WO2014127091A1 - Systèmes ultrasonores transcrâniens - Google Patents

Systèmes ultrasonores transcrâniens Download PDF

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Publication number
WO2014127091A1
WO2014127091A1 PCT/US2014/016178 US2014016178W WO2014127091A1 WO 2014127091 A1 WO2014127091 A1 WO 2014127091A1 US 2014016178 W US2014016178 W US 2014016178W WO 2014127091 A1 WO2014127091 A1 WO 2014127091A1
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WO
WIPO (PCT)
Prior art keywords
subject
ultrasound
neuromodulation
contacting surface
head
Prior art date
Application number
PCT/US2014/016178
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English (en)
Inventor
William J. TYLER
Tomokazu Sato
Daniel Z. WETMORE
Isy Goldwasser
Jonathan CHARLESWORTH
Sumon K. PAL
Steven Cook
Original Assignee
Thync, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thync, Inc. filed Critical Thync, Inc.
Publication of WO2014127091A1 publication Critical patent/WO2014127091A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/42—Details of probe positioning or probe attachment to the patient
    • A61B8/4209—Details of probe positioning or probe attachment to the patient by using holders, e.g. positioning frames
    • A61B8/4236—Details of probe positioning or probe attachment to the patient by using holders, e.g. positioning frames characterised by adhesive patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/42—Details of probe positioning or probe attachment to the patient
    • A61B8/4272—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue
    • A61B8/429—Details of probe positioning or probe attachment to the patient involving the acoustic interface between the transducer and the tissue characterised by determining or monitoring the contact between the transducer and the tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/44—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device
    • A61B8/4416—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device related to combined acquisition of different diagnostic modalities, e.g. combination of ultrasound and X-ray acquisitions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/44—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device
    • A61B8/4444—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device related to the probe
    • A61B8/4455—Features of the external shape of the probe, e.g. ergonomic aspects
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00017—Electrical control of surgical instruments
    • A61B2017/00022—Sensing or detecting at the treatment site
    • A61B2017/00039—Electric or electromagnetic phenomena other than conductivity, e.g. capacity, inductivity, Hall effect
    • A61B2017/00044—Sensing electrocardiography, i.e. ECG
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00681—Aspects not otherwise provided for
    • A61B2017/00734—Aspects not otherwise provided for battery operated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/06—Measuring instruments not otherwise provided for
    • A61B2090/064—Measuring instruments not otherwise provided for for measuring force, pressure or mechanical tension
    • A61B2090/065—Measuring instruments not otherwise provided for for measuring force, pressure or mechanical tension for measuring contact or contact pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/42—Details of probe positioning or probe attachment to the patient
    • A61B8/4245—Details of probe positioning or probe attachment to the patient involving determining the position of the probe, e.g. with respect to an external reference frame or to the patient
    • A61B8/4254—Details of probe positioning or probe attachment to the patient involving determining the position of the probe, e.g. with respect to an external reference frame or to the patient using sensors mounted on the probe
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/44—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device
    • A61B8/4427—Device being portable or laptop-like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/44—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device
    • A61B8/4444—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device related to the probe
    • A61B8/4472—Wireless probes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0004—Applications of ultrasound therapy
    • A61N2007/0021—Neural system treatment
    • A61N2007/003—Destruction of nerve tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0078—Ultrasound therapy with multiple treatment transducers

Definitions

  • the present invention relates to apparatuses (e.g., devices and systems) and methods for transcranial ultrasound neuromodulation.
  • apparatuses e.g., devices and systems
  • methods for transcranial ultrasound neuromodulation e.g., devices and systems
  • described herein are apparatuses and methods of using them for effective and safe neuromodulation by transcranial ultrasound.
  • Transcranial ultrasound neuromodulation has been proposed in order to activate, inhibit, or modulate neuronal activity.
  • noninvasive and nondestructive transcranial ultrasound techniques have been suggested to provide an alternative to other transcranial ultrasound based techniques that use a combination of parameters to disrupt, damage, destroy, or otherwise affect neuronal cell populations so that they do not function properly and/or cause heating to damage or ablate tissue.
  • Pretlow discloses an ultrasound coupling pad assembly that incorporates a support pad that is configured so that the coupling unit adheres more strongly to the transducer than the body (US patent number
  • such devices lack features that would allow the application of energy to modulate neurotransmission in a safe and effective way though the subject's skull, while preventing damage, and protecting subjects from improper use or function of the device, which may be a real risk when dealing with entirely self-contained systems.
  • U.S. patent application 13/519,951 to Guffey et al. titled “Portable ultrasound system” describes "an ultra-portable, complete therapeutic ultrasound device that can be configured to include a power-source, ultrasound driver, and ultrasound transducer, and that can be controlled by the user in a single working unit.” Although these cases preport to describe portable and ultrasound systems, the described systems lack many of the features mentioned above for providing safe and effective neuromodulation.
  • Described herein are apparatuses, including device and systems, for transcranial ultrasound that are wireless, lightweight, adherent, and self-coupling.
  • Any of the devices described herein may be configured to fit directly onto a subject's head, and may generally include a reusable (e.g., durable) portion and a disposable portion (e.g., configured for single-use or a small number of uses).
  • the disposable portion may be adapted to be the applicator portion of the device.
  • these apparatuses may be adapted specifically to fit to a subject's head, for example by including a disposable portion that has a curved subject-contacting surface that fits against the subject's head.
  • any of the apparatuses described herein may include one or more safety mechanisms, including safety mechanisms that can confirm that the device is attached to the proper region of the subject's body (e.g., the head) and/or is properly attached to drive neurostimulation.
  • the apparatuses described herein may include one or more safety interlock configured to prevent transmission of ultrasound for neurostimulation unless the subject-contacting surface is positioned on the subject's head.
  • the safety interlock may comprise an acoustic impedance sensor configured to detect an impedance between the subject's head and the couplant region.
  • the safety interlock may comprise an ultrasound imaging sensor configured to image the tissue beneath the subject-contacting surface.
  • Other safety features may include one or more sensors for detecting temperature (e.g., heating), and/or the amount of energy delivered.
  • any of the apparatuses described herein may be adapted for wireless control that regulates one or more stimulation parameters.
  • the apparatuses described herein may be adapted for wireless communication with a device that executes control logic controlling the operation of the device.
  • the control logic may be adapted to control operation of the device to allow selecting, monitoring, recording, and/or transmitting control parameters to the apparatuses.
  • the control logic may be adapted for operation by the subject wearing the device.
  • the control logic may be executable on a mobile device, including a smartphone (e.g. iPhone, Android device, etc.), handheld computer (e.g., iPad, tablet, etc.), computer (laptop, desktop, etc.), or the like.
  • the apparatuses including devices and systems, described herein are adapted for the delivery of transcranial ultrasound.
  • These apparatuses may include systems and assemblies for transcranial ultrasound neuromodulation that are self-contained, self-powered, self-adhering, and self-coupling and referred to as transcranial ultrasound neuromodulation pucks, and may include disposable and semi-disposable systems.
  • the devices and systems described herein may be referred to as a "puck" or applicator.
  • these applicators may be self-contained, e.g., including all of the driving power, and electrodes in a single apparatus that can be worn against the head.
  • Such apparatuses are typically adhesively attachable to the head, and may therefore be lightweight and compact, and adapted to be worn.
  • the transcranial ultrasound neuromodulation puck may have a cross-sectional long axis that is at least 50% longer than a cross-sectional short axis. Pucks configured to be at least 50% longer than they are wide may have improved adherence to the head by enabling adhesive components to be further from each other.
  • a transcranial ultrasound neuromodulation puck may be curved so that it can more easily fit to a curved portion of a user's head.
  • the puck curvature may be 1- dimensional (ID; e.g. curved along one dimension such that the puck would fit on the external face of a cylinder), or 2-dimensional (2D; e.g. curved along two dimensions such that the puck would fit on the external face of an ellipse).
  • ID 1- dimensional
  • 2D 2-dimensional
  • the transcranial ultrasound neuromodulation puck may be configured to have an irregular curvature that cannot be modeled as a cylinder, ellipsoid, or sphere.
  • the apparatuses may be wirelessly controlled.
  • the apparatuses described herein are wireless, and may not include any external wires.
  • the controls for the apparatus may be wirelessly communicated by an outside device.
  • the apparatus may have no manual controls on the device, or it may have only a single control (e.g., on/off button, etc.).
  • a transcranial ultrasound neuromodulation puck may have a single button.
  • a different user interface other than a button may be used.
  • the transcranial ultrasound neuromodulation puck has no buttons or other user interface components; neuromodulation may begin and end automatically when the unit is placed correctly on the head or is triggered wirelessly.
  • any of the apparatuses described may include a variety of different safety and/or monitoring components.
  • the apparatus may include an acoustic impedance sensor.
  • a transcranial ultrasound neuromodulation puck may be configured to trigger an ultrasound transducer to deliver ultrasound energy after detecting sufficiently low impedance acoustic coupling to the head and/or stop ultrasound if sufficiently low impedance acoustic coupling is no longer occurring.
  • a transcranial ultrasound neuromodulation puck may be configured to trigger an ultrasound transducer to deliver ultrasound energy after detecting that it is in close proximity to the skull.
  • a transcranial ultrasound neuromodulation puck may be configured to limit the duration of neuromodulation. Systems that limit the duration of ultrasound energy delivered improve device safety by ensuring that a unit cannot transmit too much ultrasound energy or induce too much neuromodulation in a defined period of time.
  • An ultrasound neuromodulation puck may be configured to deliver ultrasound energy that has an acoustic frequency between about 100 kHz and about 10 MHz; has a spatial-peak, temporal-average intensity between about 0.0001 mW/cm 2 and about 1 W/cm 2 at the target tissue site; does not induce heating of the brain due to ultrasound energy that exceeds about 2 degrees Celsius for more than about 5 seconds; and induces an effect on neural circuit function in one or more brain regions.
  • An ultrasound neuromodulation puck may further comprise components for delivering transcranial electrical stimulation.
  • an ultrasound neuromodulation puck further may include components for one or more alternative technologies for stimulating brain tissue to activate, inhibit, or modulate the activity of cells in the brain selected from the group that includes, but is not limited to: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), targeted electrical stimulation (TES), deep brain stimulation (DBS), stimulation through one electrode or an array of electrodes implanted on the surface of the brain or dura, and light activation of specially engineered proteins for neuromodulation known as optogenetics.
  • TMS transcranial magnetic stimulation
  • tDCS transcranial direct current stimulation
  • tACS transcranial alternating current stimulation
  • TES targeted electrical stimulation
  • DBS deep brain stimulation
  • stimulation through one electrode or an array of electrodes implanted on the surface of the brain or dura and light activation of specially engineered proteins for neuromodulation known as optogenetics.
  • An ultrasound neuromodulation puck may include components for recording brain activity of the user using a technique chosen from the group including, but not limited to:
  • EEG electroencephalography
  • MEG magnetoencephalography
  • flvlRI functional magnetic resonance imaging
  • fNIRS functional near-infrared spectroscopy
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • CT computed tomography
  • fTPI functional tissue pulsatility imaging
  • neuromodulation puck may further comprise components for measuring physiology of the user using a technique to measure a physiological signal chosen from the group including, but not limited to: electromyogram (EMG), galvanic skin response (GSR), heart rate, blood pressure, respiration rate, pupil dilation, eye movement, gaze direction, and other physiological measurement.
  • EMG electromyogram
  • GSR galvanic skin response
  • heart rate blood pressure
  • respiration rate pupil dilation
  • eye movement gaze direction
  • other physiological measurement chosen from the group including, but not limited to: electromyogram (EMG), galvanic skin response (GSR), heart rate, blood pressure, respiration rate, pupil dilation, eye movement, gaze direction, and other physiological measurement.
  • EMG electromyogram
  • GSR galvanic skin response
  • a transcranial ultrasound system may also include components to limit the number or duration of uses including a fuse, counter, or limited battery supply.
  • any of the transcranial ultrasound neuromodulation apparatuses (pucks) described herein may be modular and configurable to be integrated for use with one another.
  • a single puck or a single iteration of control logic
  • one ultrasound neuromodulation puck may be a 'master puck' and other pucks are 'slave pucks'.
  • Any of the transcranial ultrasound neuromodulation pucks described herein may be configured to operate as a phased array to improve focusing of ultrasound energy to target one or more brain regions.
  • Multiple transcranial ultrasound neuromodulation pucks may be wirelessly connected, or in some variations, connected by flexible wiring and connectors so that power and/or control circuitry can be shared between a master puck and one or more slave pucks.
  • neuromodulation system may be controlled wirelessly or by a wired connection by a tablet computer, smartphone (e.g. Android handset or iPhone), PC, laptop, or custom remote, base station unit, other computing device, or any combination thereof.
  • a tablet computer e.g. Android handset or iPhone
  • PC e.g. iPad
  • laptop e.g. Samsung handset or iPhone
  • custom remote base station unit
  • any of the apparatuses described herein may include (or may be configured for operation with) a device that assists a user in placing a disposable or semi-disposable transcranial ultrasound neuromodulation system at one or more appropriate locations to achieve a desired form of neuromodulation.
  • An apparatus may incorporate one or more sensors for determining the absolute or relative position of an ultrasound neuromodulation puck on the head.
  • any of these devices or systems may be conformable to the head or otherwise shaped to account for the curvature of the head.
  • Described herein are methods of transcranial ⁇ neuromodulating a subject using ultrasound, including operating a transcranial ultrasound neurostimulation apparatus such as those described herein. Also described herein are methods for returning and/or manually or automatically reordering disposable components of the system.
  • a transcranial ultrasound neuromodulation puck may incorporate more than one power source (e.g. battery). At least one battery supplies power to power control circuitry for an ultrasound transducer, and one or more separate batteries supply power to other electronic control components of the system.
  • the system is a transcranial ultrasound neuromodulation puck.
  • the disposable and semi-disposable systems described herein may be lightweight, small/compact (e.g. adapted for portability), have reduced energy storage requirements, and be configured to eliminate need for components to recharge a battery or connect to AC power.
  • transcranial ultrasound neuromodulation systems and methods described herein may advantageously achieve neuromodulation to affect cognitive and physiological functions that include, but are not limited to, learning and memory, attention, creativity, decision-making, and other cognitive states.
  • a self-contained, self-powered, self-adhering, and self-coupling apparatus may include a single housing holding a battery, electronic control circuitry for delivering appropriate ultrasound protocols, one or more ultrasound transducers, an acoustic couplant, and may further comprise one or more components for the assembly to adhere the puck to the head.
  • Components to adhere the apparatus to the head may include adherents, suction devices, or other systems to adhere the acoustic couplant portion of the assembly in physical contact with the head.
  • Neuromodulation may be targeted to more than one brain region.
  • multiple disposable or semi-disposable units operate independently and achieve targeting of multiple brain regions by their positioning. The timing of transcranial ultrasound
  • neuromodulation delivered by the disposable or semi-disposable systems described herein may be designed to modulate brain activity that occurs in the temporal domain, including brain rhythms and spatiotemporal patterns of neural activity between connected brain circuits.
  • neuromodulation assembly and the spatiotemporal pattern of ultrasound may be configured for targeting the ventromedial prefrontal cortex (VmPFC; Brodmann area 10). Targeting to the ventromedial prefrontal cortex (VmPFC; Brodmann area 10). Targeting to the ventromedial prefrontal cortex (VmPFC; Brodmann area 10). Targeting to the ventromedial prefrontal cortex (VmPFC; Brodmann area 10). Targeting to the ventromedial prefrontal cortex (VmPFC; Brodmann area 10).
  • VmPFC can be advantageous for modulating emotion, risk, decision-making, and fear.
  • the placement of disposable or semi-disposable transcranial ultrasound neuromodulation assembly and the spatiotemporal pattern of ultrasound may be configured for targeting the orbitofrontal cortex (OFC; Brodmann 10, 1 1, 14). Targeting to the OFC can be advantageous for modulating executive control and decision-making.
  • the placement of a disposable or semi-disposable transcranial ultrasound neuromodulation assembly and the spatiotemporal pattern of ultrasound may be configured for targeting primary or supplementary motor cortex. Targeting to motor cortex can be advantageous for improving motor learning or rehabilitation.
  • a transcranial ultrasound neuromodulation puck may incorporate one or more arrays of ultrasound transducers in a single high-density assembly.
  • transcranial ultrasound neuromodulation apparatuses that are wireless, lightweight, adherent, and self-coupling, and may include: an outer housing at least partially enclosing a power source, an ultrasound transducer, and a stimulation processor configured to control ultrasonic neuromodulation; and a subject-contacting surface configured to connect to the outer housing, the subject-contacting surface including: an acoustic couplant region configured to couple acoustic energy from the ultrasound transducer to a subject's skin; and one or more adhesive regions configured to adhesively secure the apparatus to the subject's head; and a safety interlock configured to prevent transmission of ultrasound for neurostimulation unless the subject-contacting surface is positioned on the subject's head.
  • the safety interlock comprises an acoustic impedance sensor configured to detect an impedance between the subject's head and the couplant region, wherein the stimulation processor is configured to allow transmission of ultrasound for neurostimulation when the impedance detected by the acoustic impedance sensor is consistent with the apparatus being connected to a subject's head.
  • the safety interlock comprises an ultrasound imaging sensor configured to image the tissue beneath the subject-contacting surface, wherein the stimulation processor is configured to allow transmission of ultrasound for neurostimulation when the imaging apparatus detects that the apparatus is connected to a subject's head.
  • the safety interlock may return acoustic impedance values to the stimulation processor or to a processor that is wirelessly connected to the apparatus.
  • the processor e.g., stimulation processor
  • the processor may determine if the acoustic impedance(s) detected and/or imaged portion of the subject's body are consistent with the position of the apparatus over the subject's skull, and therefore head.
  • the processor may compare the acoustic impedance to a predetermined threshold or value or range of values consistent with the sensor being over a subject's head.
  • a stimulation processor may be configured to allow transmission of ultrasound for neurostimulation when the impedance detected by the acoustic impedance sensor is below an impedance threshold.
  • the processor may compare an ultrasound image formed by an ultrasound imaging sensor to a an expected image if the apparatus is over the subject's skull, and therefore head.
  • the subject-contacting surface may be curved to conform to the subject's head.
  • the subject-contacting surface may have a cross-sectional long axis that is at least 50% longer than a cross-sectional short axis.
  • the subject-contacting surface may have a natural curvature such that the subject-contacting surface would fit the external face of a cylinder having a radius greater than 60 mm and less than 90.
  • the subject-contacting surface may have a natural curvature such that the subject-contacting surface would fit the external face of an ellipsoid having a long axis greater than 104 mm and less than 156 mm and a short axis greater than 60 mm and less than 90 mm if the long axis of the puck were aligned parallel to or within 20 degrees of the short axis of the ellipsoid.
  • the apparatus may also be lightweight.
  • the apparatus may weigh less than 8 ounces.
  • the subject-contacting surface may be disposable. Further, the subject-contacting surface may be releasably connected to the outer housing.
  • any of these apparatuses described herein may include a wireless receiver at least partially within the outer housing configured to wirelessly receive control instructions and transmit them to the stimulation processor to wirelessly control ultrasonic neuromodulation.
  • the apparatus may have no user interface elements, or may only have a single user interface element.
  • Also described are methods of transcranial ultrasound neuromodulation comprising: adhesively attaching a wireless, lightweight, self-coupling ultrasound neuromodulation apparatus to a subject's head, wherein the apparatus comprises an outer housing at least partially enclosing a power source, an ultrasound transducer, and a stimulation processor configured to control ultrasonic neuromodulation; detecting whether the apparatus is placed at an appropriate location on a subject's head; and applying ultrasound for neuromodulation from the apparatus when the apparatus is connected to a subject's head.
  • the method may also include attaching a disposable subject-contacting surface to the outer housing, wherein the subject-contacting surface is curved to conform to the subject's head and includes an acoustic couplant region configured to couple acoustic energy from the ultrasound transducer to a subject's skin and one or more adhesive regions configured to adhesively secure the apparatus to the subject's head.
  • the method may also include wirelessly receiving control instructions and transmitting them to the stimulation processor to control ultrasonic neuromodulation.
  • any of the apparatuses described herein may be adapted to receive control instructions from control logic that is operating on an off-board processor wirelessly communicating with the puck (the apparatus worn by the user).
  • a system for transcranial ultrasound neuromodulation may include: an apparatus for delivering ultrasonic neurostimulation that is wireless, lightweight, adherent, and self-coupling, the apparatus comprising: an outer housing at least partially enclosing a power source, an ultrasound transducer, a stimulation processor configured to control ultrasonic neuromodulation and a wireless receiver coupled to the stimulation processor; and a subject- contacting surface configured to connect to the outer housing, the subject-contacting surface being curved to conform to a subject's head and including: an acoustic couplant region configured to couple acoustic energy from the ultrasound transducer to a subject's skin; and one or more adhesive regions configured to adhesively secure the apparatus to the subject's head; and a non-transitory computer-readable storage medium storing a set of instructions capable of being executed by a control processor, that when executed by the control processor causes the control processor to wirelessly transmit control information to the apparatus for delivering ultrasonic neurostimulation.
  • the set of instructions of the non-transitory computer-readable storage medium when executed, may cause the control processor to present a user interface permitting selection of stimulation parameters.
  • the set of instructions of the non-transitory computer-readable storage medium when executed, may cause the control processor to activate the apparatus for delivering ultrasonic neurostimulation.
  • the subject-contacting surface of the apparatus may include an acoustic impedance sensor contact.
  • the apparatus for delivering ultrasonic neurostimulation may also include an acoustic impedance sensor configured to detect a low impedance contact between the subject's head and the couplant region, wherein the stimulation processor is configured to permit transmission of ultrasound for neurostimulation when the low impedance contact is detected.
  • the subject-contacting surface of the apparatus may include an ultrasound imaging sensor.
  • neurostimulation may also include an ultrasound imaging sensor configured to detect whether skull is underlying the apparatus at an appropriate location, orientation, and / or distance, wherein the stimulation processor is configured to permit transmission of ultrasound for neurostimulation when the presence of the skull underlying the subject-contacting portion of the apparatus is detected.
  • control processor may be part of a handheld telecommunications device; for example, the control processor may be part of a smartphone.
  • the set of instructions of the non-transitory computer-readable storage medium may be configured to wirelessly transmit control information to multiple apparatuses for delivering ultrasonic neurostimulation.
  • a method of transcranial ultrasound neuromodulation may include adhesively attaching a wireless, lightweight, self-coupling ultrasound neuromodulation apparatus to a subject's head, wherein the apparatus comprises an outer housing at least partially enclosing a power source, an ultrasound transducer, and a stimulation processor configured to control ultrasonic neuromodulation; selecting a neuromodulation control parameter from a computing device; wirelessly transmitting the neuromodulation control parameter to the neuromodulation apparatus; and applying ultrasound for neuromodulation from the neuromodulation apparatus according to the control parameter.
  • any of the apparatuses described may be adapted to allow the apparatus to conform specifically to the subject's head.
  • neuromodulation apparatus that is wireless, lightweight, adherent, and self-coupling may include: an outer housing at least partially enclosing a power source, an ultrasound transducer, and a stimulation processor configured to control ultrasonic neuromodulation; and a subject- contacting surface configured to connect to the outer housing, the subject-contacting surface including: an acoustic couplant region configured to couple acoustic energy from the ultrasound transducer to a subject's skin; a safety interlock sensor (e.g., an acoustic impedance sensor or ultrasound imaging sensor) contact; and one or more adhesive regions configured to adhesively secure the apparatus to the subject's head; wherein the subject-contacting surface is curved to conform to the subject's head.
  • an outer housing at least partially enclosing a power source, an ultrasound transducer, and a stimulation processor configured to control ultrasonic neuromodulation
  • a subject- contacting surface configured to connect to the outer housing, the subject-contacting surface including: an acoustic couplant region configured
  • FIG. 1 shows one variation of a workflow for an adherent transcranial ultrasound neuromodulation system.
  • FIG. 2 illustrates one variation of a transcranial ultrasound neuromodulation waveform, pulsed ultrasound protocol.
  • FIG. 3 shows one variation of a transcranial ultrasound neuromodulation waveform, continuous wave ultrasound protocol.
  • FIG. 4 illustrates a transcranial ultrasound neuromodulation waveform repetition.
  • FIG. 5 shows one potential target for transcranial ultrasound neuromodulation of the orbitofrontal cortex.
  • FIG. 6 illustrates potential targets for transcranial ultrasound neuromodulation of ventromedial prefrontal cortex.
  • FIG. 7 illustrates potential targets for transcranial ultrasound neuromodulation of primary motor cortex.
  • FIG. 8 illustrates potential targets for transcranial ultrasound neuromodulation of the locus coeruleus.
  • FIG. 9 illustrates potential targets for transcranial ultrasound neuromodulation of the ventral striatum.
  • FIG. 10 illustrates potential targets for transcranial ultrasound neuromodulation of the ventral tegmental area (VTA).
  • FIG. 1 1 shows a top view of one variation of a disposable/semi-disposable transcranial ultrasound system.
  • FIG. 12 is a bottom view of one variation of a disposable/semi-disposable transcranial ultrasound system.
  • FIGS. 13A shows one variation of a transcranial ultrasound neuromodulation apparatus including a disposable patient-contacting surface that is attachable to an outer housing.
  • FIG. 13B shows an exploded view of the transcranial ultrasound neuromodulation apparatus shown in FIG. 13A (including the components housed within the outer housing.
  • FIG. 14 is a view of one variation of a curved transcranial ultrasound system.
  • FIG. 15 schematically illustrates one variation of a wearable, lightweight, self- contained ultrasound system.
  • transcranial ultrasound systems configured to modulate brain function.
  • the apparatuses described herein may be used for noninvasive neuromodulation. These apparatuses may be self-contained, self-powered, self-adhering, and self-coupling and referred to as transcranial ultrasound neuromodulation pucks (or simply "pucks"). These apparatuses may include disposable and semi-disposable systems and devices. Small, lightweight disposable or semi-disposable transcranial ultrasound neuromodulation devices may be adherent and not require being held manually or by other components to the head. This may enable a user to seamlessly carry out normal activities during stimulation. In some embodiments, all components are housed in a single enclosure and one or more batteries supply energy to the system. In some embodiments, a solid couplant puck is used to couple ultrasound energy to the head.
  • neuromodulation puck has a cross-sectional long axis that is at least 50% longer than a cross- sectional short axis.
  • One advantageous feature of pucks configured to be at least 50% longer than they are wide is improved adherence to the head by enabling adhesive components to be further from each other.
  • a transcranial ultrasound neuromodulation puck is curved so that it can more easily fit to a curved portion of a user's head.
  • the puck curvature is 1- dimensional (ID; e.g. curved along one dimension such that the puck would fit on the external face of a cylinder) or 2-dimensional (2D; e.g. curved along two dimensions such that the puck would fit on the external face of an ellipsoid).
  • the term 'natural curvature' may refer to the curvature of an object without any external force exerted onto it.
  • Curved transcranial ultrasound neuromodulation pucks may be configured to be bendable or conformable when placed on the head so that curvature can increase or decrease up to 10% of the natural curvature of the puck in any, some, or all dimensions. For example, additional flexibility can be achieved by placing a foam backer layer in a puck.
  • a transcranial ultrasound neuromodulation puck may have a natural curvature such that the puck would fit the external face of a cylinder having a radius greater than 60 mm and less than 90 mm (optimally 75 mm) if the long axis of the puck were aligned perpendicular to or within 20 degrees of perpendicular to a radius of the cylinder.
  • a transcranial ultrasound neuromodulation puck may have a natural curvature such that the puck would fit the external face of an ellipsoid having a long axis greater than 104 mm and less than 156 mm (optimally 130 mm) and a short axis greater than 60 mm and less than 90 mm
  • FIG. 14 shows a view of the bottom of a transcranial ultrasound neuromodulation puck with 2D curvature.
  • the long axis of the puck is curved with a curvature corresponding to an ellipse with a 75 mm radius as shown by double-headed arrow 1501.
  • the short axis of the puck is less curved than the long axis.
  • the short axis is curved with a curvature corresponding to an ellipse with a 130 mm radius as shown by double-headed arrow 1502.
  • gel interface area 1504 adhesive areas 1503, 1506, charger contacts 1505, and housing 1507.
  • the curvatures identified above are appropriate for fitting an individual with an average size head.
  • Other embodiments of the present invention may have curvatures appropriate for individuals with smaller head sizes, such as infants, toddlers, children and other individuals of smaller than average head sizes.
  • Still further embodiments of the present invention may have curvatures appropriate for individuals with larger head sizes, such as exceptionally large individuals and individuals with cranial deformities.
  • curvatures that could be utilized with variations of the present invention, and embodiments of the present invention are contemplated for use with curved pucks with any appropriate curvature.
  • any variations of the transcranial ultrasound neuromodulation puck described herein may be configured to have a more irregular curvature such that the puck could not fit on the external face of a cylinder, ellipsoid, or sphere.
  • the shape of the puck is chosen for a particular intended area of the head.
  • a standardized model of the head is used to select the puck curvature.
  • irregularly curved pucks can be configured to have one or more variable parameters (i.e. sizes), similar to how pants are sized according to inseam and waist measurements.
  • An irregularly curved puck may employ a customized mold to personalize the curvature of a puck for an individual user's head shape.
  • An example of an irregularly curved puck is one configured to be placed on a user's forehead, spanning an area from supraorbital laterally toward the ear, for which a region along the long axis of the puck has a high angle of curvature to wrap around to the side of the head.
  • Adjustments to the curvature of the system can be made with knobs, set screws, or another electronic or mechanical interface component so that a personalized fit to the head can be achieved for any of the variations described herein.
  • kits for measuring a portion of a user's head to determine an appropriate sized device may comprise a kit for measuring a portion of a user's head to determine an appropriate sized device.
  • a kit for measuring head size and shape for determining an appropriately sized device includes, but is not limited to one or more of: a flexible tape measure or other system for measuring distance along the surface of the head; components of known curvature in one dimension; and 'dummy pucks' with size and shape of differently shaped and sized ultrasound pucks.
  • a transcranial ultrasound neuromodulation puck may have a single button.
  • a single button can be configured to have different functions depending on the context of when the button is pressed. As an example, pressing the button when the device is not delivering ultrasound causes ultrasound delivery to begin; pressing the button during an ultrasound session stops the ultrasound session; pressing the button when the device is not on a user's head restores factory settings on the puck. Additional functions of pressing the button would be readily apparent to one skilled in the art of user interface design and/or user experience design.
  • a single button can be configured to have different functions depending on the temporal pattern of button pressing.
  • different functions can be assigned for temporal patterns of button pressing chosen from the group including, but not limited to: a single brief press, a single long press, two brief button presses in rapid succession, and three brief button presses in rapid succession.
  • neuromodulation begins automatically when the unit is placed correctly on the head or is initiated wirelessly.
  • certain embodiments of the transcranial ultrasound neuromodulation puck allow for neuromodulation to stop automatically when the unit is removed from the head or is ended wirelessly.
  • a transcranial ultrasound neuromodulation puck may be configured to limit the duration of neuromodulation.
  • Systems that limit the duration of ultrasound energy delivered improve device safety by ensuring that a unit cannot transmit too much ultrasound energy or induce too much neuromodulation in a defined period of time.
  • the system is configured to be a "single use transcranial ultrasound neuromodulation" system that is only used once.
  • the system is configured to be disposable after a certain number of uses and is thus referred to as a "multiple use transcranial ultrasound neuromodulation" system.
  • the system is configured to be disposed after a number of uses within a range.
  • the system is configured to be disposed after a fixed number of uses chosen from the group that includes, but is not limited to: more than once, more than twice, more than 3 times, more than 4 times, more than 5 times, more than 10 times, more than 25 times, more than 50 times, more than 100 times, or more than 1000 times.
  • the system is configured to be disposed after a fixed period of time of use chosen from the group that includes, but is not limited to: more than 10 seconds, more than 30 seconds, more than 1 minute, more than 2 minutes, more than 3 minutes, more than 4 minutes, more than 5 minutes, more than 7 minutes, more than 10 minutes, more than 15 minutes, more than 30 minutes, more than 45 minutes, more than 1 hour, more than 2 hours, more than 3 hours, more than 5 hours, more than 10 hours, more than 20 hours, or longer.
  • a fixed-use fuse, burnout circuit, limited battery, or other electronic or mechanical system is used to cease device operation once the limit in uses or time has been reached.
  • a machine readable memory may be used to count the number of uses or length of time a disposable or semi- disposable transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation system component has been used, then a microcontroller or other electrical component compares the value in memory to a maximum number of uses or length of time to determine whether transcranial ultrasound neuromodulation will be triggered by the system.
  • RFID radiofrequency identification
  • a radiofrequency identification (RFID) tag is a component of a disposable component of a transcranial ultrasound neuromodulation puck or other transcranial ultrasound
  • neuromodulation system and configured to make certain that the disposable component is not used more often or for longer than intended.
  • a transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly may generally be lightweight with a small footprint. Small size and lightness are advantageous properties of a transcranial ultrasound neuromodulation assembly for several reasons, including, but not limited to: comfort, reduced cost, ease of adhering the unit to the head, and reduced area of acoustic coupling to the scalp to achieve tighter focusing of acoustic energy in the brain.
  • a maximum weight for a transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly may be chosen from the group of weights that includes, but is not limited to: less than about 48 ounces, less than about 32 ounces, less than about 16 ounces, less than about 8 ounces, less than about 7 ounces, less than about 6 ounces, less than about 5 ounces, less than about 4 ounces, less than about 3 ounces, less than about 2 ounces, less than about 1 ounce, or less than about 0.5 ounces.
  • Transcranial ultrasound neuromodulation may deliver energy over one or more ranges of acoustic frequencies to activate, inhibit, or modulate neuronal activity.
  • the optimal frequency range includes an acoustic frequency greater than about 100 kHz and less than about 10 MHz.
  • Appropriate transcranial ultrasound neuromodulation protocols transmit mechanical energy through the skull to a brain target without causing significant thermal or mechanical damage and induce neuromodulation.
  • transcranial ultrasound neuromodulation employs low intensity ultrasound such that the spatial- peak, temporal-average intensity (I sp ta) of the transcranial ultrasound neuromodulation protocol is less than about 1 W/cm 2 in the targeted brain tissue.
  • the acoustic intensity measure I spt a is calculated according to established techniques well known to those skilled in the art that relate to the ultrasound acoustic pressure and other transcranial ultrasound neuromodulation protocol characteristics such as the temporal average power during the transcranial ultrasound neuromodulation waveform duration.
  • ultrasound is delivered as short-lived continuous waves less than about 5 seconds or in a pulsed manner such that diverse patterns of neuromodulation are delivered.
  • Other embodiments may use continuous waves with durations longer than 5 seconds.
  • transcranial ultrasound neuromodulation protocols may utilize ultrasound waveforms of any type known in the art including but not limited to amplitude modulated waveforms, tone-bursts, pulsed waveforms, and continuous waveforms.
  • Components of the transcranial ultrasound neuromodulation device are portable and wearably attached or adherent to the subject in order to provide power, acoustically couple acoustic energy to the subject's head, and control the intensity, timing, targeting, and waveform characteristics of the transmitted acoustic waves.
  • adherent transcranial ultrasound neuromodulation puck 108 is placed at an appropriate location on a user's head, then components 105 that provide power and control the intensity, timing, targeting, and waveform characteristics of ultrasound trigger waveform 102 through low impedance acoustic coupling to the head of individual subject 101 that induces effect 107 on neural circuits in one or more brain regions. If the system is configured for a single use, then the system is removed by the user at their convenience and the disposable portion of the system is disposed of (i.e., thrown away, returned for exchanged, or otherwise removed from the reusable portion of the system).
  • the system may check to determine whether a threshold limit number of uses has been reached. If the threshold limit has been reached then the disposable portion of the system is disposed of (i.e., thrown away, returned for exchanged, or otherwise removed from the reusable portion of the system), otherwise the ultrasound puck can be reused for a subsequent neuromodulation session.
  • Pulsing of ultrasound is a feature of some ultrasound waveforms for
  • FIG. 2 shows features of ultrasound pulses in a schematic form.
  • the number of pulses for pulsed transcranial ultrasound neuromodulation waveforms is between about 1 pulse and about 125,000 pulses.
  • the 1 st (201), 2nd (202), and nth (204) pulses are shown, with the gap in the horizontal line (203) indicating additional pulses that may number between about 1 and about 125,000 pulses.
  • An ultrasound period 205 is equal to the inverse of an ultrasound frequency and pulse of pulse length 206 is repeated according to pulse repetition frequency 207 for duration 208 of transcranial ultrasound neuromodulation waveform.
  • FIG. 3 shows features of continuous ultrasound wave 302 in a schematic showing ultrasound pressure 301, period of ultrasound frequency 303, pulse length 304, and duration 305 of transcranial ultrasound neuromodulation waveform.
  • US protocols that include such CW waveforms offer advantages for neuromodulation due to their capacity to drive activity robustly.
  • one disadvantage of transcranial ultrasound neuromodulation protocols with CW pulses is that the temporal average intensity is significantly higher which may cause painful thermal stimuli on the scalp or skull and may also induce heating and thus damage in brain tissue.
  • advantageous embodiments using CW pulses may employ a lower acoustic intensity and/or a slow pulse repetition frequency of less than about 1 Hz.
  • a C W US stimulus waveform with 1 second pulse lengths repeated at 0.5 Hz would deliver US every other second.
  • Alternative pulsing protocols including those with slower pulse repetition frequencies of less than about 0.5 Hz or less than about 0.1 Hz or less than about 0.01 Hz or less than about 0.001 Hz are also beneficial.
  • the interval between pulses or pulse length may be varied during a transcranial ultrasound neuromodulation protocol that includes CW pulses.
  • repeating a transcranial ultrasound neuromodulation protocol may be used to achieve particular forms of neuromodulation during transcranial ultrasound neuromodulation session 406.
  • the number of times a transcranial ultrasound neuromodulation protocol of appropriate duration 404 is repeated is chosen to be in the range between 2 times and 100,000 times.
  • FIG. 4 presents a schematic of three repeated transcranial ultrasound neuromodulation protocols (401, 402, 403).
  • neuromodulation on brain function is detected by one or more technique selected from the group that includes, but is not limited to: (i) subjectively by the recipient as a perception, movement, concept, instruction, other symbolic communication by modifying the recipient's cognitive, emotional, physiological, attentional, or other cognitive state; (ii) through physiological measurement of brain activity by one or a plurality of: electroencephalography (EEG), magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), positron emission tomography (PET), single-photon emission computed tomography (SPECT), computed tomography (CT), functional tissue pulsatility imaging (fTPI), and other techniques for measuring brain activity known to one skilled in the art; and (iii) by making a physiological measurement of the body such as by electromyogram (EMG), galvanic skin response (GSR), heart rate, blood pressure, respiration rate, pupil dilation, eye movement, gaze direction, and other physiological measurement.
  • EEG electro
  • the transcranial ultrasound neuromodulation assembly further comprises one or more appropriate sensors, transducers, electrical control circuitry, signal processing systems or any combination thereof, configured to achieve one or more of the above listed techniques for measuring the physiology or brain activity of the user.
  • a transcranial ultrasound neuromodulation protocol may deliver ultrasound to one or more brain regions and induces neuromodulation that correlates more strongly in time with the timecourse of mechanical effects on tissue than thermal effects.
  • the acoustic frequency for transcranial ultrasound neuromodulation is generally greater than about 100 kHz and less than about 10 MHz,, i.e.
  • acoustic frequencies are between about 0.3 MHz and about 0.7 MHz.
  • acoustic intensity is a measure of power per unit of cross sectional area (e.g. mW/cm 2 ) and requires averaging across space and time.
  • the intensity of the acoustic beam can be quantified by several metrics that differ in the method for spatial and temporal averaging. These metrics are defined according to technical standards established by the American Institute for Ultrasound in Medicine and National Electronics Manufacturers
  • the spatial -peak temporal-average (I spt a) intensity of the ultrasound wave in brain tissue is greater than about 0.0001 mW/cm 2 and less than about 1 W/cm 2 , i.e.
  • I spta values are between about 100 mW/cm 2 and about 700 mW/cm 2 , usually in the range from about 200 mW/cm 2 to about 500 mW/cm 2 .
  • the l spta value for any particular transcranial ultrasound neuromodulation protocol is calculated according to methods well known in the art that relate to the ultrasound pressure and temporal average of the transcranial ultrasound neuromodulation waveform over its duration.
  • Effective ultrasound intensities for activating neurons or neuronal circuits do not cause tissue heating greater than about 2 degrees Celsius, usually less than 1 degree Celsius, for a period longer than about 5 seconds, preferably no longer than 3 seconds.
  • Pulsing of ultrasound is an effective strategy for activating neurons that reduces the temporal average intensity while also achieving desired brain stimulation or neuromodulation effects.
  • several waveforms In addition to acoustic frequency and transducer variables, several waveforms
  • a pulsed transcranial ultrasound neuromodulation protocol generally uses pulse lengths between about 0.5 microseconds and about 1 second, i.e.
  • 0.5 microseconds to 5 microseconds generally from 0.5 microseconds to 5 microseconds; optionally from 0.5 microseconds to 50 microseconds; optionally from 0.5 microseconds to 100 microseconds; optionally from 0.5 microseconds to 500 microseconds; optionally from 0.5 microseconds to 1 ms; optionally from 0.5 microseconds to 10 ms; optionally from 0.5 microseconds to 100 ms; optionally from 0.5 microseconds to 500 ms; optionally from 0.5 microseconds to 1 second; optionally from 5 microseconds to 50 microseconds; optionally from 5 microseconds to 100 microseconds;
  • a transcranial ultrasound neuromodulation protocol may use pulse repetition frequencies (PRFs) between about 50 Hz and about 25 kHz, i.e.
  • PRFs pulse repetition frequencies
  • Particularly advantageous PRFs are generally between about 1 kHz and about 3 kHz.
  • the number of cycles per pulse (cpp) is between about 5 and about 10,000,000.
  • Particularly advantageous cpp values vary depending on the choice of other transcranial ultrasound neuromodulation parameters and are generally between about 10 and about 250.
  • the number of pulses for pulsed transcranial ultrasound neuromodulation waveforms is between about 1 pulse and about 125,000 pulses.
  • the 1 st (201), 2nd (202), and nth (204) pulses are shown, with the gap in the horizontal line (203) indicating additional pulses that may number between about 1 and about 125,000 pulses.
  • neuromodulation waveforms are between about 100 pulses and about 250 pulses.
  • Tone bursts of ultrasound energy that extend for about 1 second or longer— though, strictly speaking, also pulses— are often referred to as continuous wave (CW).
  • Any of the variations described herein may deliver one or more continuous wave (CW) ultrasound waveforms less than about five seconds in duration, typically being from 1 second to 5 seconds.
  • US protocols that include such CW waveforms offer advantages for neuromodulation due to their capacity to drive activity robustly.
  • one disadvantage of transcranial ultrasound neuromodulation protocols with CW pulses is that the temporal average intensity is significantly higher which may cause painful thermal stimuli on the scalp or skull and may also induce heating and thus damage in brain tissue.
  • advantageous embodiments using CW pulses may employ a lower acoustic intensity and/or a slow pulse repetition frequency of less than about 1 Hz.
  • a CW US stimulus waveform with 1 second pulse lengths repeated at 0.5 Hz would deliver US every other second.
  • Alternative pulsing protocols including those with slower pulse repetition frequencies of less than about 0.5 Hz or less than about 0.1 Hz or less than about 0.01 Hz or less than about 0.001 Hz are also beneficial.
  • the interval between pulses or pulse length may be varied during a transcranial ultrasound neuromodulation protocol that includes CW pulses.
  • repeating a transcranial ultrasound neuromodulation protocol may be used to achieve particular forms of neuromodulation during transcranial ultrasound neuromodulation session 406.
  • the number of times a transcranial ultrasound neuromodulation protocol of appropriate duration 404 is repeated is chosen to be in the range between 2 times and 100,000 times.
  • FIG. 4 presents a schematic of three repeated transcranial ultrasound neuromodulation protocols (401, 402, 403).
  • the transcranial ultrasound neuromodulation repetition frequency may be fixed or variable.
  • Variable transcranial ultrasound neuromodulation repetition frequency values may be random, pseudo- random, ramped, or otherwise modulated.
  • the transcranial ultrasound neuromodulation repetition period is defined as the inverse of the transcranial ultrasound neuromodulation repetition frequency.
  • Providing a mixture of ultrasound frequencies is useful for efficient brain stimulation.
  • Various strategies for achieving a mixture of ultrasound frequencies to the brain of the user are known.
  • a strategy for producing ultrasound waves that contain power in a range of frequencies is to use square waves to drive the transducer or drive the transducer off-resonance.
  • Another strategy for generating a mixture of ultrasound frequencies is to choose transducers that have different center frequencies and drive each at their resonant frequency.
  • One or more of the above strategies or alternative strategies known to those skilled in the art for generating US waves with a mixture of frequencies would also be beneficial.
  • Mixing, amplitude modulation, or other strategies for generating more complex transcranial ultrasound neuromodulation waveforms can be beneficial for driving distinct brain wave activity patterns or to bias the power, phase, or spatial extent of brain oscillations such as slow-wave, delta, beta, theta, gamma, or alpha rhythms.
  • the ultrasound neuromodulation puck further comprises components for delivering transcranial electrical stimulation (TES).
  • TES and ultrasound neuromodulation are delivered at different times or concurrently.
  • Transcranial ultrasound and TES require electrical control hardware and software (or firmware) specific to the modality of stimulation, but some control circuitry is common to both systems.
  • each system is powered by a different battery. Any of the variations described herein may include components for delivering transcranial ultrasound and transcranial electrical energy contained in a single housing.
  • any of the variations described herein may use one or more other techniques for invasive or non-invasive brain stimulation in addition to transcranial ultrasound
  • the methods and devices comprise use of one or more alternative technologies for stimulating brain tissue to activate, inhibit, or modulate the activity of cells in the brain selected from the group that includes, but is not limited to: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), targeted electrical stimulation (TES), deep brain stimulation (DBS), stimulation through one electrode or an array of electrodes implanted on the surface of the brain or dura, and light activation of specially engineered proteins for neuromodulation known as optogenetics.
  • TMS transcranial magnetic stimulation
  • tDCS transcranial direct current stimulation
  • tACS transcranial alternating current stimulation
  • TES targeted electrical stimulation
  • DBS deep brain stimulation
  • stimulation through one electrode or an array of electrodes implanted on the surface of the brain or dura and light activation of specially engineered proteins for neuromodulation known as optogenetics.
  • optogenetics any of the variations described herein may include components for delivering transcranial ultrasound and a different form of brain stimulation chosen
  • any of the variations described herein may be configured so that the one or more effects of using multiple forms of neuromodulation are chosen from the list that includes, but is not limited to: increasing the spatial extent of stimulation; decreasing the spatial extent of stimulation; reshaping the spatial extent of stimulation; modifying the nature of the induced neuromodulation; increasing the intensity of neuromodulation; decreasing the intensity of neuromodulation; mitigating a cognitive or behavioral affect; enhancing a cognitive or behavioral affect; modifying the cells affected by neuromodulation; modifying the cellular compartments affected by neuromodulation; or another modification of the neuromodulating energy transmitted into the brain and/or nervous system.
  • Any of the variations described herein may use brain recordings to measure the effect of transcranial ultrasound neuromodulation.
  • One or more method of measuring brain activity is chosen from the group that includes, but is not limited to: electroencephalography (EEG), magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI), functional near-infrared spectroscopy (fNIRS), positron emission tomography (PET), single-photon emission computed tomography (SPECT), computed tomography (CT), functional tissue pulsatility imaging (fTPI), xenon 133 imaging, and other techniques for measuring brain activity known to one skilled in the art.
  • EEG electroencephalography
  • MEG magnetoencephalography
  • fMRI functional magnetic resonance imaging
  • fNIRS functional near-infrared spectroscopy
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • CT computed tomography
  • fTPI functional tissue pulsatility imaging
  • xenon 133 imaging and other techniques for measuring brain activity known to one skilled in the art.
  • components for delivering transcranial ultrasound and recording brain activity using a technique chosen from the preceding list may be contained in a single housing (e.g., incorporated into a transcranial ultrasound neuromodulation puck) or contained in a separate housing that is configured to communicate with a transcranial ultrasound neuromodulation puck.
  • EEG electroencephalogram
  • electrical hardware for amplifying, filtering, and otherwise processing EEG signals are incorporated into the transcranial ultrasound neuromodulation puck.
  • EEG electrodes and electrical hardware may be contained in one or more separate housings and may further comprise wired or wireless systems for transmitting raw and/or processed EEG signals to a transcranial ultrasound neuromodulation puck.
  • a microprocessor component of the transcranial ultrasound neuromodulation puck may apply one or more signal processing algorithms to an EEG recording to determine whether to turn transcranial ultrasound delivery on or off, or to adjust a parameter of transcranial ultrasound neuromodulation chosen from the group that includes, but is not limited to, acoustic frequency, duration, intensity, pulse repetition frequency, amplitude modulation, pulse length, or targeted brain region.
  • Physiological monitoring may be used in any of the variations described herein to measure the effect of transcranial ultrasound neuromodulation using a form of physiological monitoring chosen from the group that includes, but is not limited to: electromyogram (EMG), galvanic skin response (GSR), heart rate, blood pressure, respiration rate, pulse oximetry, pupil dilation, eye movement, gaze direction, or other physiological measurement known to one skilled in the art.
  • Physiological monitoring may be advantageous for providing feedback (e.g., real-time feedback) concerning the targeting, timing, and stimulation parameters for transcranial ultrasound neuromodulation.
  • components for delivering transcranial ultrasound and monitoring physiology may be contained in a single housing (e.g., incorporated into a transcranial ultrasound neuromodulation puck) or may be contained in a separate housing that is configured to communicate with a transcranial ultrasound neuromodulation puck.
  • a microprocessor component of the transcranial ultrasound neuromodulation puck applies one or more signal processing algorithms to one or more measurements of brain activity and/or physiology to determine whether to turn transcranial ultrasound delivery on or off, or to adjust a parameter of transcranial ultrasound neuromodulation chosen from the group that includes, but is not limited to, acoustic frequency, duration, intensity, pulse repetition frequency, amplitude modulation, pulse length, or targeted brain region.
  • any of the variations described herein may incorporate more than one transcranial ultrasound neuromodulation puck such that one puck is a master puck that controls the timing and waveform parameters of ultrasound transmitted by one or more slave pucks.
  • one or more modular pucks i.e., slave pucks
  • Each modular puck has its own adherent pad that may be incorporated into a couplant puck and a transducer as well as a connection means allowing for connection (e.g., wired, wireless) to the master puck.
  • Variations that incorporate a flexible or fixed wire or cable between a master puck and a slave puck may be configured to transmit power and control signals via the cable.
  • the slave pucks include an independent power source (e.g., battery) and receive control signals from the master puck via the connection means either wirelessly (e.g., Bluetooth Low Energy) or through a wired connection (e.g., flexible wiring extending from the master puck).
  • the control signal from the master puck may trigger a stored ultrasound waveform on the slave puck or the control signal from the master puck may be a time-varying waveform used to drive an ultrasound transducer and/or control circuitry for an ultrasound transducer.
  • the control signal from the master puck may trigger a stored ultrasound waveform on the slave puck or the control signal from the master puck may be a time-varying waveform used to drive an ultrasound transducer and/or control circuitry for an ultrasound transducer.
  • One advantageous feature of systems comprising a master and one or more slave pucks is the capacity to target different brain regions with a specified spatiotemporal pattern.
  • Spatiotemporal patterns include: concurrent neurostimulation and neurostimulation with a latency between ultrasound energy delivered by a master puck and a slave puck chosen from the group including, but not limited to about greater than 1 millisecond, about greater than 2 milliseconds, about greater than 5 milliseconds, about greater than 10 milliseconds, about greater than 15 milliseconds, about greater than 20 milliseconds, about greater than 30 milliseconds, about greater than 40 milliseconds, about greater than 50 milliseconds, about greater than 60 milliseconds, about greater than 70 milliseconds, about greater than 80 milliseconds, about greater than 90 milliseconds, about greater than 100 milliseconds, about greater than 200 milliseconds, about greater than 500 milliseconds, about greater than 1 second, about greater than 2 seconds, or longer.
  • More complicated spatiotemporal patterns of activation of master and slave pucks may be used to achieve a desired pattern of neuromodulation.
  • the specified spatiotemporal pattern may alternate between activation of a master puck and one or more slave pucks in a complex pattern that may include multiple ultrasound waveforms from a single puck before switching to ultrasound delivery from another puck or a specified
  • spatiotemporal pattern may deliver multiple ultrasound waveforms from a single puck, then switch to deliver a one or more ultrasound waveforms from another puck.
  • an application e.g., 'app'
  • a PC, laptop, smartphone, tablet, or other computerized platform containing a microprocessor running an iOS, Android, Windows, or other operating system may be configured to transmit wirelessly or via a wire a control signal for delivery of ultrasound from the system.
  • a time-varying voltage signal sent through the headphone jack output or other plug interface on the device may be used as a control for transmitting an ultrasound waveform and/or may control the timing, amplitude, or other feature of stimulation by a transcranial ultrasound neuromodulation system.
  • the trigger signal is transmitted wirelessly by the computer, smartphone, tablet, or other computing device via Bluetooth low energy (BTLE) or another wireless communication protocol.
  • BTLE Bluetooth low energy
  • the transcranial ultrasound neuromodulation system is powered by a USB or other wired communication port of a PC, laptop, smartphone, tablet, or other computing device.
  • An example of specialized hardware that permits analog communication via the headphone jack is the Hijack system developed at the University of Michigan and available via Seeed Studio that permits control signals for the timing, intensity, pulsing, or acoustic frequency to be generated by the mobile device and transmitted directly to the electrical circuitry of a transcranial ultrasound
  • a program running on a desktop or laptop computer transmits a control signal for the transcranial ultrasound neuromodulation system via serial, USB, or other transmission protocol.
  • a button or other user interface element on the transcranial ultrasound neuromodulation puck and control for turning the puck on and off or changing the settings is achieved by wireless communication with a smartphone, tablet, computer, or other electronic system.
  • neuromodulation system is configured to be user-actuated and/or automated. In this manner, embodiments of the present invention may be utilized without the need to have medical professionals or other skilled practitioners of ultrasound neuromodulation available in order to oversee the placement, control, and operation of the transcranial ultrasound neuromodulation system.
  • Lower acoustic impedance between an ultrasound transducer component of the system and the head, scalp, face, or other body part of the user is important for efficiently delivering acoustic energy to the subject.
  • Test pulses of acoustic energy can be emitted intermittently (e.g. once per second or once per 30 seconds or once per minute) and the puck further configured to measure acoustic impedance.
  • the acoustic impedance goes below a pre-set (or customizable) impedance level, the system is ready to deliver ultrasound energy.
  • Ultrasound neuromodulation can start automatically at the time when acoustic impedance becomes sufficiently low, or can start automatically with a delay.
  • the system can indicate to the user by a visual or auditory cue (or other indicator system) that sufficient acoustic coupling has been achieved, permitting the user to manually trigger ultrasound.
  • the device is engineered to automatically trigger ultrasound stimulation when the acoustic impedance between the subject and an ultrasound transducer or acoustically coupled material of the transcranial ultrasound neuromodulation system falls below a threshold value. Acoustic impedance can be detected from one or more ultrasound transducers appropriately configured.
  • the device is engineered such that impedance is determined upon an event (e.g., toggling of an on/off switch) in order to verify sufficiently low acoustic impedance prior to engaging stimulation.
  • the device is engineered to gate ultrasound stimulation so that it only occurs when the acoustic impedance between the subject and an ultrasound transducer or acoustically coupled material of the transcranial ultrasound neuromodulation system falls below a threshold value.
  • a component of the transcranial ultrasound neuromodulation device can assist a user or other individual in placing an adherent assembly containing at least one ultrasound transducer in physical contact with the head at an appropriate location to achieve a desired form of neuromodulation.
  • Systems and/or methods for guiding the user or other individual to place pucks at the one or more desired locations can be chosen from the group that includes, but is not limited to: fiduciary markers on the head; ratiometric measurements relative to fiduciary markers on the head; alignment components that detect relative location of one or more ultrasound transducers as measured by radiofrequency energy, ultrasound, or light; or a grid or other alignment system, such as the position of the ultrasound transducers themselves, projected onto the head of the user.
  • an indicator can provide feedback when effective ultrasound transducer positioning is achieved through a light-, sound-, or tactile-based indicator.
  • a user or other individual can identify fiduciary markers to assist in placement of one or more ultrasound transducers.
  • Advantageous fiduciary markers on the head include those used for placing EEG s in the standard 10/20 arrangement.
  • the nasion and inion are two fiducial markers used in the 10/20 system.
  • the nasion is the point between the forehead and the nose.
  • the inion is the lowest point of the skull from the back of the head and is normally indicated by a prominent bump.
  • the position of pucks can be determined relative to each other via sensors contained in each of the pucks chosen from the group including, but not limited to: gyroscope, accelerometer, barometer, GPS unit, RFID, or other system.
  • the signals are compared to determine the relative position of the two or more pucks in order to estimate their position on the head.
  • the known anatomy of the head can be used to constrain the estimates of the position of the two or more pucks. Having an estimate of the relative position of multiple pucks can be useful for targeting, particularly targeting using interference between transmitted ultrasound from more than one puck.
  • a positioning sensor as described above can be incorporated in one or more reference assemblies placed at a known location on the subject's head, face, neck, shoulder, back, or other body part. The measured signals from the reference assemblies are used to estimate the relative position of the one or more ultrasound pucks.
  • a transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly is configured for conformability to the head, face, or other body region.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly is made of flexible components.
  • all items larger than the curvature of the intended area of the body or head where the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly will be placed are made of flexible components.
  • flexible mechanical elements between inflexible components permit conformability to the body.
  • the transcranial ultrasound neuromodulation puck is made entirely of flexible materials (e.g.
  • a disposable transcranial ultrasound neuromodulation puck or disposable portion of a transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation system is configured to be returned to the company or a third party for recycling.
  • a refund can be provided for a disposable system returned by a user and one or more new disposable systems can be provided to a user or sent to them as a replacement for a returned or disposed of disposable transcranial ultrasound neuromodulation system component.
  • Return packaging can be provided for the user to mail a used system or used component of a system and users can subscribe to receive disposable transcranial ultrasound neuromodulation pucks or components of other transcranial ultrasound neuromodulation systems and/or disposable portions of transcranial ultrasound neuromodulation pucks or components of other transcranial ultrasound neuromodulation systems regularly or when they have used previously received systems.
  • the system may be configured to detect usage of the puck and initiate a reorder transaction based on such usage (e.g., if the puck is a single use puck - reorder pucks immediately, or check stock that the subject has based on previous orders; if the puck is a limited use puck - reorder pucks if the number of remaining uses falls below a certain number).
  • Reordering of pucks can be done on one or more of a variety of metrics, each of which could be configurable by the user if allowed by the system.
  • Metrics for reordering include, but are not limited to: stock on hand, number of usages remaining (per puck or across all pucks on hand or some subset thereof), thresholds set by user, reoccurring on specific dates, reoccurring on specific events, or any combination thereof. Recycling benefits the environment, particularly with respect to batteries or other electrical components that may be toxic if disposed of improperly.
  • two or more battery supplies may be utilized.
  • one battery supply can be configured to provide power to the one or more ultrasound transducers while a second battery supply is configured to provide power to control components and other components of the device (e.g. user interface components).
  • Certain embodiments provide a rechargeable or replaceable battery supply integrated into the main housing of the device, while a second battery supply for the transducers is contained within a disposable portion of the device.
  • battery supplies could be arranged in a variety of configurations, and embodiments of the present invention are contemplated for use with any such battery configuration.
  • the transcranial ultrasound neuromodulation systems have advantageous features including, but not limited to, miniaturization, portability, and affordability.
  • the transcranial ultrasound neuromodulation assembly incorporates disposable components.
  • the entire assembly can be disposable or the assembly can be composed of separable non-disposable and disposable components.
  • robust and reusable components of the system can be reused, saving resources and reducing cost, while permitting the replacement of other components such as single-use ultrasound transducers or single-use ultrasound couplant systems or couplant pucks (which may not reliably adhere to the head after a single use or may be replaced for purposes of sterility) or a battery (which is designed in some embodiments to provide sufficient power for only a single session or a limited number of sessions of transcranial ultrasound
  • all components of the system can be contained in one or more housings that adhere to the head without requiring additional components for wearably attaching the system to the user such as a band, cap, hat, strap, or other attachment system.
  • the transcranial ultrasound neuromodulation system can further comprise a retractable or non-retractable strap to hold the system in physical contact with the head.
  • the transcranial ultrasound neuromodulation system can have one or more features selected from the group: incorporating disposable components; contained in one or more housings that adhere to the head without requiring additional components for wearably attaching the system to the user such as a band, cap, hat, strap, or other attachment system; user-actuated or automated.
  • transcranial ultrasound neuromodulation systems differ from existing transcranial ultrasound neuromodulation systems and offer key advantages for the widespread, portable use of transcranial ultrasound neuromodulation systems, including, but not limited to: (1) single use or limited use transducer assemblies and/or acoustic coupling systems that adhere to the skin, hair, face, or head and simplify system design by reducing requirements for robustness of the transducer and/or couplant puck itself, as well as its properties with respect to adherence to the head, acoustic properties, and effectiveness of stimulation; (2) smaller, lighter, and structurally flexible form factor enables users to undertake normal, daily activities throughout stimulation sessions; (3) one or more components selected from the group that includes, but is not limited to: electrical, coupling, transducer, structural, and energy-storage components can be designed to lower tolerances and need not achieve long-term performance, permitting significantly reduced product pricing relative to existing portable ultrasound systems (e.g., 5x-1000x less), significantly expanding their use and reducing the barrier to adoption versus traditional devices; (4) by eliminating the requirement for field support for
  • a transcranial ultrasound neuromodulation puck comprises components that make it self-adhering to the skin, skull, face, hair, or other portion of the head.
  • a component that makes the transcranial ultrasound neuromodulation puck self-adhering may be an adhesive, a suction device, or another system that adheres the puck to the head. This property is advantageous for holding the puck assembly in place at a fixed location on the head for targeting a specific brain region.
  • the components contained in the adherent housing are sufficiently light (e.g., less than 16 oz, preferably less than 10 oz, and ideally less than 5 oz).
  • a self-adhering transcranial ultrasound neuromodulation assembly with a small footprint would permit adherence more readily onto a curved section of the head.
  • a self-adhering transcranial ultrasound neuromodulation assembly with a low center of gravity so that forces do not pull against the components that hold the assembly in acoustically coupled contact with the head would also permit easier adherence to the head.
  • the configuration of the transcranial ultrasound neuromodulation assembly provides physical stability.
  • a wrap-around-the-ear configuration can provide additional support for a transcranial ultrasound neuromodulation assembly by transferring weight to the ear.
  • An adherent component of a transcranial ultrasound neuromodulation puck may also be an acoustic couplant between an ultrasound transducer and the head or the acoustic couplant portion of the puck can be non-adherent and the puck adheres via a non-couplant portion of the puck.
  • a non-couplant adherent is in a ring around a couplant at the center of a puck or a non-couplant adherent portion of the puck is next to a non-adherent couplant portion of a puck.
  • the number of adherent regions present on a single puck is chosen from the group of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, and more than 100.
  • a transcranial ultrasound neuromodulation puck is reversibly self-adhering.
  • the self-adhering components for instance adhesive
  • the self-adhering component may be easily reversible and requires a small amount of force from the user to remove.
  • a self-adhering component is designed so that when removing the transcranial ultrasound neuromodulation puck little or no hair is removed.
  • the self-adhering component is stronger and removing the transcranial ultrasound neuromodulation assembly requires more force, similar to how a Band-Aid is removed. Reversible adherence to the head, face, scalp, or hair is an advantageous feature of transcranial ultrasound neuromodulation systems and assemblies.
  • an adhesive is chosen that has the property of being an acoustic couplant for the ultrasound energy delivered transcranial ⁇ , leaving little or no residue, and being removable by the user.
  • a pressure sensitive adhesive or hydrogel can be held in place on the head by a pressure sensitive adhesive or hydrogel.
  • One or more adhesives can be chosen from the list that includes, but is not limited to, hydrogel, acrylic conductive adhesive, and PIB (polyisobutylene) synthetic rubber conductive adhesive.
  • a hydrogel used as an adhesive is soft conformable gel material that enables a temporary bond with the skin and can be ionically conductive. The weakness with this technology alone is that the skin bond is weak. Appropriate hydrogels can be manufactured by Corium International and other vendors. Adhesives Research Inc. is a provider of acrylic conductive adhesive.
  • PIB polyisobutylene
  • PIB is a synthetic rubber conductive adhesive designed for direct skin contact for increased, but still temporary, durations (days to weeks).
  • PIB adhesives can be tailored to be removable or high bond.
  • One of ordinary skill in the art would appreciate that there are numerous pressure sensitive adhesives and hydrogels that could be used with embodiments of the present invention, and embodiments of the present invention are contemplated for use with any type of pressure sensitive adhesive and/or hydrogel.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly shape can be chosen from the group of shapes that include, but are not limited to: round, elliptical, rectangular, triangular, polygonal, trapezoidal, or another shape of arbitrary complexity, including shapes with rounded edges.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly long axis dimension can be less than about 12 cm, less than about 10 cm, less than about 9 cm, less than about 8 cm, less than about 7 cm, less than about 6 cm, less than about 5 cm, less than about 4 cm, less than about 3 cm, less than about 2 cm, or less than about 1 cm.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly can be round with a diameter of less than about 12 cm, less than about 10 cm, less than about 9 cm, less than about 8 cm, less than about 7 cm, less than about 6 cm, less than about 5 cm, less than about 4 cm, less than about 3 cm, less than about 2 cm, or less than about 1 cm.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly has a height of less than about 40 mm, less than about 30 mm, less than about 20 mm, less than about 10 mm, less than about 9 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, less than about 5 mm, less than about 4 mm, less than about 3 cm, less than about 2 mm, or less than about 1 mm.
  • the neuromodulation puck or other transcranial ultrasound neuromodulation assembly is less than about 5 cm in diameter and less than about 1 cm in height and weighs less than about 8 ounces.
  • the footprint of the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly is less than about 5 cm in diameter and less than about 0.5 cm in height and weighs less than about 4 ounces.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly could be configured in a variety of footprints, and embodiments of the present invention are contemplated for use with any such footprint.
  • a button, switch, touch screen, or other user interface component permits the user to turn the one or more ultrasound transducers on and/or off.
  • the user interface element on a transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly consists of an on/off switch and there are no user controllable elements for adjusting parameters of stimulation.
  • factory settings are chosen for safety and efficacy and preset in the device, to be triggered by the user by toggling the on/off switch - or automatically turned on when the system senses an effective acoustic coupling to the scalp.
  • neuromodulation puck or other transcranial ultrasound neuromodulation assembly does not require user input concerning the time of stimulation, intensity of stimulation, frequency of stimulation, or other stimulation parameter.
  • the transcranial ultrasound neuromodulation system further comprises one or more user interface components chosen from the group including, but not limited to: touchscreen interface, keyboard, mouse, joystick, knob, button, indicator screen, or another user interface.
  • parameters of stimulation are transmitted wirelessly to the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly by Bluetooth, Wi-Fi, cellular data signals, or another form of wireless communication.
  • a remote server can trigger ultrasound delivery stimulation via the Internet or other local or wide area network means, or a PC, laptop, smartphone, or tablet can be used to remotely control parameters of ultrasound neuromodulation (e.g., acoustic frequency, duration, pulsing parameters, on/off).
  • the recipient of ultrasound stimulation can trigger their own ultrasound stimulation or a third party can trigger the ultrasound stimulation.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly can incorporate a GPS antenna, RFID tag, Bluetooth transmitter, Wi-Fi transmitter, or other system for transmitting to and from it.
  • wireless communication can be used to trigger ultrasound delivery remotely or due to the presence of the transcranial ultrasound
  • a neuromodulation puck or other transcranial ultrasound neuromodulation assembly in a particular location.
  • a user may wear a transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly configured for improved learning that is only triggered when they are in a classroom and a lecture has begun.
  • a transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly configured to improve motor learning and motor performance is worn by a golfer and activated when the subject is in proximity to their golf club.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly further comprises sensors and related components with functionality that includes, but is not limited to, recording brain activity, detecting skin resistance, salinity, or humidity, measuring temperature, or measuring other physiological or ambient signals.
  • the invention may comprise hardware and/or software components that are configured to generate appropriate control sequences for transcranial ultrasound neuromodulation, transmit signals to ultrasound electrical control components, connect to one or more ultrasound transducers placed on a user for transmitting ultrasound energy transcranially, or any combination thereof.
  • the system can be configured for mobile use, including configurations for wireless
  • an electrical circuit can be constructed on a printed circuit board (PCB) or silicon chip and the electrical circuit may include a battery and an on/off switch for the user to control activation of the transcranial ultrasound neuromodulation system.
  • PCB printed circuit board
  • an electrical circuit may include fewer or additional components.
  • One of ordinary skill in the art would appreciate that an electrical circuit could be constructed of any number of materials and embodiments of the present invention are contemplated for use with any suitably constructed electrical circuit.
  • transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly is configured to be semi-disposable
  • reusable components integrated into a main housing can be permanently used for all sessions of transcranial ultrasound neuromodulation.
  • the reusable components incorporated into the main housing can be designed for re-use a number of times chosen from the group that includes, but is not limited to: more than once, more than twice, more than 3 times, more than 4 times, more than 5 times, more than 10 times, more than 25 times, more than 50 times, more than 100 times, or more than 1000 times.
  • the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly is configured to be semi-disposable.
  • semi-disposable systems generally re-use ultrasound transducer components and some electronic circuitry, while disposing of components that include, but are not limited to, acoustic couplant materials (e.g. couplant puck), a battery, and/or adherent materials for holding the puck in physical contact with the head.
  • the disposable portion of the ultrasound neuromodulation puck may include one or more component from the list: one or more acoustic couplant material; a battery; an electrical connector; a fuse or limiting switch configured to terminate (or burn out in the case of a fuse) after exceeding a desired time or current level, protecting the user from over use or undesirable current surges or fluctuations (e.g., those outside the predefined range for the electrical components of the system and/or one or more ultrasound transducers); a microcontroller; one or more capacitive micromachined ultrasound transducers (CMUTs); a user interface component; packaging; a tactile transducer; a speaker; and a visual indicator such as an LED.
  • CMUTs capacitive micromachined ultrasound transducers
  • the various elements of the disposable portions of the transcranial ultrasound neuromodulation puck or other transcranial ultrasound neuromodulation assembly are not necessarily a single disposable component.
  • the disposable portion may be two or more separate components, such as a disposable contact pad, comprising an adherent, an acoustic couplant, and one or more ultrasound transducers, while a disposable battery may be removably integrated within a semi-disposable or non-disposable portion of the device (e.g., battery compartment).
  • a fully disposable embodiment of the invention may comprise one or more CMUTs, custom electronics, and a thin film battery.
  • an indicator communicates to the user (and/or a third party) about ultrasound stimulation, including communication indicating one or more of: commencement of ultrasound stimulation; ongoing ultrasound stimulation; ultrasound stimulation will end in a certain amount of time; ultrasound stimulation will begin soon; and ultrasound stimulation has recently ended.
  • an indicator communicates to the user
  • the indicator can take the form of an LED or other visual stimulus; transducer, buzzer, or other tactile transducer; a speaker or skull-coupled transducer for transmitting vibration that can be detected as an auditory stimulus; an emitted chemical signal detected as an olfactory or gustatory signal by the user; or a signal transmitted via an application used by the subject on a PC, laptop, tablet, or smartphone.
  • an indicator could be configured to provide numerous feedback and/or communication types, and embodiments of the present invention are contemplated for use with any type of indicator.
  • a flexible circuit is longer and shaped to go behind a subject's ear in a similar fashion to an eyeglass frame.
  • the flexible circuit can be any shape for convenience and comfort of placing the assembly on the user's head.
  • Various ultrasound transducers can be used to generate the acoustic wave.
  • the transcranial ultrasound neuromodulation assembly incorporates an array of transducers.
  • capacitive micromachined ultrasound transducers are advantageous for creating ultrasound transducer arrays, because they can be manufactured inexpensively and at high density for fitting within a small ultrasound puck.
  • a CMUT array can be configured to be a phased array for focusing ultrasound energy and multiple CMUT arrays can be contained in a single transcranial ultrasound neuromodulation puck and move along tracks relative to each other for altering the targeting within the brain.
  • electrical isolation hardware is incorporated in the transcranial ultrasound neuromodulation system to protect the user from unexpected electrical surges and voltage boosting hardware is optionally configured to boost IV, 3 V, 5 V, or other low voltage inputs to about 9V or about 12V or another higher voltage level.
  • a chain of batteries in series is used to generate higher voltages required for transcranial ultrasound neuromodulation.
  • six 1.5V batteries in series can be used to create a 9V source.
  • Transformer or buck-boost strategies can be used to generate higher voltages from a low voltage battery source.
  • One of ordinary skill in the art would appreciate that there are numerous strategies for generating higher voltages from lower voltage sources.
  • a coin cell battery can supply the power for transcranial ultrasound neuromodulation.
  • These and other battery form factors are advantageous for a disposable, limited use or single use system.
  • usage of the device can be limited as to not allow a user to overuse or forget to turn off the transcranial ultrasound neuromodulation session.
  • the placement of one or more ultrasound transducers is adjusted based on a procedure that delivers a test pulse of known acoustic energy through one or more transducers and measures an induced physiological effect, subjective effect, or cognitive effect.
  • a physiological or cognitive measurement can be used to detect a cognitive state of the user.
  • the unit turns on when the user is tired and is configured to increase a user's energy, alertness, and/or wakefulness.
  • Fatigue can be detected by determining gaze patterns, pupil dilation, eyelid closure, muscle tone and/or position of facial muscles, blinking patterns, how long your eyes stay closed between blinks, or electroencephalography to measure brain rhythms that correspond to fatigue or sleep onset.
  • anxiety or stress is detected in a user by measuring galvanic skin response or another physiological measurement that correlates with anxiety or stress, and the transcranial ultrasound neuromodulation system is configured to reduce anxiety and/or stress.
  • the transcranial ultrasound neuromodulation unit is configured to modify the amplitude or phase of a brain rhythm.
  • the transcranial ultrasound neuromodulation system can be triggered to enhance synchrony in an alpha, beta, or gamma frequency band to affect attention, working memory, and/or decision-making.
  • the device or system can be configured so that the induced neuromodulation is perceived subjectively by the recipient as a sensory perception, movement, concept, instruction, other symbolic communication, or modifies the recipient's cognitive, emotional, physiological, attentional, or other cognitive state.
  • a transcranial ultrasound neuromodulation system can be configured for therapeutic use or for use by a consumer without oversight by a technician, medical professional, or other skilled practitioner of transcranial ultrasound neuromodulation.
  • neuromodulation can be targeted to more than one brain region.
  • transcranial ultrasound neuromodulation can target a first brain region to induce a set of behavioral, cognitive, or other effects, while concurrently (or in close temporal relation) targeting a second brain region with transcranial ultrasound neuromodulation to counteract or complement a subset of the effects of stimulation targeting the first brain region.
  • the functional effect of neuromodulation can be shaped to reduce unwanted side effects.
  • the first and second brain regions can be anatomically nearby brain regions or anatomically distant brain regions.
  • the device is configured to target a first brain region and a second brain region to counteract an unwanted effect occurring in or mediated by the second brain region caused by stimulation of the first region.
  • the device can also be configured to target additional brain regions to counteract the effects of stimulating a first and/or second brain region.
  • the latency can be chosen from the group of: less than about 30 seconds; less than about 10 seconds; less than about 5 seconds; less than about 1 second; less than about 500 milliseconds; less than about 250 milliseconds; less than about 100 milliseconds; less than about 50 milliseconds; less than about 40 milliseconds; less than about 30 milliseconds; less than about 20 milliseconds; less than about 10 milliseconds; less than about 5 milliseconds; less than about 2 milliseconds; or less than about 1 millisecond.
  • the timing and latency of ultrasound stimulation of multiple brain regions can be determined based on feedback from a measurement of brain activity, behavior, cognition, sensory perception, motor performance, emotion, or state of arousal.
  • the transcranial ultrasound neuromodulation device is configured to induce spike-timing dependent plasticity in one or more targeted brain regions and/or to re-create patterns of neural activity in and/or between distinct brain regions during which transduction delays of between about 1 ms and about 30 ms occur.
  • neuromodulation can be designed to activate, inhibit, or modulate brain activity that occurs in the temporal domain (e.g., brain rhythms) in one or more brain regions.
  • transcranial ultrasound neuromodulation is targeted to multiple connected regions in the brain that normally communicate with a known temporal latency.
  • neuromodulation on the brain can be measured by one or more cognitive assessment chosen from the group that includes, but is not limited to: a test of motor control, a test of cognitive state, a test of cognitive ability, a sensory processing task, an event related potential assessment, a reaction time task, a motor coordination task, a language assessment, a test of attention, a test of emotional state, a behavioral assessment, an assessment of emotional state, an assessment of obsessive compulsive behavior, a test of social behavior, an assessment of risk-taking behavior, an assessment of addictive behavior, a standardized cognitive task, an assessment of "cognitive flexibility" such as the Stroop task, a working memory task (such as the n-back task), tests that measure learning rate, and a customized cognitive task.
  • a cognitive assessment chosen from the group that includes, but is not limited to: a test of motor control, a test of cognitive state, a test of cognitive ability, a sensory processing task, an event related potential assessment, a reaction time task, a motor coordination task, a
  • neuromodulation can be achieved exclusively via one or more ultrasound transducers placed on portions of the head that do not have hair to reduce the need for additional material or system components for coupling acoustical energy to the scalp.
  • Acoustic coupling between an ultrasound transducer and the skin can be achieved with a semi-permeable sack between the transducer and the skin that upon being squeezed releases a small amount of ultrasound gel, hydrogel or other material with similar acoustic impedance to the head.
  • the released acoustic couplant may be chosen to be one that evaporates after the transcranial ultrasound neuromodulation session and does not require cleanup.
  • the battery can be charged by one or more of solar panels or by harvesting energy from the movements of a user for example by using
  • piezopolymers or piezoelectric fiber composites are piezopolymers or piezoelectric fiber composites.
  • the placement of one or more ultrasound transducers and targeting of ultrasound energy is configured for targeting the orbitofrontal cortex for neuromodulation (OFC; Brodmann 10, 1 1 , 14; FIG. 5).
  • OFC orbitofrontal cortex
  • Brodmann 10, 1 1 , 14; FIG. 5 Targeting to the OFC can be advantageous for modulating executive control and decision making.
  • the placement of one or more ultrasound transducers and targeting of ultrasound energy is configured for targeting the ventromedial prefrontal cortex for neuromodulation (VmPFC; Brodmann area 10, FIG. 6).
  • Targeting to the VmPFC can be advantageous for modulating emotion, risk, decision-making, and fear.
  • the placement of one or more ultrasound transducers and targeting of ultrasound energy is configured for targeting the primary motor cortex for neuromodulation (Ml ; Brodmann area 4; FIG. 7). Targeting to Ml can be advantageous for affecting motor function.
  • the placement of one or more ultrasound transducers and targeting of ultrasound energy is configured for targeting the locus coeruleus for neuromodulation (LC; FIG. 8).
  • Targeting to the LC can be advantageous for modulating norepinephrinergic tone, learning and memory, sleep, processing of stressful stimuli, and other effects.
  • the placement of one or more ultrasound transducers and targeting of ultrasound energy is configured for targeting the ventral striatum for neuromodulation (FIG. 9).
  • Targeting to the ventral striatum can be advantageous for modulating emotional and motivational aspects of behavior.
  • the placement of one or more ultrasound transducers and targeting of ultrasound energy is configured for targeting the ventral tegmental area for neuromodulation (VTA; FIG. 10).
  • VTA ventral tegmental area for neuromodulation
  • Targeting to the VTA can be advantageous for modulating reward circuitry, motivation, drug addiction, intense emotions relating to love, and other effects mediated by this dopaminergic system.
  • a transcranial ultrasound neuromodulation puck can be configured via a user interface on the puck (e.g., selector switch) or wireless interface via another device (e.g. smartphone, tablet, laptop, desktop computer, or other computing device) for targeting a particular brain region.
  • a smartphone application connected to an application programming interface (API) can be configured to enable the user to control an ultrasound puck to transmit ultrasound energy with an appropriate spatiotemporal pattern to achieve a particular type of neuromodulation by a wired signal from a peripheral device, via signals transmitted through a headphone jack, or over a wireless connection via a local area network, Bluetooth, or another wireless transmission protocol.
  • the puck can be conveniently changed between two or more types of transcranial ultrasound neuromodulation.
  • the device can incorporate a built-in acoustic impedance meter.
  • Advantageous embodiments provide the user with feedback about the impedance of the acoustic contact between a puck containing an ultrasound transducer and the body of the user.
  • Feedback about acoustic impedance can be provided through one or more of: a graphical user interface, one or more indicator lights, or other user interface or control unit.
  • feedback to the user about the impedance is designed to inform the user to adjust the positioning or coupling of a transcranial ultrasound neuromodulation system to couple it more firmly to the body and thus reduce impedance.
  • the transcranial ultrasound neuromodulation system or device can be configured to target one or more regions of cerebral cortex, where the region of cerebral cortex chosen from the group that includes, but is not limited to the: striate visual cortex, visual association cortex, primary and secondary auditory cortex, somatosensory cortex, primary motor cortex, supplementary motor cortex, premotor cortex, the frontal eye fields, prefrontal cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, anterior cingulate cortex, and other area of cerebral cortex.
  • the region of cerebral cortex chosen from the group that includes, but is not limited to the: striate visual cortex, visual association cortex, primary and secondary auditory cortex, somatosensory cortex, primary motor cortex, supplementary motor cortex, premotor cortex, the frontal eye fields, prefrontal cortex, orbitofrontal cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, anterior cingulate cortex, and other area of cerebral cortex.
  • the transcranial ultrasound neuromodulation system or device can be configured to target one or more deep brain regions chosen from the group that includes, but is not limited to: the limbic system (including the amygdala), hippocampus, parahippocampal formation, entorhinal cortex, subiculum, thalamus,
  • hypothalamus white matter tracts, brainstem nuclei, cerebellum, neuromodulatory nucleus, or other deep brain region.
  • the transcranial ultrasound neuromodulation system or device can be configured to target one or more brain regions that mediate sensory experience, motor performance, and the formation of ideas and thoughts, as well as states of being chosen from the group that includes, but is not limited to: emotion, physiological arousal, sexual arousal, attention, creativity, relaxation, empathy, connectedness, and other cognitive states.
  • the transcranial ultrasound neuromodulation system or device can be configured to modulate neuronal activity underlying multiple sensory domains and/or cognitive states occurring concurrently or in close temporal arrangements.
  • the effect of delivering ultrasound energy to one or more brain regions can be a modulation of one or a plurality of biophysical or biochemical processes chosen from the group that includes, but is not limited to: (i) ion channel activity, (ii) ion transporter activity, (iii) secretion of signaling molecules, (iv) proliferation of the cells, (v) differentiation of the cells, (vi) protein transcription of cells, (vii) protein translation of cells, (viii) protein phosphorylation of the cells, and (ix) protein structures in the cells.
  • the transcranial ultrasound neuromodulation puck can take the form of a sticker or tattoo; the transcranial ultrasound neuromodulation puck can be worn for extended periods of time exceeding about one hour, about 12 hours, about 1 day, about 3 days, about 1 week, about 1 month, or longer; and/or the transcranial ultrasound neuromodulation puck can be water resistant or water proof (e.g. can be worn in the shower, in the rain, or while swimming).
  • Example 1 a transcranial ultrasound neuromodulation puck
  • FIGS. 1 1-14 show different views of a disposable / semi-disposable transcranial ultrasound neuromodulation system.
  • the apparatus in FIGS. 1 1-14 shows a round transducer, two printed circuit boards for electronic circuitry, and a battery within a housing that is attached or attachable to a subject-contacting surface including an adhesive.
  • FIG. 1 1 shows line drawing 1204 of the top of a transcranial ultrasound
  • neuromodulation puck including a button 1202 to turn on the system and an LED indicator ring 1201 to indicate when ultrasound is being delivered to the user.
  • FIG. 12 shows line drawing 1302 of the top of a transcranial ultrasound
  • neuromodulation puck including gel interface area 1303, adhesive areas 1306, 1307, charger contacts 1304, and housing 1305.
  • FIGS. 13 A and 13B show exploded line drawings schematics of a transcranial ultrasound neuromodulation puck with a bottom view (FIG. 13A) and top view (FIG. 13B).
  • the bottom view shows disposable portion 1401, adhesive areas 1402, 1403, solid acoustic couplant puck 1404, charger contacts 1405, and housing 1407.
  • the top view shows disposable portion 1420, adhesive areas 1419, 1417, solid acoustic couplant puck 1418, charger contacts 1415, housing 1416, 1410, printed circuit boards 1412, 1414, ultrasound transducer 1413, battery 1411, on/off button 1408, and LED indicator ring 1409 to indicate when ultrasound is being delivered to the user.
  • FIG. 14 shows a view of the bottom of a curved transcranial ultrasound
  • the puck is curved in two dimensions.
  • the long axis of the puck is curved with a curvature corresponding to an ellipse with a 75 mm radius as shown by double-headed arrow 1501.
  • the short axis of the puck is less curved than the long axis.
  • the short axis is curved with a curvature corresponding to an ellipse with a 130 mm radius as shown by double- headed arrow 1502.
  • gel interface area 1504 adhesive areas 1503, 1506, charger contacts 1505, and housing 1507.
  • transcranial ultrasound neuromodulation session refers to a period of time when pulsed or continuous transcranial ultrasound stimulation is delivered to a subject for the purpose of neuromodulation.
  • Stelf-contained refers to a feature of a system or assembly wherein all components of the system or assembly are incorporated in a single housing or enclosure.
  • Self-powered refers to a feature of a self-contained system or assembly wherein power is provided by one or more energy sources incorporated in the self-contained system and no external energy source provides power to the self-contained system or assembly.
  • Self-adhering refers to a feature of a self-contained system or assembly wherein at least one component of the self-contained system or assembly is configured to cause the self-contained system or assembly to adhere to the head in order to successfully deliver a transcranial ultrasound neuromodulation session and "adhere" is defined as in the Merriam- Webster dictionary as "to hold fast or stick by or as if by gluing, suction, grasping, or fusing".
  • Self-coupling refers to a feature of a self-contained system or assembly wherein at least one component of the self-contained system or assembly is configured to couple ultrasound energy to the head by forming a low acoustic impedance contact between an ultrasound transducer and the head of the user.
  • transcranial ultrasound neuromodulation puck refers to a device for transcranial ultrasound neuromodulation, which has one, or more properties selected from the group comprising: self-contained, self-powered, self-adhering, and self- coupling.
  • the term "master puck” refers to an assembly comprising a power source (e.g. battery), a machine-readable form of computer memory, components for transmitting analog and/or digital signals to a "slave puck", and control components capable of controlling delivery of ultrasound energy from both: (1) one or more transducers contained in the master puck and (2) one or more "slave pucks" containing one or more ultrasound transducers.
  • a power source e.g. battery
  • a machine-readable form of computer memory e.g., a machine-readable form of computer memory
  • components for transmitting analog and/or digital signals to a "slave puck” e.g., a "slave puck” containing one or more ultrasound transducers.
  • slave puck refers to an assembly comprising components for receiving and interpreting analog and/or digital signals from a "master puck” and one or more ultrasound transducers that deliver ultrasound energy transcranially upon receipt of an appropriate transmitted from a "master puck” contained in a distinct assembly and communicated by a wired or wireless protocol to the "slave puck”.
  • Slave pucks contain a power source (e.g. battery) or are connected via a wire or cable to a power source present in another assembly (e.g. a "master puck” or battery pack).
  • Transcranial ultrasound neuromodulation generally permits spatial targeting of stimulation to both superficial and deep neuronal target regions.
  • transcranial ultrasound neuromodulation systems that are wireless, lightweight, adherent and self-coupling are particularly advantageous because they enable portability.
  • a further benefit of portable transcranial ultrasound neuromodulation systems described herein is that they can be self- actuated by a user without assistance from a technician, medical professional, scientist, or other skilled practitioner of ultrasound.
  • self-actuated systems require additional controls to ensure their safe operation.
  • Transcranial ultrasound neuromodulation protocols typically require appropriate waveforms (acoustic frequency, pulsing parameters, ramping, and other waveform features, as described herein) to induce neuromodulation at a target area of neuronal tissue, as described above.
  • waveforms acoustic frequency, pulsing parameters, ramping, and other waveform features, as described herein.
  • These waveforms when transmitted transcranially via a low acoustic impedance contact between one or more ultrasound transducers and a user's skull, are typically safe: they may induce only minimal, non-damaging heating of tissue and do not typically cause cavitation or shearing forces that would damage neuronal tissue.
  • the relatively uniform acoustic environment of the brain and other sub-cranial structures is beneficial in this case for ensuring that ultrasound protocols for neuromodulation can be safely transmitted transcranially.
  • the self-actuated, portable transcranial ultrasound neuromodulation systems described herein may incorporate features (and may implement methods) for ensuring safe operation, and particularly, for ensuring that a transcranial ultrasound neuromodulation apparatus as described herein is operably coupled to deliver ultrasound transcranially in a safe manner.
  • any of the apparatuses and methods described herein may be configured to ensure that ultrasound is delivered through/over an appropriate portion of the skull so that energy is transmitted into the brain at a targeted neuronal region and does not cause damage in other regions of the body.
  • any of these apparatuses and methods may be configured specifically to achieve one or more of the group: (1) ensure that a low acoustic impedance coupling is achieved; (2) ensure that a transducer assembly is acoustically coupled overlying an acceptable portion of the skull (i.e.
  • transcranial ultrasound neuromodulation system is coupled to the skull, as opposed to a different part of the body, including those that have a superficial bone such as the kneecap or sternum that may be difficult to distinguish from the skull by other means.
  • any of the apparatuses described herein may include a safety interlock that prevents improper use of the apparatus.
  • a safety interlock may use one or more of the mechanisms described below to enable delivery of transcranial ultrasound neuromodulation under safe conditions.
  • the apparatus may include a safety interlock that includes an acoustic impedance detector, imaging and/or image analysis.
  • the apparatus may alternatively or additionally include a safety interlock that detects and responds to heat and/or electromagnetic interference.
  • a transcranial ultrasound neuromodulation system may be configured to provide (force) safe operation by ensuring a low acoustic impedance coupling is achieved between a transducer assembly and the head (i.e. scalp or skin) or a user before delivery of ultrasonic neurostimulation/neuromodulation energy.
  • Acoustic coupling may be estimated based on the reflectance and/or transmittance of acoustic energy through a medium.
  • acoustic impedance is not directly measured, and it may be challenging to estimate acoustic impedance because of the variable skull thickness between individuals and within individual for different areas of the skull.
  • Apparatuses e.g., devices and systems, that incorporate an ultrasound receiver on the opposite side of the primary ultrasound transducer can be used to estimate the proportion of energy that is being transmitted into and through the brain.
  • An ultrasound receiver/transceiver may include, but is not limited to, a hydrophone, microphone, or other measurement system.
  • any of the systems described herein may detect reflection of ultrasound energy from tissues underlying the transcranial ultrasound neuromodulation transducer using an ultrasound receiver.
  • the acoustic impedance sensor may include an ultrasound receiver/transceiver that is contained within the same assembly as the primary ultrasound transducer.
  • Various positions of the ultrasound receiver relative to the primary neuromodulation transducer may be used to distinguish between a signal generated from underlying skull relative to another portion of the head or body.
  • a center-surround architecture can be employed wherein either the primary high-power transducer is in the center and surrounded by a receiver/transceiver for measuring reflectance - or the reverse orientation.
  • the secondary transducer (for measuring reflectance) may be referred to as an acoustic sensor, reflection sensor, or impedance sensor.
  • An apparatus configured for estimating acoustic impedance may measure both reflectance and transmittance of ultrasound energy.
  • the signals detected by the impedance sensor may be processed to determine an acoustic impedance value.
  • the apparatuses described, including in particular the impedance sensor sub-system may include appropriate hardware, software and/or firmware to improve the signal to noise of the received acoustic waveform, including, but not limited to: time-domain filtering, averaging over time, intermittent measurements, measurements triggered to a known event (such as a movement of the ultrasound neuromodulation assembly detected by an onboard accelerometer), and other linear and non-linear signal processing.
  • any of the apparatuses described herein may include one or more sensors that use reflected acoustic energy from the skin, skull, and other sub-cranial structures to image the tissue underlying the transcranial ultrasound neuromodulation apparatus.
  • low-fidelity imaging may be used (and/or higher resolution imaging).
  • a single transducer or an ultrasound array (including simple arrays, such as 2x2, 3x2, 3x3, 4x2,4x3, 4x4, etc.) may be used to image the underlying tissue to determine whether the transcranial ultrasound neuromodulation apparatus is indeed overlying an appropriate portion of skull.
  • low-fidelity ultrasound from even a single transducer could be used to determine whether the apparatus is overlying a bony area, and particularly over a skull.
  • the skull may be recognized in part by the morphological characteristics such as curvature and thickness, in comparison to a soft tissue area as would be seen, for example, over the torso.
  • Ultrasound waveform protocols pulsesing, ramping, chirping, amplitude and frequency modulation, etc.
  • known in the art can be delivered through a center- surround ultrasound transducer and/or emitter and receiver pair.
  • Processing algorithms for ultrasound imaging such as those known in the art can be configured to distinguish between the skull and other areas of the body with bones near the surface that should not be targets for the ultrasound systems herein such as the kneecap, ribs, and cheeks.
  • the shape of the apparatus may provide additional safety features.
  • the size and shape, including curvature, of the apparatus may prevent it from being applied to many region of the body that would be inappropriate for operation of a transcranial ultrasound neuromodulation/neurostimulation device.
  • the apparatus may include one or more sensors that determine and confirm that the apparatus is completely flush against the body (e.g., head). Any appropriate contact sensor may be used, including pressure sensors, electrical impedance sensors, thermal sensors, or the like.
  • a pair of electrical impedance sensors near opposite ends of an elongated may be included that determine if the electrical impedance (e.g., between pairs of electrodes applied to the skin) is consistent with application to the skin, even hairy skin.
  • the subject-contacting surface is only slightly flexible (e.g., stiff or semi-rigid)
  • the subject-contacting surface may not fully contact the subject when worn over regions of the body having a different surface curvature, including the torso and face.
  • control logic may be configured to include a positioning confirmation module that confirms the position of the apparatus on the subject.
  • control logic may include an
  • a transcranial ultrasound neuromodulation apparatus running on a smartphone or tablet that is configured to instruct a user to take an image, set of images, or video of themselves wearing the transcranial ultrasound neuromodulation apparatus, then use visual processing algorithms to determine the location of a transcranial ultrasound neuromodulation apparatus on the body of a subject and compares that location against a set of criteria to determine whether wireless triggering of the ultrasound
  • the control logic may allow (turn on) operation of the device after confirming positioning of an ultrasound apparatus on the subject's body.
  • control logic may also confirm proper pairing between the apparatus and the control logic that controls (drives) the operation.
  • a transcranial ultrasound neuromodulation apparatus that is connected to and wirelessly controlled by a device being controlled by the control logic (e.g., app) may confirm that the same unit visualized with the camera of the device is the unit to which the control logic is wirelessly connected.
  • confirming the identity of a visualized unit may comprise incorporating a unique visual identifier on the external surface of the transcranial ultrasound neuromodulation apparatus such as a QR code, then comparing the unique visual identifier with the hardware ID before triggering ultrasound neuromodulation wirelessly.
  • Another way to uniquely identify a particular unit is for the app to cause the transcranial ultrasound neuromodulation apparatus to deliver a temporal pattern of light from one or more LEDs contained on the transcranial ultrasound
  • neuromodulation apparatus and visible on its external surface.
  • Confirming the identity of a visualized unit may comprise facial recognition (for security), body region analysis (for coarse positioning of the transcranial ultrasound
  • the neuromodulation apparatus e.g. is it on the face or on the chest
  • facial segmentation for precise positioning of the transcranial ultrasound neuromodulation apparatus e.g. on the forehead vs. on the cheek
  • the orientation and position of the transcranial ultrasound neuromodulation apparatus can also be used to estimate the beam path and brain regions that will be targeted. This latter functionality may be useful for providing instructions to a user for repositioning the apparatus if necessary.
  • Excessive heating of the transcranial ultrasound neuromodulation apparatus and/or tissue can cause injury and/or damage to the ultrasound apparatus.
  • many of the apparatuses described herein may include safety systems that are configured to automatically stop the ultrasound transducers if heating occurs beyond a threshold value for a minimum period of time.
  • any of these apparatuses may include a thermocouple that measures temperature.
  • One or more thermocouples can be integrated into the apparatus, including, but not limited to: near the transducer; in or near an adhesive region that secures the apparatus to the subject's head; and in or near an acoustic couplant.
  • Other temperature measurement hardware can be selected including, but not limited to, infrared sensors, thermometers, and specialized ICs that detect overheating.
  • any of the transcranial ultrasound neuromodulation apparatuses described herein may also include components to protect from, measure, and / or shut down the apparatus in response to strong magnetic or electric fields. Such strong magnetic fields may occur, for example, in a magnetic resonance imaging unit or other harsh operational environments.
  • a transcranial ultrasound neuromodulation assembly can incorporate a Faraday cage or other insulating cage to protect against external electromagnetic interference.
  • detectors of distortions to the ultrasound transducer drive waveforms can be used to estimate the effect of electromagnetic interference and stop ultrasound delivery to the subject under these
  • FIG. 15 illustrates schematic diagrams of various exemplary transcranial ultrasound neuromodulation apparatuses.
  • the workflow diagram shows a transcranial ultrasound neuromodulation apparatus that is wireless, lightweight, adherent, and self-coupling.
  • any of the apparatuses described herein may include an enclosed power source 1601.
  • One or more capacitors may be included in the circuitry to provide quick energy to ensure that drive signal remains clean under transducer load(s).
  • the apparatus may also include a low voltage regulator/conditioner 1605 and/or a high voltage regulator/conditioner 1606.
  • the apparatus may include "volume efficient" (e.g., small or small-scale) components, including multi-layer ceramic capacitors that have a high capacitance per volume, especially capacitors that also have low effective series inductance and effective series resistance.
  • a power source supplies energy to high voltage regulator and low voltage regulator.
  • the power source 1601 may include one or more batteries, but other energy sources are possible in addition to or instead, including one or more capacitors.
  • the transcranial ultrasound neuromodulation apparatus in FIG. 15 is wireless 1610, lightweight, adherent 1615, and self-coupling. Many of the components illustrated in FIG. 15 may be contained within the housing and/or subject-contacting surface portion of the transcranial ultrasound neuromodulation apparatus. External components may include the remote server
  • the apparatus may include low voltage regulators to create steady, low (1-12V) voltages commonly used in modern microcontrollers/FPGAs 1631, BT and WiFi chips 1610, USB, oscillator clocks 1633, and sensors 1666.
  • the high voltage supply higher voltage and current may be used for the generation of acoustic waveforms by the components of the ultrasound (US) driver 1641 , transducer 1644, and couplant pathway.
  • the apparatus may also incorporate charging circuitry and battery monitoring circuitry to determine the amount of charge and other parameters of battery function (not shown).
  • Components may provide control of the timing, intensity, waveform, targeting, and other parameters of transcranial ultrasound neuromodulation 1647, 1633, 1631.
  • a user interface 1671 portion of the transcranial ultrasound system i.e. button, touch screen interface, slider, or other user interface component
  • direct control may be used to deliver a stop signal, to reset wireless communication systems for pairing, and to turn the device on and off.
  • Smartphone, laptop, or other local external controller 1655 may include non-transitory computer-readable storage medium storing a set of instructions (control logic) capable of being executed by a control processor, that when executed by the control processor causes the control processor to wirelessly transmit control information to the apparatus for delivering ultrasonic neurostimulation.
  • the external control hardware could be used to start stimulation, change settings, check usage, perform firmware updates, and other routine bidirectional communication.
  • remote server communicates to a smartphone, laptop, or other local external controller via the Internet or other communications network to provide additional instructions and control and may provide communication to and from a database on a remote server where settings, usage information, firmware updates, error reporting, etc. can be stored, downloaded, or even shared between users.
  • the apparatus may include a primary MCU, PSoC, FPGA, ASIC, or similar programmable master control chip 1631, with secondary chips for potential offloading of processing or storing of data.
  • the main processor (stimulation processor) may be configured to communicate to more powerful local, external control hardware (i.e. smartphone with a dedicated app, laptop, specialized external controller 1655) via Bluetooth, Wi-Fi, USB, GiGE, or other standard communication ports and/or protocols 1610 commonly found on electronics.
  • the transcranial ultrasound neuromodulation apparatus may include a specialized chip dedicated for this communication and interfacing between the apparatus' main control chip and the external control hardware.
  • the apparatus in addition to the controller chip, may have additional dedicated timing clocks or oscillators 1633 running at the acoustic frequency, the pulse repetition frequency, or some multiple thereof.
  • the combination of the controller chip, optional oscillator clocks, and counters may be used to generate low power waveform timing signals (e.g., ⁇ 6.5 V), carrying timing information about the acoustic frequency, pulse repetition frequency, duty cycle, duration, and other temporal aspects of the final waveform.
  • These timing signals may be received by a power stage consisting of MOSFETs and optional MOSFET drivers 1640 to convert the incoming low voltage, low power signals into higher voltage and/or higher current signals with greater electrical power than the final acoustic power (accounting for losses in later stages).
  • the MOSFETs may be replaced with other transistor technologies (IGBT, BJT, etc.) or similar semiconductor technology based switches (thyristor).
  • the drivers may consist of simple standard MOSFET drivers, dedicated half bridge drivers, drivers with dead time and shoot- through protection, and other features.
  • the driver and MOSFET may be in a single IC chip instead of as discrete components, with safety and control features also built in.
  • Higher power signals may then optionally be passed through inductors and/or filters to control current surges or reduce harmonics 1643.
  • the "cleaned" waveform may then be passed through an optional transformer 1642 to raise the voltage level to a level to suitably drive ultrasound transducers, creating a higher voltage waveform.
  • This higher voltage waveform may additionally be passed through inductors and/or filters to control current surges or reduce harmonics, creating a final driving waveform 1647.
  • This final driving waveform may then be passed to the ultrasound transducer 1644, and the electrical energy is converted into acoustic energy.
  • the ultrasound transducer 1644 typically emits acoustic energy through matching layers of suitable impedance and thickness, including the final flexible, soft, and acoustically matched (to biological tissue) couplant 1648, 1615.
  • the couplant is a solid couplant made of silicone, polyurethane, or similarly pliable, moldable, and acoustically- matched materials 1648. This couplant will transfer to an acoustically matched adhesive layer 1615. Alternatively, adhesive material is sprayed onto this couplant material. This adhesive layer may be applied by the subject to the subject's skin/scalp/hair.
  • measurements may be performed to determine critical factors in conversion to acoustic power, efficient coupling of ultrasound to the body, temperature changes in ICs and skin, and similar operational factors. (E.g. thermocouple on MOSFET and skin to prevent over-temperature operation; receiving piezo or PVDF element to measure acoustic reflections, etc.) These measurements will be sent to the controlling chip and used to make modifications to simulation parameters or for critical shutdown.
  • the device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.
  • the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation only unless specifically indicated otherwise.
  • first and second may be used herein to describe various features/elements, these features/elements should not be limited by these terms, unless the context indicates otherwise. These terms may be used to distinguish one feature/element from another feature/element. Thus, a first feature/element discussed below could be termed a second feature/element, and similarly, a second feature/element discussed below could be termed a first feature/element without departing from the teachings of the present invention.
  • numeric value may have a value that is +/- 0.1% of the stated value (or range of values), +/- 1 % of the stated value (or range of values), +/- 2% of the stated value (or range of values), +/- 5% of the stated value (or range of values), +/- 10% of the stated value (or range of values), etc. Any numerical range recited herein is intended to include all sub-ranges subsumed therein.

Abstract

L'invention concerne des appareils pour une neuromodulation ultrasonore transcrânienne. L'invention concerne des appareils, pour une neuromodulation ultrasonore transcrânienne, qui sont autonomes, autoalimentés, autoadhésifs, à couplage automatique et communément appelés curseurs de neuromodulation ultrasonore transcrânienne, qui peuvent être jetables ou semi-jetables. Ces appareils peuvent comprendre une ou plusieurs commandes pour confirmer leur position sur la tête du sujet, par exemple à l'aide d'une impédance acoustique. Ces dispositifs de neuromodulation ultrasonore transcrânienne peuvent être commandés sans fil et peuvent être configurés pour s'adapter précisément à la tête du sujet. Les systèmes de neuromodulation ultrasonore transcrânienne décrits dans la présente invention sont avantageux pour obtenir une neuromodulation ayant une incidence sur l'apprentissage et sur la mémoire, l'attention, la créativité, la prise de décision et d'autres états cognitifs.
PCT/US2014/016178 2013-02-14 2014-02-13 Systèmes ultrasonores transcrâniens WO2014127091A1 (fr)

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