Noninvasive modulation of essential tremor with focused ultrasonic waves

Abstract

A method is provided for modulating neural activity in a human subject, the method including positioning a pair of phased-array ultrasound transducers on opposing sides of a skull of a subject and focusing low-intensity ultrasound transcranially onto the ventral intermediate nucleus (VIM) of a subject. The low-intensity ultrasound is delivered at a frequency at or below 650 kHz and causes a reduction in tremor amplitude.

Description

NONINVASIVE MODULATION OF ESSENTIAL TREMOR WITH FOCUSED ULTRASONIC WAVESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Patent Application No. 63 / 720,272 filed on November 14, 2024, and titled “Noninvasive Modulation of Essential Tremor with Focused Ultrasonic Waves,” which is hereby incorporated by reference in its entirety TECHNICAL FIELD

[0002] The present disclosure relates to systems and methods for systematically applying low-intensity, reversible ultrasound neuromodulation to a brain target to treat essential tremor.BRIEF DESCRIPTION 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 drawings of an ultrasound device to garget a target region in a head of a subject, according to embodiment herein.

[0005] FIG. 2 illustrates a embodiment of an experimental setup consisting of an accelerometer configured to be utilized in tandem with the ultrasound device of FIG. 1.

[0006] FIG. 3 illustrates an embodiment of example accelerometer signals as produced via the feedback system of FIG. 2, according to embodiments described herein.

[0007] FIG. 4 illustrates an embodiment of example subject during a trial, according to embodiments described herein.

[0008] FIG. 5A illustrates tremor power corresponding to a first subject both pre- and post-sonification to the VIM nucleus of the thalamus, according to embodiments described herein.

[0009] FIG. 5B illustrates tremor power corresponding to a second subject both pre- and post-sonification to the VIM nucleus of the thalamus, according to embodiments described herein.

[0010] FIG. 5C illustrates tremor power corresponding to a third subject both pre- and post-sonification to the VIM nucleus of the thalamus, according to embodiments described herein.

[0011] FIG. 6 illustrates a plot of relative tremor power as a function of the number of times stimulation was repeated, according to embodiments described herein.

[0012] FIG. 7A-1 illustrates pre and post stimulation tremor total power for a first subject.

[0013] FIG. 7A-2 illustrates pre and post stimulation tremor total power for a second subject.

[0014] FIG. 7A-3 illustrates pre and post stimulation tremor total power for a first subject.

[0015] FIG. 7B-1 illustrates an average and standard error tremor total power dynamics over the entire trial duration for a first subject.

[0016] FIG 7B-2 illustrates an average and standard error tremor total power dynamics over the entire trial duration for a first subject.

[0017] FIG. 7B-3 illustrates an average and standard error tremor total power dynamics over the entire trial duration for a first subject.14930-0767-7305MDETAILED DESCRIPTION

[0018] Mental and neurological disorders affect nearly one fifth of the world's population. Approximately one third of patients across mental and neurological conditions are treatmentresistant. Neuromodulation has the potential to provide a targeted reset of the malfunctioning circuits, but current state-of-the-art approaches, detailed below, have significant limitations. These limitations leave millions of patients in the United States and worldwide not adequately treated.

[0019] Mental and neurological disorders involve neural networks situated deep in the brain, including limbic, basal ganglia, memory, and brain stem networks. Progress in treatments of these has been hampered by the lack of tools to effectively and safely modulate and reset these circuits. Deep brain stimulation (DBS) has shown promise in providing a selective reset of the involved deep brain circuits, but the surgical implantation of stimulating leads is associated with high costs and risks, including brain hemorrhage, infection, and in some cases, death.

[0020] 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. This broad activation often results in cognitive side effects such as memory loss.

[0021] Low-intensity transcranial focused ultrasound has the potential to modulate deep brain circuits in humans entirely noninvasively. Ultrasound can be focused through the intact skull and scalp into circumscribed deep brain regions In addition, arrays of transducers can focus ultrasound into specified brain targets programmatically, without moving the device or the subject. The precise focusing on command opens unique new possibilities to systematically modulate malfunctioning circuits in each individual. This capability is particularly important for patients with mental and neurological disorders for whom the malfunctioning networks and nuclei are poorly understood

[0022] Effective modulation of neural circuits with low-intensity focused ultrasound has been demonstrated in rodents. To test this capacity of this emerging technology in humans, we applied low-intensity focused ultrasound to a deep brain thalamic target, the ventral intermediate nucleus (VIM), in subjects with essential tremor. Left and right VIMs are paired nuclei located in the thalamus. VIM is a motor thalamic nucleus that connects motor cortex with cerebellum and is collocated with the termination of the dentrorubinalthalamic tract, which mediates motor coordination and fine motor control. This target is a primary choice for deep brain stimulation and ablative treatments for its implication in tremor motor control, established clinical efficacy, and lower risk of mood or cognitive effects. Ultrasonic modulation of the VIM reduces the tremor amplitude, just like in previous studies that used deep brain stimulation, but now entirely noninvasively.

[0023] We found that ultrasonic modulation of the VIM can dramatically reduce tremor amplitude, and there were no side effects reported by the subjects.24930-0767-7305M

[0024] 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, such as essential tremor.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[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, less34930-0767-7305Mthan 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] 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 a frame 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 frame 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.

[0033] 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 ultrasound device 100 may provide the ability for an operator to steer the ultrasonic waves 115 into the brain target region 20a using the controller 101 (e.g., an electronic controller) coupled to the 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

[0034] 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.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.

[0035] 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 the44930-0767-7305Mbrain, 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.

[0036] The controller 101 may be configured to provide voltages of specific waveforms to the transducers 102. In some embodiments, the voltages and wave forms may be defined by the required stimulation parameters for the brain target region. Generally, low-intensity ultrasound should be safe and thus the stimulation parameters would ideally comply with the FDA 510k guidelines on safe ultrasound exposure, i.e. , not exceeding peak intensity of 190 W / 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).

[0037] The controller 101 may be configured to implement any of the example methods disclosed herein. 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.

[0038] 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 some54930-0767-7305Mexamples, 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 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.

[0039] 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.

[0040] 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.

[0041] 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., a64930-0767-7305Mdisplay screen or monitor), one or more output drivers (e.g., display drivers), one or more audio speakers, and one or more audio drivers.

[0042] The computing device of the controller 101 also may include a communication interface. The communication interface may include hardware, software, or both. The communication interface of the controller 101 may provide one or more interfaces for communication (such as, for example, packet-based communication) between the computing device and one or more additional computing devices or one or more networks. For example, communication interface of the controller 101 may include a network interface controller (NIC) or network adapter for communicating with an Ethernet or other wire-based network or a wireless NIC (WNIC) or wireless adapter for communicating with a wireless network, such as a WI-FI Any suitable network and any suitable communication interface of the controller 101 may be used. For example, the computing device of the controller 101 may communicate with an ad hoc network, a personal area network (PAN), a local area network (LAN), a wide area network (WAN), a metropolitan area network (MAN), or one or more portions of the Internet or a combination of two or more of these. One or more portions of one or more of these networks may be wired or wireless. As an example, one or more portions of controller 101 may communicate with a wireless PAN (WPAN) (such as, for example, a BLUETOOTH WPAN), a WI-FI network, a WI-MAX network, a cellular telephone network (such as, for example, a Global System for Mobile Communications (GSM) network), or other suitable wireless network or a combination thereof. The computing device of the controller 101 may include any suitable communication interface for any of these networks, where appropriate.

[0043] 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.

[0044] 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

[0045] An ultrasound system of this disclosure may be configured to treat a variety of conditions or disorders in the brain. The transducers 102 may be positioned or selectively positionable to treat the variety of conditions or disorders in the brain. For example, an ultrasound device 10074930-0767-7305Mand the controller 101 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 device 100 and the controller 101 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 device 100 and the controller 101 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 device 100 and the controller 101 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 device 100 and the controller 101 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 device 100 and the controller 101 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 device 100 and the controller 101 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.

[0046] In some embodiments, the transducers 102 may be disposed substantially parallel to each other on either side of the frame 103. Further the transducers 102 may be aligned with each other across the frame 103. The frame 103 may be configured as a substantially rigid member, configured to maintain the relative positions of the transducers 102.

[0047] The transducers 102 may be positioned or selectively positionable to treat the variety of conditions or disorders in the brain. For example, an ultrasound device 100 and the controller 101 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 100 and the controller 101 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 100 and the controller 101 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 ventral84930-0767-7305Mposteromedial nucleus. In some embodiments, an ultrasound system including the ultrasound device 100 and the controller 101 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 100 and the controller 101 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 100 and the controller 101 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 100 and the controller 101 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.

[0048] In some cases, the transducers 102 are positioned symmetrically with respect to the mid-sagittal plane of the head of the subject. The ultrasound device 100 is configured to correct for the ultrasound aberration of the head 10 and coupling medium 104. The system can compensate for the attenuation of ultrasound by the respective segment of the head 10 and the coupling medium 104. 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.

[0049] In some embodiments, the system can compensate for attenuation of ultrasound using an Relative Through-T ransmit (RTT) procedure that determines transmission coefficients between each transducer and a target region of the brain. Such an RTT 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.

[0050] 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.

[0051] 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

[0052]

[0053] In many embodiments, a method of activating the two transducers to generate ultrasonic waves effective to stimulate the target region of the brain of the subject without ablating the target94930-0767-7305Mregion 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.

[0054] In some embodiments of the method, 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, 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.

[0055] In some embodiments of the method, the target region may comprise a region of the brain associated with depression. In these and other embodiments of the method, the target region may include one or more of a cingulate cortex of the brain or a subcallosal cingulate cortex of the brain

[0056] In some embodiments of the method, the target region may comprise a region of the brain associated with chronic pain. In these and other embodiments of the method, 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.

[0057] In some embodiments of the method, the target region may comprise a region of the brain associated with addiction. In these and other embodiments of the method, 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.

[0058] In some embodiments of the method, the target region may comprise a region of the brain associated with food craving. In these and other embodiments, the target region may include one or more of a nucleus accumbens of the brain or a nucleus accumbens shell of the brain.

[0059] In some embodiments of the method, the target region may comprise a region of the brain associated with anxiety In these and other embodiments of the method, the target region may include one or more of an amygdala of the brain or a stria terminalis of the brain.

[0060] In some embodiments of the method, the target region may comprise a region of the brain associated with post-traumatic brain disorder. In these and other embodiments of the method, 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.

[0061] 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.

[0062] FIG 2 illustrates a embodiment of a feedback system 125 consisting of an accelerometer 124 configured to be utilized in tandem with the ultrasonic device 100 of FIG. 1, according to embodiments described herein. The feedback system 125 is a subject-worn sensor with the accelerometer 124 being the sensor. With use of feedback system 125, low-intensity transcranial104930-0767-7305Mfocused ultrasound can be delivered noninvasively through the intact skull and scalp into circumscribed deep brain regions, and phased-array systems can focus acoustic energy programmatically without repositioning the subject. This architecture enables systematic modulation of malfunctioning circuits, including deep motor thalamic nuclei implicated in essential tremor.

[0063] In the illustrated configuration, accelerometer 124 is configured to continuously measures tremor amplitude over the tremor-dominant hand 128. A securement band 126 is configured to fix accelerometer 124 to tremor-dominant hand 128. In some embodiments, accelerometer 124 can be MRI-compatible and capable of multiple axes (e g., three-axis) measurement (x, y, z) with analog output digitized at >1000 Hz, permitting resolution of tremorrange frequencies (1-20 Hz) and synchronization with the ultrasound trigger signal.

[0064] Studies were done on subjects (e g., three subjects) with essential tremor prior to their involvement in surgical ablation of the VIM. In these subjects, low-intensity, low-frequency ultrasonic energy was applied to the VIM for 15 seconds each trial at 10% duty cycle and an average of 23 trials per subject over a period of 90 minutes

[0065] Operation of the device targeting the ventral intermediate nucleus (VIM) of the thalamus was based on anterior commissure (AC) and posterior commissure (PC) coordinates derived from subject-specific MRIs VIM was localized using automatic AC and PC detection and then offset 15 mm lateral and 6 mm anterior to the PC along the AC-PC line In some cases, the dimensions (e.g., lateral, elevational, and axial) of the intensity field at the target correspond to 2.4 mm x 3.6 mm x 20.4 mm in y, z, and x dimensions (of the Montreal Neurological Institute coordinate system).

[0066] FIG. 3 illustrates an embodiment of example accelerometer signals as produced via the feedback system 125 of FIG. 2, according to embodiments described herein. As seen in the illustrated embodiment, signals from three different trials (e.g., first trial 130, second trial 132, and third trial 134) are shown. As shown in FIG. 3, example accelerometer signals (e.g., first trial 130, second trial 132, and third trial 134) were normalized and bandpassed through 1-20 Hz. The signals represent tremor or motor oscillatory activity.

[0067] First trial 130, second trial 132, and third trial 134 represent data from three distinct subjects. Outputs from the ultrasound hardware were co-recorded, enabling precise segmentation of pre-, during-, and post-sonication intervals. Accordingly, example trials one, two, and three are exemplarily signals from a first, a second, and a third, individual subject, respectively.

[0068] FIG. 4 illustrates an embodiment of example subject during a trial. As seen in the illustrated embodiment, a subject undergoing the trial begins in a first position 136, raises an arm or hand to be in a second position 138, and after a specified time returns to a resting, or third position.

[0069] More specifically, in each trial, each subjects were asked to raise their hand above their body to capture a tremor of the subject (e g , as seen in second position 138), via the accelerometer 124 and accelerometer signal. An ultrasonic energy pulse was applied for 15 seconds, following this instruction.114930-0767-7305M

[0070] Subjects then held their arm in the raised position for an additional 15 seconds following the offset of the ultrasound. In some cases, upon instruction, subjects raised the tremor-dominant arm to a second position 138 with partial abduction and approximately 30° of elbow flexion.

[0071] After, the subjects rested with arms at their side (e.g., as seen in third position 140). Subjects rested for a period of 1-2 minutes between trials and the process repeated over a 90 minute time period (the duration for the experiment).

[0072] FIGS. 5A-C illustrate plots 500a, 500b, 500c of tremor power across different subjects both pre- and post- sonification to the VIM nucleus of the thalamus. Accordingly, FIG. 5A illustrates tremor power corresponding to a first subject both pre- and post- sonification to the VIM nucleus of the thalamus, according to embodiments described herein. FIG. 5B illustrates tremor power corresponding to a second subject both pre- and post- sonification to the VIM nucleus of the thalamus, according to embodiments described herein. FIG. 5C illustrates tremor power corresponding to a third subject both pre- and post- sonification to the VIM nucleus of the thalamus, according to embodiments described herein.

[0073] As seen in the illustrated plots, each plot displays pre-treatment baseline amplitude, within-trial pre- and post-windows, and responses across stimulation repetitions. These data test whether ultrasonic perturbation of a deep motor thalamic node can yield overt motor changes, an effect not previously demonstrated robustly in humans with low-intensity ultrasound.

[0074] As seen in the illustrated plots, mean±s.e.m tremor amplitude in the post-sonication window averaged across the final ten stimulation trials of each session relative to pre-treatment baseline measures, separately for each subject. The difference was assessed using a two-sample t-test: *** p < 0.001.

[0075] FIG. 6 illustrates a plot 600 of relative tremor power as a function of the number of times stimulation was repeated, according to embodiments described herein. Data were normalized to baseline (initial value = 1 ) and analyzed using linear fits to quantify cumulative effects across repeated low-intensity exposures.

[0076] As seen in the illustrated embodiment, plot 600 shows a durable decrease of tremor in response to repeated stimulation. Total tremor amplitude computed over each stimulation repetition (i.e. , each trial: pre-sonication window, sonication window, post-sonication window) as a function of the number of each stimulation repetition. The data were normalized to baseline, so that each trace starts at the value of 1 The dashed lines shows linear fits to the data. Stars denote the cases in which the slope was significant (*** p < 0.001; “ p < 0.01).

[0077] FIGS. 7A-1 through 7A-3 illustrate pre and poststimulation tremor total power for each subject across active trials as discussed with respect to FIGS. 2-5. FIG. 7A-1 illustrates the pre and post stimulation tremor total power for a first subject. FIG. 7A-2 illustrates the pre and post stimulation tremor total power for a second subject. FIG. 7A-3 illustrates the pre and post stimulation tremor total power for a third subject

[0078] FIGS. 7B-1 through 7B-3 illustrate an average and standard error tremor total power dynamics over the entire trial duration for each subject across active trials as discussed with respect to FIGS. 2-5. FIG. 7B-1 illustrates an average and standard error tremor total power124930-0767-7305Mdynamics over the entire trial duration for a first subject FIG. 7B-2 illustrates an average and standard error tremor total power dynamics over the entire trial duration for a second subject. FIG. 7B-3 illustrates an average and standard error tremor total power dynamics over the entire trial duration for a third subject.

[0079] Accordingly, transient reductions occurred within seconds of ultrasound onset and cumulative decreases across the session, at least 50% and in some cases greater than 95%. These data confirm that low-intensity focused ultrasound can modulate motor behavior via noninvasive neuromodulation of a deep thalamic node central to tremor generation.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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 or134930-0767-7305Muse of specific steps or actions may be modified. The scope of the invention is therefore defined by the following claims and their equivalents.144930-0767-7305M

Claims

CLAIMSWhat is claimed is:

1. A transcranial ultrasound system comprising:an ultrasound transducer array configured to deliver focused acoustic energy; and a controller operatively coupled to the transducer array and configured to focus the acoustic energy of the ultrasound at a deep-brain target to deliver sufficient energy to modulate neuronal activity without ablating a target region of a brain of a patient.

2. The transcranial ultrasound system of claim 1 , wherein the deep-brain target comprises a ventral intermediate nucleus (VIM) or both the left and right VIMs.

3. The transcranial ultrasound system of claim 1 or 2, further comprising a subject-worn sensor configured to measure tremor amplitude along multiple axes and to generate a signal indicative of motor oscillatory activity.

4. The transcranial ultrasound system of claim 3, wherein the subject-worn sensor comprises a securement band configured to wrap around a hand of the patient.

5. The transcranial ultrasound system of any one of claims 3 to 4, wherein the subject-worn sensor comprises a three-axis accelerometer6. The transcranial ultrasound system of any one of claims 1 to 5, wherein the acoustic energy comprises a focal volume that overlaps the ventral intermediate nucleus of a thalamus of the patient.

7. The transcranial ultrasound system of any one of claims 1 to 6, wherein the controller is further configured to compensate for skull attenuation.

8. The transcranial ultrasound system of any one of claim 1 to 7, wherein the controller drives the ultrasound transducer to emit 10 ms pulses at approximately 650 kHz every 100 ms.

9. The transcranial ultrasound system of any one of claims 1 to 8, wherein an intensity field of the acoustic energy has lateral, elevational, and axial dimensions of approximately 2.4 mm x 3.6 mm x 20.4 mm.

10. The transcranial ultrasound system of any one of claims 1 to 9, wherein the transducer array comprises opposing arrays separated by a fixed distance.

11. A system for noninvasive neuromodulation comprising:a pair of phased-array ultrasound transducers positioned on opposing sides of a skull of a subject; anda controller configured to focus ultrasound of the pair of phased-array ultrasound transducers at a deep-brain target to deliver sufficient energy to modulate neuronal activity without ablating a target region of a brain of a patient.

12. The system for noninvasive neuromodulation of claim 11 , wherein the controller drives the transducers to emit 10 ms pulses at approximately 650 kHz every 100 ms13. The system for noninvasive neuromodulation of claim 11 or 12, wherein the transducers are driven to not exceed peak intensity of 190 W / cm2and not exceed time-average intensity of 0.72 W / cm2to avoid ablation while enabling neuromodulation of deep-brain target.154930-0767-7305M14. The system for noninvasive neuromodulation of any one of claims 11 to 13, further comprising a subject-worn sensor configured to measure tremor amplitude along multiple axes and to generate a signal indicative of motor oscillatory activity.

15. The system for noninvasive neuromodulation of any one of claims 11 to 14, wherein the subject-worn sensor comprises a securement band configured to wrap around a hand of the patient.

16. A method for modulating neural activity in a human subject, comprising:positioning a pair of phased-array ultrasound transducers on opposing sides of a skull of a subject;focusing low-intensity ultrasound transcranially onto a ventral intermediate nucleus (VIM) of a subject, wherein the low-intensity ultrasound is delivered at a frequency below 650 kHz and causes a reduction in tremor amplitude.

17. The method of claim 16, wherein a duty cycle of the low-intensity ultrasound is 10%.

18. The method of claim 16 or 17, further comprising determining a subject-specific location of a deep-brain target based on anatomical reference coordinates defining the anterior and posterior commissures19. The method of any one of claims 16 to 18, wherein the low-intensity ultrasound is configured to treat essential tremor.

20. The method of any one of claims 16 to 19, wherein the low-intensity ultrasound is configured to reduce tremor amplitude by at least 50%164930-0767-7305M

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