Systems and methods for compensation of ultrasound attenuation

Abstract

A method for compensating for ultrasonic attenuation by the head and hair in a wearable ultrasound device, for controlled transcranial ultrasonic therapies that deliver into the brain deterministic ultrasound pressure and intensity, is provided. The method includes positioning a wearable ultrasonic device within degassed water, the device comprising a first ultrasonic transducer and a second ultrasonic transducer; obtaining a first signal amplitude from the device by emitting a first ultrasonic pulse from the first transducer and receiving the first pulse via the second transducer; positioning the device onto the head of a subject; obtaining a second signal amplitude from the device by emitting a second ultrasonic pulse from the first transducer and receiving the second pulse via the second transducer; and scaling an amplitude of the driving voltage of ultrasonic pulses delivered via the device based on a comparison of the first signal amplitude and the second signal amplitude.

Description

SYSTEMS AND METHODS FOR COMPENSATION OF ULTRASOUND ATTENUATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 684,834 filed on August 19, 2024 and titled “Systems and Methods for Analytical and Deterministic Compensation of Ultrasound Attenuation by The Head and Ultrasound Coupling” and to United States Provisional Patent Application No. 63 / 752,735 filed on February 1 , 2025 and titled “Methods and Systems for Analytical and Deterministic Compensation of Ultrasound Attenuation by the Head and Ultrasound Coupling,” which are hereby incorporated by reference in their entireties.TECHNICAL FIELD

[0002] The present disclosure relates to systems and methods for measurement and analytical and deterministic compensation of ultrasound attenuation by the head and ultrasound coupling.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, according to embodiments described 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 front view of an ultrasound delivery system on the body of the 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 routine for compensating for ultrasonic attenuation in a wearable ultrasound device, according to embodiments disclosed herein.

[0012] FIG. 6 illustrates a scatter plot 600 plotting the computed transmission coefficient (Tc) against the actual transmission coefficient (TA), according to embodiments described herein.DETAILED DESCRIPTION

[0013] Transcranial low-intensity ultrasound provides a new set of methods to noninvasively and reversibly manipulate neural circuits (Landhuis, 2017; Meng ef al., 2020). The approaches have included transient (Kubanek ef al., 2020; Menz ef al., 2013; Riis and Kubanek, 2021 ) and14920-3362-0319' 1durable (Dallapiazza et al. , 2017; Folloni et al., 2019; Khalighinejad et al., 2020; Oh et al., 2019; Veiling and Shklyaruk, 1988; Verhagen et al., 2019) modulation of neural circuits, the delivery of specific drugs across the intact (Airan et al., 2017; Lea-Banks et al., 2019, 2021 ; Wang et al. , 2018) and transiently opened (Anastasiadis et al., 2021 ; Lipsman et al. , 2018) blood-brain barrier, and high-intensity surgeries (Ghanouni et al., 2015). Unlike other noninvasive approaches, ultrasound-based methods reach millimeter-level precision deep in the brain (Ghanouni et al. , 2015), thus providing precise interventions with minimal side effects.

[0014] However, the effectiveness and safety of these emerging approaches have been hampered by the acoustically complex human head For example, the human skull alone attenuates the ultrasound by a factor of 4.5-64 depending on individual and skull segment (Fry and Barger, 1978; Riis et al. , 2022; White et al., 2006). Hair (Eames et al., 2014; Raymond and Hynynen, 2005), acoustic coupling to the head (Casarotto et al., 2004; Klucinec et al. , 2000), and entrapped bubbles or air pockets between the transducer and the subject's head (Frinking et al. , 1999) present additional significant barriers. The joint outcome of these barriers is a severe (Riis et al. , 2024) and highly variable attenuation (Chang et al., 2016; Webb et al. , 2018), which has precluded the delivery of deterministic ultrasound intensity into the brain The uncertainties about the intensities delivered into the brain have severely limited emerging therapeutic applications. This is because these approaches — including neuromodulation, drug delivery, and surgeries — are sensitive to the delivered ultrasound intensity (FDA, 2019; Ghanouni ef al., 2015; Kubanek, 2018; Tyler ef al., 2018; Wang et al., 2018).

[0015] Current methods to address the ultrasound attenuation by the head are either invasive or not safe for routine applications in humans. For instance, the ultrasound intensity delivered into the brain could be measured using receivers implanted in the brain (Clement and Hynynen, 2002; Thomas and Fink, 1996) or using microbubbles injected into a person's blood stream (Gateau et al., 2010; O'Reilly and Hynynen, 2013; Soulioti et al., 2020). The invasiveness of these methods has limited their deployment. Noninvasive imaging approaches based on MRI, including thermometry and acoustic radiation force imaging (Ghanouni et al., 2015; Li et al., 2022; Phipps et al., 2019), require high ultrasound intensities to heat up or mechanically push on a target in the brain, which have raised safety concerns. Computed Tomography (CT) scans can be used to estimate the ultrasound dephasing by the skull (Almquist ef al , 2016; Ghanouni ef al , 2015; Leung ef al., 2021 ) — which is important for maximizing the delivered intensity for an effective ablation, but this ionizing form of energy has been less successful in measuring the attenuation of ultrasound by the skull (Leung ef al., 2019; Webb ef al., 2021 ) and is incapable of accounting for the attenuation by scalp and acoustic coupling. These are crucial limitations for the delivery of controlled intensity into the brain, for which the ultrasound attenuation constitutes the key factor (Riis et al. , 2024).

[0016] To address this lingering barrier, we have previously developed an approach that directly measures and compensates for all obstacles in the ultrasound path and can be routinely applied to the human brain. The approach, Relative Through-Transmit (RTT), is based on ultrasound — the same form of energy and frequency as that used for the ensuing interventions. RTT applies24920-3362-0319' 1a low-intensity ultrasound pulse through each segment of the head to directly measure its acoustic attenuation and compensates for these measured values prior to performing an intervention. Because RTT measures the attenuation directly, it does not require other scans of the head or free parameters. We found that RTT restores transcranial intensities that operators intend to deliver into the brain (Riis ef al. , 2024). Furthermore, RTT enabled effective and safe modulation of deep brain circuits in humans (Riis et al., 2024).

[0017] Nonetheless, RTT has three key limitations First, it is based on iterative, rather than analytical, solutions. Iterative solutions do not generally converge on the optimum. Second, iterative solutions are highly sensitive to noise and a given problem and thus provide a different solution for even small changes in the input. And third, preconditioning the problem matrix M for invertibility (Riis et al., 2024) is a relatively arbitrary step, which further decreases the reliability of the method. The suboptimal RTT solutions lead to two undesirable outcomes: 1 ) an overestimation of the actually delivered intensity — in which case the intervention would not be effective or 2) an underestimation of the actually delivered intensity — in which case the intervention could be harmful to the subject Indeed, the RTT compensation data show relatively high variability and provide suboptimal and unstable solutions (Riis et al , 2024)

[0018] This disclosure describes a new analytical method, called Analytical Relative Through- Transmit (ARTT), which overcomes these two key limitations. Embodiments of the ultrasound systems disclosed herein may be used or adapted for use with various parts or regions of the body. Accordingly, it will be understood that while specific examples recited herein may refer to use of the ultrasound system to treat symptoms or conditions related to the brain, spleen, liver, pancreas, heart, dorsal root ganglion, or peripheral nerves, analogous concepts, devices, and systems may be used on / with various other anatomical regions of the body

[0019] 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.

[0020] The directional terms “proximal” and “distal” are used herein to refer to opposite locations relative to a medical device in use by a practitioner The proximal end of the device is defined as the end of the device closest to the practitioner when the device is in use by the practitioner. The distal end is the end opposite the proximal end.

[0021] 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 are34920-3362-0319' 1presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.

[0022] 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.

[0023] 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 400 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.

[0024] As used herein, “stimulation” of the target brain 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

[0025] In many embodiments, the frequency of the ultrasonic waves 115 generated by the transducers 102 may be about 100 kHz to about 400 kHz, about 100 kHz to about 300 kHz, about 200 kHz to about 400 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 400 kHz, less than about 500 kHz, less than about 450 kHz, less than about 400 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.

[0026] 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 ultrasound device 100 may be configured to provide deep brain therapy. Moreover, embodiments of the ultrasound device 100 and related methods of use may be configured to deliver ultrasonic neuromodulation for repeated use at home The 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 ultrasound device 100. More particularly, the ultrasound device 100 and related methods of use may be utilized without the need for MRI images of the head or other precision44920-3362-0319' 1neuronavigational tools Moreover, the ultrasound device 100 and related methods of use enable repeated and reproducible use, including in in-home settings.

[0027] As shown in FIG. 1 , the ultrasonic waves 115 generated by the two transducers 102 have a focal width 120 larger than the target brain 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 target brain region 20a, the configuration of the ultrasound system 100 increases the likelihood or even ensures that the target brain region 20a is engaged by the ultrasonic waves 115 (e.gr, 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 target brain region 20a. This focal width 120 allows the target brain 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.

[0028] The ultrasound device 100 may be coupled to the head 10 at multiple points or regions. For example, the transducers 102 may be secured to the 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 target brain region 20a.

[0029] The transducers 102 may be held by the head support 103 in a position that focuses the ultrasonic waves 1 15 into the desired target brain 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 target brain 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 target brain 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

[0030] 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 embodiments54920-3362-0319' 1described 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 ultrasound device 100 may provide the ability for an operator to steer the ultrasonic waves 115 into the target brain region 20a using the controller 101 (e.g., an electronic controller) coupled to the 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), the disclosures of which are incorporated herein by this reference.

[0031] The positioning of the transducers 102 allow the 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.gr, the target brain region 20a) of the subject. The targeting of the ultrasonic waves 115 into specific brain regions (e g , the target brain region 20a) for a given condition or disorder may be mediated using fixed transducer holders (e.g. , the holder assembly 105), such that the ultrasonic waves 115 are aimed specifically into the desired target brain region 20a.

[0032] An ultrasound system of this disclosure comprising the 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 or64920-3362-0319' 1more 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.

[0033] 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 target brain 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)

[0034] 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.

[0035] 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 101.74920-3362-0319' 1

[0036] 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.

[0037] The computing device of the controller 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.

[0038] 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.

[0039] 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 for84920-3362-0319' 1communicating 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

[0040] 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.

[0041] In many embodiments, the frequency of the ultrasonic waves 115 generated by the transducers 102 may be about 100 kHz to about 400 kHz, about 100 kHz to about 300 kHz, about 200 kHz to about 400 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 400 kHz, less than about 500 kHz, less than about 450 kHz, less than about 400 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.

[0042] 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. The ultrasound device 200 is configured to be use in systems and methods that allow for reproducible positioning of the ultrasound device 200 with respect to the head 10. For example, the 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 ultrasound device 200 to be fitted on the head 10 of the subject while providing reproducible positioning of the ultrasound device 200 (e.g., the transducers 202a, 202b) on the head 10 of subject(s) across multiple treatment sessions and / or94920-3362-0319' 1multiple subjects. The 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).

[0043] Unless otherwise noted or specified, the ultrasound system 200 may include any aspect of the ultrasound system 100 described above. Accordingly, like features are designated with like reference numerals with the leading digits incremented to “2 ” For example, the ultrasound system 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 system 100.

[0044] The 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 of the subject positioned between the two transducers 202a, 202b, according to embodiments The head support assembly 203 may comprise a 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 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.

[0045] 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 ultrasound device 200 to the fit the head 10 of the subject.

[0046] 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,104920-3362-0319' 1the 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

[0047] 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

[0048] Similar to the ultrasound device 100, an ultrasound system of this disclosure comprising the 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 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 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 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 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 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 ultrasound device 200 and the114920-3362-0319' 1controller 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 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.

[0049] 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.

[0050] The ultrasound device 300 is configured to be use in systems and methods that allow for reproducible positioning of the ultrasound device 300 with respect to the head 10. For example, the 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 ultrasound device 300 to be fitted on the head 10 of the subject while providing reproducible positioning of the 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 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).

[0051] Unless otherwise noted or specified, the ultrasound system 300 may include any aspect of the ultrasound systems 100, 200 described above Accordingly, like features are designated with like reference numerals with the leading digits incremented to “3 ” For example, the ultrasound system 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 system 100, 200.

[0052] 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 322 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.

[0053] 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 303 and a second transducer 302a is secured or securable to a second side region 323b of the first member 303, according to embodiments herein. The two transducers 302a, 302b may be selectively movable and / or repositionable on the two side regions 323a, 323b124920-3362-0319' 1of the first member 303. 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 loosing 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.

[0054] 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.

[0055] In some embodiments, the head support assembly 303 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 303 or outward away from the axis of the first member 303 to adjust an inner diameter or circumference of the first member 303.

[0056] In some embodiments, the head support assembly 303 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 effective134920-3362-0319' 1to 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 303 or outward away from the axis of the first member 303 to adjust an inner diameter or circumference of the first member 303.

[0057] 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.

[0058] In many embodiments, the head support assembly 303 comprises one or more ear support members 311 configured to rest on one or more ears 1 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

[0059] Similar to the ultrasound device 100, 200 an ultrasound system of this disclosure comprising the 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 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 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 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 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 ultrasound device 300 and the controller 301 may be144920-3362-0319' 1configured 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 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 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

[0060] 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 ultrasound device 300 is configured to correct for the ultrasound aberration of the head 10 and coupling medium 304. An ARTT procedure (described in further detail with respect to FIG. 5) can be used to compensate for such ultrasound attenuation caused by the head 10 and the coupling medium 304. More specifically, such an ARTT procedure measures and computes the transmission coefficients between the transducers 302a and 302b and the ultrasound target region. The system can then 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.

[0061] 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 systems 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.

[0062] In particular embodiments, the 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 of154920-3362-0319' 1the 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

[0063] In these embodiments of the method 400 using the 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.

[0064] In these embodiments of the method 400 using the 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.

[0065] In these embodiments of the method 400 using the 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 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.

[0066] In particular embodiments, the ultrasound device 200 may be used in the method 400 In these embodiments of the method 400 using the 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 method164920-3362-0319' 1400 using the 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.

[0067] 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 400 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.

[0068] 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.

[0069] 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

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.174920-3362-0319' 1

[0075] 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.

[0076] This method of treating a condition of a brain of a subject may use the 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.

[0077] FIG. 5 is a flow diagram of a method 500 of stimulating a target region of a brain of a subject, according to embodiments disclosed herein. The method 500 may utilize any of the ultrasound systems 100, 200, 300 disclosed herein. As previously discussed, in some implementations, the ultrasound delivery system is configured to correct for the ultrasound aberration of the head and coupling using the ARTT procedure.

[0078] In this method, the operator aims to deliver into the target ultrasound pressure Paand Pb e.g., from transducers 302a and 302b (of FIGS. 3A-3B), respectively, which are attached to a holder such that the two transducers are positioned symmetrically or approximately symmetrically with respect to the mid-sagittal plane of the head

[0079] To begin, the transmission coefficients Taand Tb define the pressure transmission between transducers 302a and 302b, respectively, and the target, and are not known The ARTT procedure described herein can find these values (e.g., through direct measurement and analytical computation). Otherwise stated, the ARTT procedure measures and computes the transmission coefficients Taand Tbbetween the transducers, respectively, and the ultrasound target. Once the Taand Tb values are computed, the ultrasound delivery system, or more specifically the controller (as seen in FIGS. 3A-3B) can adjust the driving voltages applied to each transducer by a factor of — and — for the transducers 302a and 302b, respectively. This way, the ultrasound delivery TaTt> system has compensated for the attenuation of ultrasound by the respective segment of the head and ultrasound coupling medium.

[0080] The procedure to determine coefficients Taand Tb can begin by obtaining an initial, ground truth value. To do so, the transducers are positioned, e.g., through use of a holding frame184920-3362-0319' 1or the wearable ultrasound device, in the respective positions that will be used for the subsequent brain therapies, and the wearable ultrasound device or at least the transducers of the ultrasound delivery system are immersed in (degassed) water. In such an environment or medium, the system can be activated (e.g. , an ultrasonic pulse can be emitted from one or more transducers). Ultrasonic fields at the desired target coordinates are measured using a calibrated hydrophone, which provides the ground truth measurements of the ultrasound pressure at the respective target location(s) for a given driving voltage applied to the transducers.

[0081] To account for the attenuation of the head and coupling using ARTT, the transmission coefficients Taand Tb, Ta, Tbe (0, 1 ), the procedure can continue with the system within degassed water (in which no obstacles are present). A brief, low-intensity ultrasound pulse is emitted from one transducer (e.g., transducers 302a or 302b as seen in FIGS. 3A-3B) and received by the opposing or opposite transducer. In some embodiments, the intensity of the ultrasonic pulse can be at least one of the same, shorter, longer, weaker, or stronger than that used in Riis et al., 2024, and of the same, lower, or higher carrier frequency. The signal amplitude received on the opposing transducer is recorded as Vwater.

[0082] The procedure is then repeated with the device or system placed on the head of a subject (e.g., a second environment), and the ultrasound coupling medium placed between the transducers. The device, segment of the head, and ultrasound coupling medium are positioned such that the same transducers can be used to perform the desired ultrasonic intervention or therapy following the completion of the ARTT procedure. Otherwise stated, ARTT procedure can be performed just prior, and in the identical position, as subsequent ultrasonic therapy. During such, the pulse is emitted from the same transducer(s) in the same manner as within the degassed water (e g , the ultrasonic pulse has the same parameters) The corresponding signal amplitude measured on the receiving transducer is recorded as Vhead.

[0083] Because of the attenuating obstacles faced by the ultrasound in this second environment, the relative amplitudes of the received signals are Vhead < Vwater. Since the ultrasonic pulse passes through both sides of the head, it is Vhead - Vwater(Ta)(Tb). Based on the equation Vhead = water(Ta)(Tb), the geometric mean of the transmission coefficients (defined as TG as TG=jTaTb) can be input such that Vhea - Vwater TG2. Then, it is apparent that the square root of the fraction of the measured values is equal to this geometric mean:VLIEAD= TGThis geometric Aj Vwater mean, directly measured, is the key output of ART and is used to compute the pressure delivered through the head at target, as apparent from the mathematical expressions below.

[0084] The pressure delivered from each transducer at the target in a free field (e.g., in a degassed water or other obstacle free environment) can be defined as P, the total pressure at the target delivered from both transducers as PT. When the head is introduced in between the transducers, it can hold that PT = P(Ta)+ P(Tb), since ultrasound pressures are additive and also attenuated by the transmission coefficients corresponding to each segment of the head. This equation can be rewritten as Pt= (2P)Ta +2Tb. In this equation, the last term represents the arithmetic mean of the transmission coefficients, TA=T,, + TbThis way, PT= 2PTA. Therefore, the194920-3362-0319' 1pressure obtained at target during actual transmission is governed by the arithmetic mean, TA=Ta +2Tb- The ARTT procedure provided herein provides the geometric mean of the same values, T<;Accordingly, the actual pressure at target, PT= 2PTAis then estimated as= 2PTG. Here, all values are measured and thus available: P as the pressure from one transducer measured using a hydrophone placed at a target; and TGmeasured using ARTT as TG= Iv,iead. water

[0085] In some cases, it can hold that Ta= Tb. For instance, it has been found when ultrasound frequencies < 1 MHz are used for transcranial therapies and transducers are positioned over the left and right sides of the head, symmetrically about the mid-sagittal plane of the head, Tacan be approximately equal to Tb. In such cases (as was found in Riis et al., 2021 ), this assumption can be incorporated into an alternate definition of TG, TG= Ta= Tb, such that Vhead= Vwater(TG')2. Thus, TGcan be computed from a similar method as used before (e.g. , analytically asand so the computation of the delivered pressure can be exact.

[0086] Given the above finding, ARTT was deployed through 22 human ex-vivo skulls using this transducer configuration, and it is found that indeed TG~ TA. The ARTT computed values and the actual values indeed show good correspondence, lying normally distributed Thus, the ART method provides an accurate compensation for the head, and the method is entirely analytical and deterministic, always producing the same result.

[0087] As discussed, geometric and arithmetic means can provide similar values for a broad range of arguments, so it can be expected that TG~ TAalso for other configurations of the two transducers with respect to the head, e.g., along the anterior-posterior axis, or along any other axis that is approximately perpendicular to the surface of the head.

[0088] Since PT= 2PTA, the pressure at target PTis attenuated by the head, resulting in a relative drop of the total pressure delivered from the two transducers= TA. To recover this relative drop, and using the measured TGas the estimate of TA, TGis used to scale up the driving voltages, which the controller provides to transducers, by a factor of From the above Tg- TA=Vhecia:this scaling factor thus amounts tov"ntFr. This compensates for the attenuation of the j^water ^head ultrasound by the obstacles located between the (opposing) transducers, respectively, and the ultrasound target in the brain.

[0089] Thus, the computed value of TGis used to scale up the driving voltages, which the controller (e.g., controller 301 as seen in FIGS. 3A-3B) provides to the transducers, by a factor of otherwise stated, once the transmission coefficients are calculated, the controlleradjusts the driving voltages applied to each transducer by a factor derived from the ratio, difference, or a comparison of Vhead and l / water Accordingly, the control and / or device or system can compensate for attenuation of the ultrasound by the obstacles located between the transducers, and the ultrasound target in the brain as ultrasonic therapy is applied. Accordingly, this compensation can be accomplished by scaling an amplitude of the driving voltage of ultrasonic204920-3362-0319' 1pulses delivered via the wearable ultrasonic device that is based on a ratio, comparison, or difference between the measured signal amplitudes ( Vhead and water) taken from an obstacle-free environment and the head of a subject.

[0090] In some cases, the above equations are independent of frequency or duration of the ultrasound, and the method can therefore be applied to a broad range of ultrasound transducers and operating regimens. In addition, the relative correction byVwateris independent of the -yvhea ultrasound pressure delivered into the target. ARTT compensates for all obstacles in the ultrasound path, including the brain, skull, hair, acoustic coupling, and any entrapped air pockets.

[0091] In some embodiments, the ultrasonic pulse emission procedure can be (additionally) reversed, e.g , an ultrasonic pulse is transmitted from the originally receiving transducer, to the originally emitting transducer. Such can be performed for one or both environments. Following the reversed procedure, one or more taken measurements are averaged together E g , such can be accomplished separately for water and Vhead. In some embodiments, this improves the signal- to-noise ratio of the received signals and corresponding values for water and / ,aad.

[0092] Additionally, in some embodiments, the procedure to determine / water and Vhead measurements can be repeated many times (e.g., multiple pulses are emitted and received) and averaged to maximize the signal-to-noise ratio of the received signal. In some embodiments, the pulse amplitude, duration, or frequency can be adjusted such that the / water and / ,aadsignals have a high signal-to-noise ratio

[0093] The emitted pulse signal is set to a high enough amplitude to ensure that both Vhead and / water can be accurately detected. In some embodiments, the carrier frequency of the ultrasonic pulse used to determine / water and Vhead is equal to or within a factor of 2 of that used for subsequent ultrasonic therapy. In some cases, when within that range, the obtained diagnostic information is directly applicable to the treatments. In preferred embodiments, the carrier frequencies of the ARTT ultrasonic pulses and the waveforms of the subsequent ultrasonic treatments are matched exactly In this way, the ARTT compensation is most informative about the ultrasound attenuation encountered during the treatments.

[0094] In some embodiments, there may be no corrective efforts for the ultrasound phase. In some cases, for ultrasound frequencies < 1 MHz and transmission through the right and left sides of the head, phase may play a negligible role in the delivery of controlled intensity at the target (Riis et al., 2024).

[0095] In some embodiments of the procedure, the transducers can be single-element transducers In other embodiments, the transducers can be arrays that each contain multiple individually controlled elements by the controller. In those cases, the above procedures are repeated for each corresponding pair of elements (e.g., within arrays of transducer elements) located symmetrically with respect to the mid-sagittal plane of the head.

[0096] FIG. 5, method 500, and the blocks illustrated therein, can correspond or represent the above compensation procedure. For instance, in block 502, method 500 positions a wearable ultrasonic device within degassed water, the wearable ultrasonic device comprising a first ultrasonic transducer and a second ultrasonic transducer dispose opposite one another214920-3362-0319' 1

[0097] In block 504, method 500 obtains a first signal amplitude from the wearable ultrasonic device by emitting a first ultrasonic pulse from the first transducer and receiving the first ultrasonic pulse via the second transducer.

[0098] In block 506, method 500 positions the wearable ultrasonic device onto the head of a subject.

[0099] In block 508, method 500 obtains a second signal amplitude from the wearable ultrasonic device by emitting a second ultrasonic pulse from the first transducer and receiving the second ultrasonic pulse via the second transducer.

[0100] In block 510, method 500 scales an amplitude of the driving voltage of ultrasonic pulses delivered via the wearable ultrasound device based on a difference of the first signal amplitude and the second signal amplitude.

[0101] In some embodiments of this method of treating a condition of a brain of a subject, the condition of the brain may include depression, and the target region may one or more of a cingulate cortex of the brain or a subcallosal cingulate cortex of the brain

[0102] In some embodiments of this method of treating a condition of a brain of a subject, the condition of the brain may include chronic pain and the target region includes 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.

[0103] In some embodiments of this method of treating a condition of a brain of a subject, the condition of the brain may include addiction and 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.

[0104] In some embodiments of this method of treating a condition of a brain of a subject, the condition of the brain may include food craving, and the target region may include one or more of a nucleus accumbens of the brain or a nucleus accumbens shell of the brain.

[0105] In some embodiments of this method of treating a condition of a brain of a subject, the condition of the brain may include anxiety, and the target region may include one or more of an amygdala of the brain or a stria terminalis of the brain.

[0106] In some embodiments of this method of treating a condition of a brain of a subject, the condition of the brain may include post-traumatic brain disorder, and 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.

[0107] FIG. 6 illustrates a scatter plot 600 plotting the computed transmission coefficient 601 (Tc) against actual transmission coefficient 602 (TA), according to embodiments described herein. As shown, the computed transmission coefficient 601 , or TGas computed analytically, is plotted on the Y axis of the plot 600; the actual transmission coefficient 602, or TAas determined empirically or through measurement, is plotted on the X axis of the plot 600

[0108] The data as shown comprises transmission coefficients obtained from 22 degassed ex- vivo human skulls. T o gather the data, two disc transducers were positioned near the temples of each skull, facing each other symmetrically with respect to the mid-sagittal plane of the head (as224920-3362-0319' 1previously described) An opening was made at the bottom of each skull to measure the delivered pressures (at thus TA) using a calibrated hydrophone.

[0109] Each point on the graph represents a distinct measurement instance obtained from experimental trials, such as those conducted with ex-vivo skull specimens as previously described herein. As shown, the resulting distribution of data points lies close to the unity line (e.g., a 1 :1 slope), thus indicating a strong correlation between the transmission coefficients computed via the above-described methods (e.g., as described with respect to FIG. 5), and actual transmission coefficients as measured. This high correlation supports the conclusion that the ARTT-derived transmission coefficients (e.g., Tc) provide an accurate and reliable estimate of the effective transmission coefficients (TA) across a range of configurations and conditions Thus, the proposed method is confirmed as being effective and reproducible so as to compensate for ultrasound attenuation.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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 the234920-3362-0319' 1steps 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.244920-3362-0319' 1

Claims

CLAIMSWhat is claimed is:

1. A method for compensating for ultrasonic attenuation in a wearable ultrasonic device, comprising: positioning a wearable ultrasonic device within degassed water, the wearable ultrasonic device comprising a first transducer and a second transducer disposed opposite one another; obtaining a first signal amplitude from the wearable ultrasonic device by emitting a first ultrasonic pulse from the first transducer and receiving the first ultrasonic pulse via the second transducer; positioning the wearable ultrasonic device onto a head of a subject; obtaining a second signal amplitude from the wearable ultrasonic device by emitting a second ultrasonic pulse from the first transducer and receiving the second ultrasonic pulse via the second transducer; and scaling an amplitude of the driving voltage of ultrasonic pulses delivered via the wearable ultrasonic device based on a ratio of the first signal amplitude and the second signal amplitude.2 The method of claim 1 , wherein the first signal amplitude is obtained while the wearable ultrasonic device is disposed within degassed water and wherein the second signal amplitude is obtained while the wearable ultrasonic device is disposed on the head of a subject.

3. The method of claim 1 or 2, further comprising emitting a third ultrasonic pulse from the second transducer and receiving the third ultrasonic pulse via the first transducer.

4. The method of any one of claims 1 to 3, wherein obtaining the first signal amplitude or the second signal amplitude comprises obtaining a plurality of signal amplitude measurements and averaging the plurality of signal amplitude measurements5. The method of any one of claims 1 to 4, wherein a pulse amplitude, a duration, or a frequency of the first ultrasonic pulse or the second ultrasonic pulse is adjusted.

6. The method of any one of claims 1 to 5, wherein a carrier frequency of the first ultrasonic pulse or the second ultrasonic pulse is equal to or within a factor of 2 of the carrier frequency of a third ultrasonic pulse used for ultrasonic therapy.

7. The method of claim 6, wherein the third ultrasonic pulse is configured to target brain regions involved in Alzheimer's disease or post-traumatic brain disorder8. The method of claim 6, wherein the third ultrasonic pulse is configured to target brain regions involved in cognitive decline, memory functions, chronic pain, addiction, food craving, anxiety, or depression.

9. The method of claim 6, wherein the third ultrasonic pulse is configured to target the hippocampus, amygdala, nucleus basalis of Meynert, cingulate cortex, subcallosal cingulate cortex, anterior cingulate cortex, medial cingulate cortex, ventral posterolateral nucleus, ventral posteromedial nucleus, nucleus accumbens, nucleus accumbens shell, bed nucleus of the stria terminalis, or entorhinal cortex.

10. The method of any one of claims 1 to 9, wherein the first ultrasonic transducer and the second ultrasonic transducer comprise single-element transducers.254920-3362-0319' 111 . The method of any one of claims 1 to 10, where the first ultrasonic transducer and the second ultrasonic transducer comprise arrays that each contain multiple individually controlled elements.

12. An ultrasound delivery system comprising: a first transducer; a second transducer positioned opposite the first transducer with respect to a mid-sagittal plane of a head when the ultrasound delivery system is placed onto the head of a subject; a controller configured to: obtain a first signal amplitude from a first ultrasonic pulse emitted from the first transducer and received at the second transducer while the first transducer and the second transducer are in a first environment; obtain a second signal amplitude from a second ultrasonic pulse emitted from the first transducer and received at the second transducer while the first transducer and the second transducer are in a second environment; and determine a ratio between the first signal amplitude and second signal amplitude and to scale an amplitude of a driving voltage of a third ultrasonic pulse based on the determined ratio13. The ultrasound delivery system of claim 12, wherein the first environment is degassed water.

14. The ultrasound delivery system of claim 12 or 13, wherein the second environment is on a head of a subject.

15. The ultrasound delivery system of any one of claims 12 to 14, wherein the third ultrasonic pulse is used for ultrasonic therapy.

16. The ultrasound delivery system of any one of claims 12 to 15, wherein the third ultrasonic pulse is configured to target brain regions involved in cognitive decline, memory functions, chronic pain, addiction, food craving, anxiety, or depression.

17. The ultrasound delivery system of any one of claims 12 to 16, wherein the third ultrasonic pulse is configured to target the hippocampus, amygdala, nucleus basalis of Meynert, cingulate cortex, subcallosal cingulate cortex, anterior cingulate cortex, medial cingulate cortex, ventral posterolateral nucleus, ventral posteromedial nucleus, nucleus accumbens, nucleus accumbens shell, bed nucleus of the stria terminalis, or entorhinal cortex.18 A non-transitory computer-readable storage medium, the computer-readable storage medium including instructions that when executed by a computer, cause the computer to: receiving, by a processor, a first signal amplitude from a first ultrasonic pulse emitted from a first transducer and received at a second transducer while the transducers are in a first environment; receiving, by the processor, a second signal amplitude from a second ultrasonic pulse emitted from the first transducer and received at the second transducer while the transducers are in a second environment; determining a ratio between the first signal amplitude and the second signal amplitude; and264920-3362-0319' 1scaling an amplitude of a driving voltage of a third ultrasonic pulse emitted from the first transducer based on the determined ratio between the first signal amplitude and the second signal amplitude.

19. The non-transitory computer-readable storage medium of claim 18, further comprising emitting a fourth ultrasonic pulse from the second transducer and receiving the fourth ultrasonic pulse via the first transducer.

20. The non-transitory computer-readable storage medium of claim 18 or 19, wherein the first environment is degassed water and the second environment is on a head of a subject.274920-3362-0319' 1

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