Electroencephalogram (EEG) guided ultrasound neuromodulation

Abstract

A system including an ultrasound transducer, a plurality of electroencephalogram (EEG) electrodes, and an electronic controller. The electronic controller delivers, using the ultrasound transducer, ultrasound neuromodulation at a plurality of locations of a region of a brain at a set of ultrasound parameters, measures, using the plurality of EEG electrodes, a plurality of EEG response potentials at the plurality of locations, and adjusts the set of ultrasound parameters to a set of desired ultrasound parameters based on the EEG response potentials until an intensity is sufficient to elicit an EEG response.

Description

ELECTROENCEPHALOGRAM (EEG) GUIDED ULTRASOUND NEUROMODULATIONCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 642,580, filed on May 3, 2024, the entire contents of which are incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under grant number F32MH123019 and grant number R00NS100986 awarded by the National Institutes of Health. The government has certain rights in the invention.FIELD OF THE DISCLOSURE

[0003] The present disclosure is directed to ultrasound therapy techniques.BACKGROUND

[0004] One type of ultrasound therapy is ultrasound neuromodulation. Ultrasound neuromodulation includes stimulating an area of tissue using focused sound waves on the area of tissue to modulate neural activity. Ultrasound neuromodulation is non-invasive because it is delivered through an intact skull. Variations in the skull from patient to patient require that ultrasound therapies be tailored to each specific individual. In existing solutions, delivering precise, targeted ultrasound treatments provides inconsistent results, in part, due to uncertainty in delivered sound wave intensities. This uncertainty may lead to safety concerns or to decreased efficacy, resulting in additional treatments that are an additional cost to the individual.

[0005] Thus, systems and methods that provide precise and safe ultrasound therapy with reduced cost and without the need for additional, unnecessary ultrasound therapies would be desirable.SUMMARY

[0006] In response to ultrasound therapy (e.g., ultrasound neuromodulation), neural anatomy of an individual produces ultrasound-induced voltage potentials. Accordingly, the ultrasound- induced voltage potentials indicate that the delivered soundwaves are located in the target tissue area and that the delivered soundwaves are of sufficient intensity to engage neural activity. Variations in skull thickness and composition make it such that an ultrasound transducer voltage and element phases required to elicit neural engagement varies from patient to patient. Thus, in some implementations, it would be advantageous to use the ultrasound-induced voltage potentials to guide ultrasound therapy to targeted areas of an individual and to determine an optimal ultrasound transducer voltage to deliver sufficient intensity of soundwaves. Thus, there is a need for ultrasound systems that deliver ultrasound therapy guided by ultrasound-induced voltage potentials.

[0007] In one aspect, the disclosure provides a system for conducting electroencephalogram (EEG) guided ultrasound neuromodulation. The system includes a device including an ultrasound transducer disposed on a head of a subject. The ultrasound transducer transmits ultrasound waves. The system includes a plurality of EEG electrodes coupled to the device and attached to the head of the subject. The plurality of EEG electrodes measures EEG response potentials. The system includes an electronic controller connected to the device and in communication with the plurality of EEG electrodes. The electronic controller delivers, using the ultrasound transducer, ultrasound neuromodulation at a plurality of locations of a region of a brain of the subject at a set of ultrasound parameters, measures, using the plurality of EEG electrodes, a plurality of EEG response potentials at the plurality of locations, and adjusts the set of ultrasound parameters to a set of desired ultrasound parameters based on the plurality of EEG response potentials until an intensity is sufficient to elicit an EEG response.

[0008] In some aspects, the region of the brain is at least one selected from the group consisting of a left hemisphere of the brain and a right hemisphere of the brain.

[0009] In some aspects, the region of the brain is a lateral geniculate nucleus (LGN) of at least one selected from the group consisting of the left hemisphere of the brain and the right hemisphere of the brain.

[0010] In some aspects, the set of ultrasound parameters includes at least one selected from the group consisting of an ultrasound intensity and an ultrasound pressure.

[0011] In some aspects, the set of desired ultrasound parameters includes at least one selected from the group consisting of an ultrasound intensity and an ultrasound pressure.

[0012] In some aspects, the electronic controller is configured to adjust the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound intensity based on the plurality of EEG response potentials and adjust the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound pressure based on the plurality of EEG response potentials.

[0013] In some aspects, the electronic controller is configured to transmit the plurality of EEG response potentials at the plurality of locations to an output device, display, using the output device, the plurality of EEG response potentials at the plurality of locations, transmit the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters to the output device, and display, using the output device, the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters.

[0014] In some aspects, the electronic controller identifies a target location of the plurality of locations for delivering ultrasound neuromodulation based on the plurality of EEG response potentials. The plurality of locations includes a maximum response location having the greatest EEG response potential of the plurality of EEG response potentials and a minimum response location having the least EEG response potential of the plurality of EEG response potentials.

[0015] In some aspects, the electronic controller is configured to identify the target location based on EEG response potentials at the maximum response location and the minimum response location.

[0016] In some aspects, the target location is at least one selected from the group consisting of the maximum response location and the minimum response location.

[0017] In another aspect, the disclosure provides a method of conducting electroencephalogram (EEG) guided ultrasound neuromodulation. The method includes delivering, using an ultrasound transducer, ultrasound neuromodulation at a plurality of locations of a region of a brain of a subject at a set of ultrasound parameters, measuring, using a plurality of EEG electrodes, a plurality of EEG response potentials at the plurality of locations, and adjusting, via an electronic controller, the set of ultrasound parameters to a set of desired ultrasound parameters based on the plurality of EEG response potentials until an intensity is sufficient to elicit an EEG response.

[0018] In some aspects, the region of the brain is at least one selected from the group consisting of a left hemisphere of the brain and a right hemisphere of the brain.

[0019] In some aspects, the region of the brain is a lateral geniculate nucleus (LGN) of the at least one selected from the group consisting of the left hemisphere of the brain and the right hemisphere of the brain.

[0020] In some aspects, the set of ultrasound parameters includes at least one selected from the group consisting of an ultrasound intensity and an ultrasound pressure.

[0021] In some aspects, the set of desired ultrasound parameters includes at least one selected from the group consisting of an ultrasound intensity and an ultrasound pressure.

[0022] In some aspects, the method includes adjusting, via the electronic controller, the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound intensity based on the plurality of EEG response potentials and adjusting, via the electronic controller, the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound pressure based on the plurality of EEG response potentials.

[0023] In some aspects, the method includes transmitting, via the electronic controller, the plurality of EEG response potentials at the plurality of locations to an output device, displaying, via the output device, the plurality of EEG response potentials at the plurality of locations, transmitting, via the electronic controller, the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters to the output device, anddisplaying, via the output device, the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters.

[0024] In some aspects, the method includes identifying, via the electronic controller, a target location of the plurality of locations for delivering ultrasound neuromodulation based on the plurality of EEG response potentials. The plurality of locations includes a maximum response location having the greatest EEG response potential of the plurality of EEG response potentials and a minimum response location having the least EEG response potential of the plurality of EEG response potentials.

[0025] In some aspects, the method includes identifying, via the electronic controller, the target location based on EEG response potentials at the maximum response location and the minimum response location.

[0026] In some aspects, the target location is at least one selected from the group consisting of the maximum response location and the minimum response location.

[0027] Other aspects of various embodiments will become apparent by consideration of the detailed description and accompanying drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0028] FIG. 1 illustrates an ultrasound system, according to some embodiments.

[0029] FIG. 2 is an image showing target locations for ultrasound therapy, according to some embodiments.

[0030] FIG. 3 illustrates graphs showing ultrasound evoked potentials, according to some embodiments.

[0031] FIG. 4 illustrates graphs showing that ultrasound-induced changes in behavior correlate with maximum ultrasound evoked potential response and minimum ultrasound evoked potential response, according to some embodiments.

[0032] FIG. 5 is a flowchart illustrating a method of conducting electroencephalogram (EEG) guided ultrasound neuromodulation, according to some embodiments.DETAILED DESCRIPTION

[0033] Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways.

[0034] All statements herein reciting principles, aspects, and embodiments of the disclosure, as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents as well as equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure.

[0035] Various other components may be included and called upon for providing for aspects of the teachings herein. For example, additional materials, combinations of materials and / or omission of materials may be used to provide for added embodiments that are within the scope of the teachings herein. Adequacy of any particular element for practice of the teachings herein is to be judged from the perspective of a designer, manufacturer, seller, user, system operator or other similarly interested party, and such limitations are to be perceived according to the standards of the interested party.

[0036] In the disclosure hereof any element expressed as a means for performing a specified function is intended to encompass any way of performing that function including, for example, a) a combination of circuit elements and associated hardware which perform that function or b) software in any form, including, therefore, firmware, microcode or the like as set forth herein, combined with appropriate circuitry for executing that software to perform the function. Applicants thus regard any means which can provide those functionalities as equivalent to those shown herein. No functional language used in claims appended herein is to be construed as invoking 35 U.S.C. § 112(f) interpretations as “means-plus-function” language unlessspecifically expressed as such by use of the words “means for” or “steps for” within the respective claim.

[0037] When introducing elements of the present invention or the embodiment(s) thereof, the articles “a,” “an,” and “the” are intended to mean that there are one or more of the elements. Similarly, the adjective “another,” when used to introduce an element, is intended to mean one or more elements. The terms “including” and “having” are intended to be inclusive such that there may be additional elements other than the listed elements. The term “exemplary” is not intended to be construed as a superlative example but merely one of many possible examples.

[0038] The present disclosure provides systems and methods for conducting electroencephalogram (EEG) guided ultrasound neuromodulation. The systems and methods include the use of EEG electrodes for measuring response potentials in response to ultrasound neuromodulation. With this configuration, the systems and methods adjust ultrasound parameters for delivering targeted ultrasound neuromodulation. Additional details of the ultrasound systems and methods of conducting EEG guided ultrasound neuromodulation are described below.

[0039] In some instances, transcranial ultrasound neuromodulation (TUSN) is a non-invasive and spatially specific therapy that delivers treatments tailored to specific needs of individuals. Each treatment may be modified to adequately correct for variation across individual skulls and neural anatomy. Ultrasound-induced voltage potentials (measured with electroencephalography; EEG) may be used to guide TUSN therapies. For example, some embodiments of the disclosure measure EEG responses in awake nonhuman primates during sonication of 12 targets surrounding two deep brain nuclei, such as the left and right lateral geniculate nucleus (LGN).

[0040] Reliable ultrasound evoked potentials can be measured with EEG following deep brain ultrasonic modulation in nonhuman primates. Robust responses may be observed following just 10 repetitions of ultrasonic stimuli. Moreover, the ultrasound evoked potentials are evoked for specific deep brain targets. Further, behavioral studies may show a correspondence between a target with a maximum EEG response and ultrasound-based modulation of visual choice behavior. In some instances, EEG-based guidance may be used for ultrasound neuromodulation therapies.

[0041] Through its capacity to perturb deep brain regions with millimeter and microsecond precision, transcranial ultrasound may deliver precise treatment of mental and neurological disorders. Recent studies have demonstrated ultrasound’s capacity to modulate visual circuits, mood networks, motivation, and disease of brain function in both nonhuman primate and human subjects. The results of such studies have led to an explosion of interest in clinical trials using ultrasound to treat depression, epilepsy, chronic pain, and other conditions. Each of these studies is limited, however, by inconsistent results that are, in part, due to uncertainty about acoustic intensity at a target location. The skull, which aberrates and attenuates ultrasound signals, may introduce at least a four-fold variation in the acoustic intensity delivered to the target location across patients. Additional variation in a subject’s neural response to ultrasound further contributes to uncertainty in treatment outcomes. One existing solution to this problem is to measure a threshold at which ultrasound evokes changes in neural activity in each patient and then adjust the acoustic intensity relative to the threshold. Transcranial magnetic stimulus (TMS) treatments, for example, use this approach. Results in small animal models suggest that such an approach may be possible for transcranial ultrasound as well. In rodents, ultrasound can elicit motor evoked potentials and overt muscle contractions. However, these effects have yet to be observed in larger animal studies which have instead relied on changes in behavior or changes in amplitude of EEG potentials evoked by other modalities (e.g., TMS) to infer the effects of ultrasound on neural tissue. As described below, ultrasound demonstrates capacity to evoke a transient EEG response in the awake primate brain. The evoked EEG potential is specific to targeted neural anatomy and independent of a geometry of an ultrasound transducer. Accordingly, patient-specific calibration methods may be used to address variation in patient skulls that has so far precluded the delivery of a controlled and consistent acoustic intensity into the brain.

[0042] With respect to FIGS. 1-5, two male macaque monkeys (e.g., macaca mulatta, subjects B, and H, ages 7 and 6 years and weight 15.0, and 10.8 kilograms (kg), respectively) are “patients” or “subjects” in the described embodiments below. All procedures were conducted as approved by the Institutional Animal Care and Use Committee of the University of Utah. Although the embodiments described below are with respect to nonhuman primates, it should be understood that the embodiments described herein are also applicable to human patients.

[0043] FIG. 1 illustrates an ultrasound system (e.g., a system) 100, according to some embodiments. For example, the ultrasound system 100 conducts EEG guided ultrasound neuromodulation. As shown by the embodiment illustrated in FIG. 1, the ultrasound system 100 is a system for remote ultrasound delivery into a brain of a subject (e.g., a patient) 120 to stimulate deep brain regions. The ultrasound system 100 includes an ultrasound device (e.g., a device) 105 having an ultrasound transducer 110. The ultrasound transducer 110 is configured to transmit and receive ultrasound waves. For example, the ultrasound transducer 110 receives an electrical current and converts the electrical current into ultrasound waves. The ultrasound transducer 110 transmits the ultrasound waves into a region of the brain of the subject 120. In some embodiments, the ultrasound transducer 110 includes processing circuitry configured to process reflected ultrasound waves. In some embodiments, the ultrasound transducer 110 is a 256-element phased array transducer that is affixed to (e.g., disposed on) the head of an awake and head fixed subject (e.g., a nonhuman primate [NHP] subject or a human subject). The ultrasound system 100 includes a plurality of EEG electrodes 115. In some embodiments, each subject is implanted with the plurality of EEG electrodes 115 (e.g., four titanium pins) that enable the placement of the ultrasound device 105 (e.g., a custom 3-dimensional frame) that simultaneously provides for head fixation and placement of the ultrasound transducer 110. In some embodiments, the plurality of EEG electrodes 115 is connected to the ultrasound device 105. In some embodiments, the plurality of EEG electrodes 115 is coupled to the ultrasound device 105 and electrically coupled to a brain of the subject 120 to measure ultrasound evoked potentials. In some embodiments, the region of the brain is a lateral geniculate nucleus (LGN) of a hemisphere of the brain. The plurality of EEG electrodes 115 is configured to measure ultrasound evoked potentials (e.g., EEG response potentials). For example, the plurality of EEG electrodes 115 measure EEG response potentials across 6 sessions in subject B and 8 sessions in subject H. After head fixation, each session proceeds in a dark room to minimize influence of visual stimuli on EEG recordings.

[0044] With reference to FIG. 2, an image 200 shows a plurality of target grids 205 on the brain of the subject 120. In some embodiments, the plurality of EEG electrodes 115 measure EEG response potentials during sonication of 24 targets arranged in the plurality of target grids 205 (e.g., two grids) with three rows and four columns each. The plurality of target grids 205may be centered on the left and right LGN, as shown in the image 200. In some embodiments, the plurality of target grids 205 include a plurality of target locations for delivering ultrasound therapy (e.g., ultrasound neuromodulation). In some embodiments, during a therapy session, each target of the plurality of target grids 205 is sonicated between 5 and 10 times with the ultrasound system 100 using a randomization without replacement approach. Sonication of left and right hemispheres of the brain of the subject 120 by the ultrasound system 100 is interleaved. In some embodiments, all steering is programmatic, and a position of the ultrasound transducer 110 is identical across target locations and sessions.

[0045] In some embodiments, for each session, time between sonications is random with a mean of 17 seconds. In some embodiments, a maximum delay is 50 seconds, and a minimum delay is 14 seconds. In some embodiments, a standard deviation is 4 seconds. In some embodiments, an average session length in subject B (6 total sessions) is 70 minutes, ranging from a minimum of 66 minutes to a maximum of 73 minutes. In some embodiments, each target is sonicated 10 times per session. In some embodiments, an average session length in subject H (8 total sessions) is 50 minutes, ranging from a minimum of 33 minutes to a maximum of 68 minutes. In some embodiments, in 4 of the 8 sessions, each target is sonicated 10 times and in the other four sessions each target is sonicated 5 times. In some embodiments, each target is sonicated a total of 60 times in both subjects.

[0046] Referring back to FIG. 1, the ultrasound system 100 delivers ultrasound waves (e.g., via the ultrasound transducer 110) to deep brain regions in the subject 120. As noted, the plurality of EEG electrodes 115 measure EEG recordings as EEG response potentials in response to ultrasound neuromodulation. As illustrated by the embodiment shown in FIG. 1, the ultrasound system 100 includes an electronic controller 125, an electronic processor 130, a memory 135, a signal generator 140, and an output device 145. In some embodiments, the electronic controller 125, the electronic processor 130, the memory 135, the signal generator 140, and the output device 145 may be implemented in the ultrasound device 105. In other embodiments, the electronic controller 125, the electronic processor 130, the memory 135, the signal generator 140, and the output device 145 may be implemented external to the ultrasound device 105 in an external device. The electronic controller 125 may be an integrated circuit device, such as a Microchip microcontroller. However, in other embodiments, the electroniccontroller 125 is implemented as another type of processor-based control device. The electronic controller 125, which includes the electronic processor 130 and the memory 135, may be configured to control various operations of the ultrasound system 100. For example, in some embodiments, the electronic controller 125 is configured to control operation of the ultrasound transducer 110 and the signal generator 140 and deliver ultrasound waves from the ultrasound transducer 110.

[0047] As illustrated in FIG. 1, the electronic controller 125 is electrically and / or communicatively connected to a variety of modules or components of the ultrasound system 100. For example, the electronic controller 125 is electrically and / or communicatively connected to the ultrasound device 105, the plurality of EEG electrodes 115, the signal generator 140, and the output device 145.

[0048] In some embodiments, the electronic controller 125 includes a plurality of electrical and electronic components that provide power, operational control, and protection to the components and modules within the electronic controller 125 and / or the ultrasound system 100. For example, the electronic controller 125 includes, among other things, the electronic processor 130 (for example, a microprocessor or another suitable programmable device) and the memory 135.

[0049] The memory 135 includes, for example, a program storage area and a data storage area. The program storage area and the data storage area can include combinations of different types of memory, such as read-only memory (ROM) and / or random-access memory (RAM). Various non-transitory computer readable media, for example, magnetic, optical, physical, or electronic memory may be used. The electronic processor 130 is communicatively coupled to the memory 135 and executes software instructions that are stored in the memory 135, or stored on another non-transitory computer readable medium such as another memory or a disc. Instructions may include instructions, which when executed by the electronic processor 130, cause the ultrasound system 100 to implement any of a variety of ultrasound control actions as described herein. The software may include one or more applications, program data, filters, rules, one or more program modules, and other executable instructions.

[0050] In some embodiments, the signal generator 140 is electrically connected to the ultrasound transducer 110 via the ultrasound device 105. The signal generator 140 is configured to deliver a signal to the ultrasound transducer 110 for conducting ultrasound therapy. For example, the signal generator 140 receives a control signal from the electronic controller 125. Based on the control signal, the signal generator 140 delivers the signal as an electrical current to the ultrasound transducer 110. The ultrasound transducer 110 converts the electrical current into ultrasound waves for delivery to the subject 120.

[0051] In some embodiments, the output device 145 is configured to be viewed by a user. For example, the output device 145 is a display. In other embodiments, the output device 145 is a separate electronic controller or a user input. In such embodiments where the output device 145 is a display, the output device 145 is configured to display a plurality of EEG response potentials. For example, the electronic controller 125 receives the plurality of EEG response potentials from the plurality of EEG electrodes 115. The electronic controller 125 transmits the plurality of EEG response potentials to the output device 145 and the output device 145 displays the EEG response potentials.

[0052] Referring again to FIG. 2, the image 200 shows target locations for ultrasound therapy, according to some embodiments. The plurality of target grids 205 include target locations surrounding a location 210 of a left hemisphere of the brain and a location 215 of a right hemisphere of the brain. In some embodiments, the location 210 is an LGN of the left hemisphere and the location 215 is an LGN of the right hemisphere. In other embodiments, the location 210 and the location 215 are different target regions in the brain. The target locations are on a single axial plane and varied by 4 mm in front / back and left / right dimensions. Point B and point H mark approximate locations of a geometric focus of the ultrasound transducer 110 within a sonication plane in subjects B and H, respectively. In some embodiments, relative to the ultrasound transducer 110, an estimated depth of a plane containing the LGN is 58 millimeters (mm) in subj ect B and 51 mm in subj ect H.

[0053] In some embodiments, the plurality of EEG electrodes 115 include alligator clips for measuring EEG response potentials, which are electrically connected to the plurality of EEG electrodes 115. In some embodiments, the plurality of EEG electrodes 115 are placed on thehead of the subject 120 for stability and head fixation but approximate 10 / 20 EEG electrode positions are P3 and P4 for rear EEG electrodes of the plurality of EEG electrodes 1 15 and FP1 and FP2 for front EEG electrodes of the plurality of EEG electrodes 115.

[0054] In some embodiments, the plurality of EEG electrodes 115 measures EEG response potentials from the two rear EEG electrodes of the plurality of EEG electrodes 115 (connected to the front EEG electrodes of the plurality of EEG electrodes 115 serving as ground). In some embodiments, impedance between electrode channels and ground is less than 1 kilo-ohm (k ). In some embodiments, the ultrasound system 100 records measured EEG response potentials with a 128-channel recording system (e.g., RHS2000, from Intan Technologies, Los Angeles, CA). In some embodiments, the electronic controller 125 low-pass filters each EEG response potential at 7.6 kilohertz (kHz) and samples at 20 kHz. In some embodiments, the EEG response potentials show strong interference at 60 hertz (Hz) and at second and third harmonics of 60 Hz. The electronic controller 125 applies notch filters at 60, 120, and 180 Hz with a 4 Hz bandwidth to raw EEG response potentials before averaging. In some embodiments, when filtered EEG response potentials exceed 500 microvolts (pV), these filtered EEG response potentials are excluded since such high signals are not likely to be physiological. A temporal EEG response is the EEG response potential recorded in one second after sonication, averaged across all sonications not excluded by the 500 pV threshold.

[0055] In some embodiments, the ultrasound system 100 uses strength of the EEG response potentials to guide ultrasound neuromodulation of awake behavior. For example, in subject B, the electronic controller 125 selects four targets, two targets in each hemisphere with a maximum (active sonication) and minimum (control) EEG response potential. The plurality of EEG electrodes 115 measure the strength of the EEG response potentials to determine behavioral effects of ultrasound neuromodulation delivered to each target of the plurality of targets. In some embodiments, behavioral modulation may be measured with a visual discrimination task. Briefly, the subject 120 fixates on a central target. After a random delay, targets appear in a right / left visual hemifield, separated by a random delay between -90 and 90 milliseconds (ms) in which negative delays mean a right target appeared first while positive delays mean a left target appeared first. In some embodiments, the subject 120 is rewarded if they look at the target that appeared first within a 1.5 second period.

[0056] In some embodiments, one sonication is delivered in each session. The sonication follows a baseline period of 375 trials. A task continues without interruption during and after the sonication. Behavior of the subject 120 may be quantified by fitting a sigmoid to a choice behavior of the subject 120 and identifying a delay at which the subject 120 has equal preference for the left / right target. Changes in behavior are quantified by the preference of the subject 120 for the left target at the baseline delay. In some embodiments, behavioral trials are performed after measurement of EEG response potentials. Location and intensity of the sonication is guided by the result of the EEG response potentials.

[0057] In some embodiments, ultrasound parameters for ultrasound neuromodulation and measuring EEG response potentials are shown below in Table 1. For example, the ultrasound parameters are within a range of values that do not cause histological tissue damage. The ultrasound parameters of Table 1 (and the ultrasound parameters used by the ultrasound system 100) are within a range of values that do not cause histological tissue damage. In some embodiments, the ultrasound parameters include an ultrasound intensity and an ultrasound pressure. The ultrasound parameters are also referred to herein as ultrasound evoked potential (UEP) parameters. Note that, while spatial peak temporal average intensity (ISPTA) is high for an individual pulse (15 watts per square centimeter [W / cm2]), the ISPTA across the session was quite low (90 mW7cm2). In some embodiments, in-situ pressure is estimated by derating free field intensity by a factor of 21%. In some embodiments, an average derating factor across the two subjects is 21%. In some embodiments, a half power beamwidth (HPBW) of the ultrasound transducer 110 when steered to an approximate location of the LGN (e.g., 11, 3, and 15 mm from a natural focus in the left / right, anterior / posterior, and superior / inferior dimensions, respectively) is measured in water using a hydrophone.Table 1 shows sonication parameters for ultrasound neuromodulation and measuring EEG response potentials. Left to right columns: Spatial peak temporal average intensity (ISPTA;W / cm2), spatial peak pulse average intensity (ISPPA; W / cm2), duty cycle (DC; percent [%]), pressure (P; megapascals [MPa]), pulse repetition frequency (PRF; Hz), pulse repetition interval (PRI; ms), pulse duration (PD; ms), center frequency (F; megahertz [MHz]), mechanical index (MI), sonication duration (SD; ms).

[0058] In some embodiments, the ultrasound system 100 applies brief pulses of transcranial focused ultrasound to deep brain targets to elicit target-specific evoked EEG potentials.Targeting is achieved electronically via the components of the ultrasound system 100. The ultrasound transducer 110 is fixed to the head of the subject 120 in the same location. FIG. 3 shows EEG response potentials for each of the 24 targets of the plurality of target grids 205 shown in FIG. 2. As described below, each axis shows average response to 60 stimuli after removing trials in which the voltage of the EEG response potential exceeds 500 pV. The resulting number of averaged trials is shown in a bottom left of each plot. In both subjects B and H, ultrasound elicits the strongest responses at a target location of the plurality of target locations of 4 mm medial and 4 mm posterior to an assumed location of the LGN (e.g., the location 210 and the location 215 of FIG. 2). The spatially confined response is consistent across subjects, in spite of differences in placement of the ultrasonic transducer 110 as shown by the image 200. Ultrasound waves can perturb neural activity in deep brain targets. In some instances, the target location that evoked the strongest EEG response potential leads to strongest effects on visual choice behavior. In other words, the EEG response potentials may be used to guide targeting to achieve behavioral effects. As described below, FIG. 4 shows that evoked-potential-optimized targets lead to notable and significant (e.g., time window of 17 to 22 minutes following sonication, two-tailed t-test, p < 0.05) effects on visual choice behavior, as shown in a graph 405 of FIG. 4. No significant effect is observed for control targets, as shown in a graph 410 of FIG. 4. In some embodiments, the HPBW of the ultrasound transducer 110 in free field is 1.5, 5, and 5 mm in the left / right, anterior / posterior, and superior / inferior dimensions, respectively.

[0059] FIG. 3 illustrates graphs showing ultrasound evoked potentials, according to some embodiments. FIG. 3 illustrates the EEG response potentials (e.g., mean ± s.e.m) as a function of time at the 24 target locations of the plurality of target grids 205, as shown in FIG. 2. Rectangles on the graphs show 100 ms sonications. Each plot is referenced to a stimulus onset. A graph 300 illustrates results for Subject B as shown on top and a graph 305 illustrates resultsfor Subject H as shown on bottom. Numbers in the bottom left of each axis give a number of averages used to create each plot (e.g., after removing traces in which the EEG response potentials exceed 500 pV). Time points at which a two tailed T-test shows a significant deviation from a baseline measurement (e.g., average value between -500 and 0 ms) are marked with a black line at a top (e.g., p < 0.05) and a bottom (e.g., p < 0.001) of each plot. In some embodiments, the strongest ultrasound evoked potentials are at the same anatomical locations in both subjects.

[0060] FIG. 4 illustrates graphs 400 showing that ultrasound-induced changes in behavior correlate with maximum ultrasound evoked potential response and minimum ultrasound evoked potential response, according to some embodiments. As noted, the graph 405 shows evoked- potential-optimized targets with significant effects on visual choice behavior over time. The graph 410 shows no significant effects for control targets over time. FIG. 4 illustrates a choice preference (e.g., mean ± s.e.m.) in subject B as a function of time, aligned to stimulus onset, in response to stimulation of the plurality of target locations that result in maximum EEG response potentials and minimum EEG response potentials. For example, the graph 405 shows a maximum response location 415 of the location 210 and a maximum response location 420 of the location 215. The graph 410 shows a minimum response location 425 of the location 210 and a minimum response location of the location 215. In some embodiments, the graph 405 and the graph 410 include n = 8 sessions. In other words, the graphs 400 indicate awake behavior measured while a subject is completing a task. The graph 405 shows a change when a targeted location is one that produces the maximum EEG response potential. The graph 410 shows a change in behavior when a targeted location is one that produces the minimum EEG response potential.

[0061] In some embodiments, the systems and methods described herein show a measurable and transient physiological response to ultrasound stimulus of deep brain anatomy. The physiological response is specific to targeted anatomy and is engaged independently of the location of the ultrasound transducer 110. In some instances, behavioral data shows that the strength of the physiological response correlates with modulation of awake behavior. Stimulation of target locations with maximum EEG response shows substantial effects on visual choice behavior. Stimulation of locations without a physiological response does not affectchoice behavior. In some instances, treatment guidance algorithms may be used for physiological feedback to provide robust, repeatable ultrasound therapies.

[0062] Studies in rodents, which have small cranium, show that ultrasound can engage auditory or vestibular pathways. In some embodiments, by working with non-human primates, in which the ultrasound focus is confined with respect to brain dimensions, and by evaluating responses to multiple deep brain targets in each session. Energy delivered to both the target locations and the control targets are the same, yet there is a target dependence for both neural and behavioral effects. The effects cannot be explained by generic potential artifacts.

[0063] The systems and methods described herein show that ultrasound modulation of deep brain targets can elicit robust evoked potentials. Ultrasound based modulation of behavior correlates with magnitude of the evoked potential. A robust EEG response potential to ultrasound may provide a physiological marker to validate target engagement during neuromodulation procedures. Such validation may enhance the efficacy of neuromodulation protocols that are plagued by uncertainty in the acoustic intensity delivered to targeted tissue. The systems and methods described herein adjust ultrasound parameters (e.g., ultrasound intensity, ultrasound pressure, and the like) to deliver ultrasound neuromodulation sufficient to elicit an evoked EEG response potential. Measurement of the evoked EEG response potential indicates engagement of the targeted tissue. In other words, the measured EEG response potential indicates that the target tissues are being engaged by transmitted ultrasound waves during ultrasound neuromodulation.

[0064] FIG. 5 is a flowchart of a method 500 of conducting EEG guided ultrasound neuromodulation, according to some embodiments. For example, the method 500 is implemented to control ultrasound neuromodulation delivered from the ultrasound transducer 110 to the subject 120. It should be understood that the order of the steps disclosed in method 500 could vary. Although some steps are illustrated as occurring in serial order, in other embodiments, the steps disclosed may be performed in parallel order. Furthermore, additional steps may be added to the process and not all of the steps may be required.

[0065] In one embodiment, the method 500 is performed by the electronic controller 125. However, in other embodiments, the method 500 may be performed via other components withinthe ultrasound system 100, such as a combination of the electronic controller 125, the ultrasound transducer 110, and the plurality of EEG electrodes 1 15.

[0066] The method 500 begins at step 505 when the ultrasound transducer 110 delivers ultrasound neuromodulation at a plurality of locations of a region of a brain of the subject 120 at a set of ultrasound parameters. For example, the electronic controller 125 transmits a control signal to the signal generator 140 to generate a signal for ultrasound neuromodulation. The signal generator 140 transmits the signal (in some examples, a plurality of signals) as an electrical current to the ultrasound transducer 110. The ultrasound transducer 110 converts the electrical current into ultrasound waves and the ultrasound transducer 110 transmits the ultrasound waves to the region at the plurality of locations to perform ultrasound neuromodulation. In some embodiments, the set of ultrasound parameters includes an ultrasound intensity and an ultrasound pressure. The method 500 then proceeds to step 510.

[0067] At step 510, the electronic controller 125 measures, using the plurality of EEG electrodes 115, a plurality of EEG response potentials at the plurality of locations. For example, the plurality of EEG electrodes 115 sense the plurality of EEG response potentials in response to the ultrasound neuromodulation. The plurality of EEG electrodes 115 transmit signals indicative of the plurality of EEG response potentials to the electronic controller 125. The electronic controller 125 measures the plurality of EEG response potentials based on the received signals indicative of the plurality of EEG response potentials. The method 500 then proceeds to step 515.

[0068] At step 515, the electronic controller 125 adjusts the set of ultrasound parameters to a set of desired ultrasound parameters based on the plurality of EEG response potentials until an intensity is sufficient to elicit an EEG response. In some embodiments, the set of desired ultrasound parameters includes an ultrasound intensity and an ultrasound pressure. The electronic controller 125 adjusts the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound intensity based on the plurality of EEG response potentials. The electronic controller 125 adjusts the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound pressure based on the plurality of EEG response potentials. The electronic controller 125 adjusts the set of ultrasound parametersto the set of desired ultrasound parameters such that the intensity of the desired ultrasound parameters is sufficient to elicit the EEG response (e.g., an EEG response potential) that is measurable by the plurality of EEG electrodes 115. The measurement of the EEG response potential indicates that the ultrasound neuromodulation at the set of desired ultrasound parameters is sufficient to engage target tissue and elicit the EEG response potential. The method 500 then returns to step 505.

[0069] In some embodiments, the electronic controller 125 identifies a target location of the plurality of locations for the plurality of target grids 205 for delivery of ultrasound neuromodulation based on the plurality of EEG response potentials. For example, the electronic controller 125 identifies the target location as a location of the plurality of locations for the plurality of target grids 205 that produces a sufficient EEG response potential.

[0070] It should be understood that the method 500 may be performed multiple times to control ultrasound neuromodulation based on consecutively measured EEG response potentials.

[0071] In some embodiments, the electronic controller 125 is configured to transmit the plurality of EEG response potentials at the plurality of locations to the output device 145. The output device 145 displays the plurality of EEG response potentials at the plurality of locations. In some embodiments, the electronic controller 125 is configured to transmit the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters to the output device 145. The output device 145 displays the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters.

[0072] In some embodiments, the plurality of locations includes a maximum response location having the greatest EEG response potential of the plurality of EEG response potentials and a minimum response location having the least EEG response potential of the plurality of EEG response potentials. The electronic controller 125 is configured to identify the target location based on EEG response potentials at the maximum response location and the minimum response location. In some embodiments, the target location is the maximum response location. In other embodiments, the target location is the minimum response location.

[0073] Various features and aspects of the present disclosure are set forth in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A system for conducting electroencephalogram (EEG) guided ultrasound neuromodulation, comprising: a device including an ultrasound transducer disposed on a head of a subject, the ultrasound transducer configured to transmit ultrasound waves; a plurality of EEG electrodes coupled to the device and attached to the head of the subject, the plurality of EEG electrodes configured to measure EEG response potentials; and an electronic controller connected to the device and in communication with the plurality of EEG electrodes, the electronic controller configured to: deliver, using the ultrasound transducer, ultrasound neuromodulation at a plurality of locations of a region of a brain of the subject at a set of ultrasound parameters; measure, using the plurality of EEG electrodes, a plurality of EEG response potentials at the plurality of locations; and adjust the set of ultrasound parameters to a set of desired ultrasound parameters based on the plurality of EEG response potentials until an intensity is sufficient to elicit an EEG response.

2. The system of claim 1, wherein the region of the brain is at least one selected from the group consisting of a left hemisphere of the brain and a right hemisphere of the brain.

3. The system of claim 2, wherein the region of the brain is a lateral geniculate nucleus (LGN) of the at least one selected from the group consisting of the left hemisphere of the brain and the right hemisphere of the brain.

4. The system of claim 1, wherein the set of ultrasound parameters includes at least one selected from the group consisting of an ultrasound intensity and an ultrasound pressure.

5. The system of claim 1, wherein the set of desired ultrasound parameters includes at least one selected from the group consisting of an ultrasound intensity and an ultrasound pressure.

6. The system of claim 5, wherein the electronic controller is configured to: adjust the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound intensity based on the plurality of EEG response potentials; and adjust the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound pressure based on the plurality of EEG response potentials.

7. The system of claim 1, wherein the electronic controller is configured to: transmit the plurality of EEG response potentials at the plurality of locations to an output device; display, using the output device, the plurality of EEG response potentials at the plurality of locations; transmit the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters to the output device; and display, using the output device, the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters.

8. The system of claim 1, wherein the electronic controller is configured to identify a target location of the plurality of locations for delivering ultrasound neuromodulation based on the plurality of EEG response potentials, wherein the plurality of locations includes a maximum response location having the greatest EEG response potential of the plurality of EEG response potentials and a minimum response location having the least EEG response potential of the plurality of EEG response potentials.

9. The system of claim 8, wherein the electronic controller is configured to identify the target location based on EEG response potentials at the maximum response location and the minimum response location.

10. The system of claim 9, wherein the target location is at least one selected from the group consisting of the maximum response location and the minimum response location.

11. A method of conducting electroencephalogram (EEG) guided ultrasound neuromodulation, comprising: delivering, using an ultrasound transducer, ultrasound neuromodulation at a plurality of locations of a region of a brain of a subject at a set of ultrasound parameters; measuring, using a plurality of EEG electrodes, a plurality of EEG response potentials at the plurality of locations; and adjusting, via an electronic controller, the set of ultrasound parameters to a set of desired ultrasound parameters based on the plurality of EEG response potentials until an intensity is sufficient to elicit an EEG response.

12. The method of claim 11, wherein the region of the brain is at least one selected from the group consisting of a left hemisphere of the brain and a right hemisphere of the brain.

13. The method of claim 12, wherein the region of the brain is a lateral geniculate nucleus (LGN) of at least one selected from the group consisting of the left hemisphere of the brain and the right hemisphere of the brain.

14. The method of claim 11, wherein the set of ultrasound parameters includes at least one selected from the group consisting of an ultrasound intensity and an ultrasound pressure.

15. The method of claim 11, wherein the set of desired ultrasound parameters includes at least one selected from the group consisting of an ultrasound intensity and an ultrasound pressure.

16. The method of claim 15, further comprising: adjusting, via the electronic controller, the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound intensity based on the plurality of EEG response potentials; andadjusting, via the electronic controller, the set of ultrasound parameters to the set of desired ultrasound parameters including a desired ultrasound pressure based on the plurality of EEG response potentials.

17. The method of claim 11, further comprising: transmitting, via the electronic controller, the plurality of EEG response potentials at the plurality of locations to an output device; displaying, via the output device, the plurality of EEG response potentials at the plurality of locations; transmitting, via the electronic controller, the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters to the output device; and displaying, via the output device, the plurality of EEG response potentials at the plurality of locations based on the set of desired ultrasound parameters.

18. The method of claim 11, further comprising: identifying, via the electronic controller, a target location of the plurality of locations for delivering ultrasound neuromodulation based on the plurality of EEG response potentials, wherein the plurality of locations includes a maximum response location having the greatest EEG response potential of the plurality of EEG response potentials and a minimum response location having the least EEG response potential of the plurality of EEG response potentials.

19. The method of claim 18, further comprising: identifying, via the electronic controller, the target location based on EEG response potentials at the maximum response location and the minimum response location.

20. The method of claim 19, wherein the target location is at least one selected from the group consisting of the maximum response location and the minimum response location.

Images