, both US and TMS stimulation energy are delivered to the head of the subject in pulsed form. The pulsed stimulation may vary in intensity, duration, and frequency depending on the desired neuromodulatory effect. In some cases, the US and TMS pulses are applied concurrently, such that the delivery is simultaneous or effectively concurrent (e.g., within a temporal window of 5-20 milliseconds). In other embodiments, US and TMS stimulation may be applied in an alternating fashion, such that pulses of one modality are interleaved with pulses of the other, either regularly or intermittently. In some embodiments, the204928-3495-6655' 1pulses may overlap. In other embodiments, the pulses do not overlap Such an alternating approach may also be implemented with rapid switching such that the functional effect of the treatment is substantially simultaneous, near-simultaneous, or effectively simultaneous.

[0096] As shown with respect to plot 600, concurrent stimulation can induce spike-timing dependent plasticity, thus modulating synaptic connectivity between the regions stimulated by TMS and US (Caporale and Dan, 2008). In this schema, TMS and US pulses are applied or pulsed simultaneously or near-simultaneously within a narrow time window (e.g , 5-20 ms) or temporal offset, thereby enhancing the probability of associative plasticity and functional coupling between the targeted brain regions

[0097] As shown with respect to plots 700, 800 sequential applications can potentiate the circuits independently. In this approach, one modality precedes the other, such that either TMS stimulation is applied first, followed by US stimulation, (as is the case with respect to plot 700); or US stimulation is applied first, followed by TMS stimulation (as is the case with respect to plot 800). Otherwise stated, in some cases, the system is configured to deliver the magnetic stimulation energy and the ultrasonic stimulation energy sequentially in distinct stimulation periods or longer temporal offset

[0098] Sequential stimulation may potentiate or modulate the targeted neural circuits independently, while still leveraging complementary effects of the combined system. In some embodiments, sequential stimulation sessions may last for a duration of about 5 minutes to about 40 minutes per modality, though longer or shorter durations may be used depending on clinical application, patient tolerance, or specific therapeutic protocols. In some embodiments, even within sequential stimulation, a pulsed form of energy delivery is used

[0099] FIG 9 illustrates a method 900 for noninvasive neuromodulation of brain regions in a wearable ultrasound device, according to embodiments disclosed herein.

[0100] In block 902, method 900 includes driving at least one ultrasound transducer to generate ultrasonic waves.

[0101] In block 904, method 900 includes directing the generated ultrasonic waves to a deep brain target region.

[0102] In block 906, method 900 includes delivering an intended ultrasonic stimulation energy to the deep brain target region via the ultrasonic waves

[0103] In block 908, method 900 includes driving at least one transcranial magnetic stimulation (TMS) coil to generate pulses of magnetic energy.

[0104] In block 910, method 900 includes directing the generated pulses to a superficial cortical region via the pulses of magnetic energy.

[0105] In block 912, method 900 includes delivering an intended magnetic stimulation energy via the generated pulses of magnetic energy.

[0106] 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.214928-3495-6655' 1

[0107] 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.

[0108] 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.

[0109] 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

[0110] 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 scope of 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.

[0111] What is claimed is:224928-3495-6655' 1

Claims

CLAIMS1. A system for noninvasive neuromodulation of brain regions, comprising: one or more ultrasound transducers configured to deliver ultrasonic stimulation energy to an intended deep brain region; and a transcranial magnetic stimulation (TMS) coil configured to deliver magnetic stimulation energy to an intended superficial cortical region; wherein the system is configured to: deliver the ultrasonic stimulation energy to a deep brain region; and deliver the magnetic stimulation energy to a superficial brain region; wherein the intended deep brain region and the intended superficial cortical region comprise a pairing according to a neurological or psychological disorder.

2. The system for noninvasive neuromodulation of claim 1, wherein the system is configured to focus the ultrasonic stimulation energy at the intended deep brain region.

3. The system for noninvasive neuromodulation of claim 1 or 2, wherein the system is configured to focus the ultrasonic stimulation energy using the one or more ultrasound transducers operating in a frequency range that provides a focal width larger than a diameter of deep brain nuclei.

4. The system for noninvasive neuromodulation of any one of claims 1 to 3, wherein the one or more ultrasound transducers operate in a frequency range of 200 kHz to 650 kHz5. The system for noninvasive neuromodulation of any one of claims 1 to 4, wherein the one or more ultrasound transducers comprise a plurality of transducer units that provide an ability to steer the ultrasonic stimulation energy into the intended deep brain region using a multi-channel electronic controller6. The system for noninvasive neuromodulation of any one of claims 1 to 5, wherein the system is configured to compensate for skull-induced aberrations to maintain focal precision at the intended deep brain region.

7. The system for noninvasive neuromodulation of any one of claims 1 to 6, wherein 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 procedure8 The system for noninvasive neuromodulation of any one of claims 1 to 7, wherein the ultrasonic stimulation energy and the magnetic stimulation energy are applied with a timing difference within 5-20 milliseconds.

9. The system for noninvasive neuromodulation of any one of claims 1 to 7, wherein the system is configured to deliver the magnetic stimulation energy and the ultrasonic stimulation energy sequentially in distinct stimulation periods.

10. The system for noninvasive neuromodulation of claim 9, wherein the ultrasonic stimulation energy and the magnetic stimulation energy are applied sequentially, one after another, with a temporal offset along a range between about 5 minutes and about 60 minutes.11 . The system for noninvasive neuromodulation of any one of claims 1 to 10, wherein neurological or psychological disorder comprises cognitive decline.234928-3495-6655' 112. The system for noninvasive neuromodulation of any one of claims 1 to 11 , wherein intended deep brain region and intended superficial cortical region are associated with memory functions, Alzheimer's disease depression, chronic pain, food craving, anxiety, post-traumatic stress disorder (PTSD), or addiction13. The system for noninvasive neuromodulation of any one of claims 1 to 12, wherein the intended deep brain region comprises a hippocampus, a entorhinal cortex, a amygdala, a nucleus accumbens (NACs), a nucleus basalis of Meynert, a bed nucleus of a stria terminalis (BNST), a subcallosal cingulate cortex (SCC), an anterior cingulate cortex (ACC), a medial cingulate cortex (MCC), a ventral posterolateral nucleus of a thalamus, or a ventral posteromedial nucleus of the thalamus.

14. The system for noninvasive neuromodulation of any one of claims 1 to 13, wherein the intended superficial cortical region comprises a dorsolateral prefrontal cortex (DLPFC), or a primary motor cortex (M1 ).

15. A method for noninvasive neuromodulation of brain regions, comprising: driving at least one ultrasound transducer to generate ultrasonic waves; directing the generated ultrasonic waves to a deep brain target region; delivering an intended ultrasonic stimulation energy to the deep brain target region via the ultrasonic waves; driving at least one transcranial magnetic stimulation (TMS) coil to generate pulses of magnetic energy; directing the generated pulses to a superficial cortical region via the pulses of magnetic energy; and delivering an intended magnetic stimulation energy via the generated pulses of magnetic energy.

16. The method for noninvasive neuromodulation of claim 15, wherein the ultrasonic stimulation energy and magnetic stimulation energy are delivered with a timing difference within 5-20 milliseconds.

17. The method for noninvasive neuromodulation of claim 15, wherein the method is configured to deliver magnetic stimulation energy and the ultrasonic stimulation energy sequentially in distinct stimulation periods18. A non-transitory computer-readable storage medium, the computer-readable storage medium including instructions that when executed by a computer, cause the computer to: drive at least one ultrasound transducer to generate ultrasonic waves; direct the generated ultrasonic waves to a deep brain target region; deliver an intended ultrasonic stimulation energy to the deep brain target region via the ultrasonic waves; drive at least one transcranial magnetic stimulation (TMS) coil to generate pulses of magnetic energy; direct the generated pulses to a superficial cortical region via the pulses of magnetic energy; and244928-3495-6655' 1deliver an intended magnetic stimulation energy via the generated pulses of magnetic energy.

19. The non-transitory computer-readable storage medium of claim 18, wherein the ultrasonic stimulation energy and magnetic stimulation energy are delivered with a timing difference within 5-20 milliseconds.

20. The non-transitory computer-readable storage medium of claim 18, wherein the magnetic stimulation energy and ultrasonic stimulation energy are delivered sequentially in distinct stimulation periods.254928-3495-6655' 1

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